FROM THE AMERICAN ACADEMY OF PEDIATRICS

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

Marylou Behnke, MD, Vincent C. Smith, MD, COMMITTEE ON SUBSTANCE ABUSE, and COMMITTEE ON FETUS AND abstract NEWBORN Prenatal substance abuse continues to be a significant problem in this KEY WORDS country and poses important health risks for the developing fetus. The prenatal drug exposure, alcohol, nicotine, marijuana, cocaine, ’ methamphetamine, growth and development primary care pediatricians role in addressing prenatal substance fi ABBREVIATIONS exposure includes prevention, identi cation of exposure, recognition AAP—American Academy of Pediatrics of medical issues for the exposed newborn infant, protection of the THC—tetrahydrocannabinol infant, and follow-up of the exposed infant. This report will provide This document is copyrighted and is property of the American information for the most common drugs involved in prenatal expo- Academy of Pediatrics and its Board of Directors. All authors sure: nicotine, alcohol, marijuana, opiates, cocaine, and methamphet- fi fl have led con ict of interest statements with the American – Academy of Pediatrics. Any conflicts have been resolved through amine. Pediatrics 2013;131:e1009 e1024 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. Substance abuse has been a worldwide problem at all levels of society The guidance in this report does not indicate an exclusive since ancient times. Attention has been directed toward the use of legal course of treatment or serve as a standard of medical care. and illegal substances by pregnant women over the past several Variations, taking into account individual circumstances, may be decades. Almost all drugs are known to cross the placenta and have appropriate. some effect on the fetus. The effects on the human fetus of prenatal All technical reports from the American Academy of Pediatrics cigarette use have been identified and studied since the 1960s,1 the automatically expire 5 years after publication unless reaffirmed, 2–4 revised, or retired at or before that time. effects of alcohol and opiate use have been studied since the 1970s, 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 www.pediatrics.org/cgi/doi/10.1542/peds.2012-3931 Prevalence estimates for prenatal substance use vary widely and have doi:10.1542/peds.2012-3931 been difficult to establish. Differences are likely attributable to such PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). things as the use of different sampling methods and drug-detection Copyright © 2013 by the American Academy of Pediatrics 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

PEDIATRICS Volume 131, Number 3, March 2013 e1009 that the use of specific drugs waxes and cigarette use by pregnant and used for identification, methods of and wanes over time nationwide as nonpregnant women. An additional adulteration of the sample, and ana- the popularity of certain substances important finding from this survey lytical techniques, thus altering the changes. was that the rate of cigarette smoking sensitivity and specificity for each drug Although a variety of prevalence for those 15 to 17 years of age actually of interest. The most common analyt- studies have been conducted over was higher for pregnant women than ical method used for screening bi- the past 2 decades, there is 1 national for nonpregnant women (22.7% vs ological specimens is an immunoassay survey that regularly provides in- 13.4%, respectively). This report details designed to screen out drug-free formation on trends in substance many sociodemographic variables re- samples. Threshold values generally abuse among pregnant women. The lated to drug use in the American are set high to minimize false-positive National Survey on Drug Use and population, and the reader is referred test results but may be too high to Health (formerly called the National to the Substance Abuse and Mental detect low-dose or remote exposure. Household Survey on Drug Abuse), Health Services Administration Web Because immunoassay is a relatively sponsored by the Substance Abuse site for the full report (http://www.oas. nonspecific test, positive results re- and Mental Health Services Adminis- samhsa.gov/nhsda.htm). quire confirmation by using gas tration (http://www.oas.samhsa.gov/ chromatography/mass spectrometry. nhsda.htm), is an annual survey pro- IDENTIFICATION OF PRENATAL In addition, confirmation of the presence viding national and state level in- EXPOSURE of a drug is not always associated with formation on the use of alcohol, Two basic methods are used to identify drug abuse. Alternative explanations in- tobacco, and illicit drugs in a sample drug users: self-report or biological clude passive exposure to the drug, in- of more than 67 000 noninstitu- specimens. Although no single ap- gestion of other products contaminated tionalized people older than 12 years. proach can accurately determine the withthedrug,oruseofprescription Data are combined into 2-year epochs presence or amount of drug used medications that either contain the drug and include reported drug use for during pregnancy, it is more likely that or are metabolized to the drug.14 Thus, pregnant women between the ages of fetal exposure will be identified if careful patient histories remain essen- 15 and 44 years. Current illegal drug a biological specimen is collected tial to the process of identification. use among pregnant women re- along with a structured interview.8 The 3 most commonly used specimens mained relatively stable from 2007– Self-reported history is an inexpensive to establish drug exposure during the 2008 (5.1%) to 2009–2010 (4.4%). and practical method for identifying prenatal and perinatal period are These average prevalence rates are prenatal drug exposure and is the only urine, meconium, and hair; however, significantly lower than reported method available in which information none is accepted as a “gold standard.” current illicit drug use rates for non- can be obtained regarding the timing Urine has been the most frequently pregnant women (10.9%). Importantly, of the drug use during pregnancy and tested biological specimen because of the rate of current drug use among the amount used. Unfortunately, self- its ease of collection. Urine testing the youngest and possibly the most report suffers from problems with identifies only recent drug use, be- vulnerable pregnant women was the veracity of the informant and recall cause threshold levels of drug highest (16.2% for 15- to 17-year-olds, accuracy.9,10 Histories obtained by metabolites generally can be detected compared with 7.4% among 18- to 25- trusted, nonjudgmental individuals or in urine only for several days. A no- year-olds and 1.9% among 26- to 44- via computerized survey forms; ques- table exception to this is marijuana, year-olds). Table 1 summarizes these tions referring back to the previous the metabolites of which can be ex- data along with information regarding trimester or prepregnancy usage, not creted for as long as 10 days in the current alcohol use, binge drinking, current use; and pregnancy calendars urine of regular users15 or up to 30 TABLE 1 Comparison of Drug Use Among used to assist recollection each im- days in chronic, heavy users. Urine is Women 15 to 44 Years of Age by prove the accuracy of the information a good medium as well for the de- Pregnancy Status: 2009–2010 obtained.11–13 tection of nicotine, opiate, cocaine, Pregnant Nonpregnant Several biological specimens can be and amphetamine exposure.16,17 Women, % Women, % used to screen for drug exposure. Each Meconium is also easy to collect Illicit drug use 4.4 10.9 Alcohol use 10.8 54.7 specimen has its own individual var- noninvasively. It is hypothesized that Binge drinking 3.7 24.6 iations with regard to the window of drugs accumulate in meconium through- Cigarette use 16.3 26.7 detection, the specific drug metabolites out pregnancy, and thus, meconium is

e1010 FROM THE AMERICAN ACADEMY OF PEDIATRICS FROM THE AMERICAN ACADEMY OF PEDIATRICS thought to reflect exposure during the laws required the reporting of women major structural development is second and third trimester of preg- who used drugs during pregnancy to complete, drugs have more subtle nancy when meconium forms. How- the legal system through states’ child effects, including abnormal growth ever, use of meconium to determine the abuse statutes. In 2003, the Keeping and/or maturation, alterations in timing or extent of exposure during Children and Families Safe Act (Public neurotransmitters and their recep- pregnancy is controversial18 because of Law 108-36) was passed by Congress, tors, and brain organization. These are alackofstudiesregardingtheeffects requiring physicians to notify their considered to be the direct effects of of the timing and quantity of the post- state child protective services agency drugs. However, drugs also can exert partum specimen collection as well of any infant identified as affected by a pharmacologic effect on the mother as the effects of urine or transitional illegal substances at birth or experi- and, thus, indirectly affect the fetus. stool contamination of the meconium encing drug withdrawal. Currently, For example, nicotine acts on nicotinic samples.19 Meconium has been used issues of whether to use biological cholinergic receptors within the mes- for the detection of nicotine, alcohol, specimens to screen for drug abuse; olimbic pathway, and neuropathways marijuana, opiate, cocaine, and am- whether to screen the mother, her activated by alcohol enhance inhibitory phetamine exposure.16,20 infant, or both; and which women and γ-aminobutyric acid (GABA) receptors Hair is easy to collect, although some infants to screen are issues compli- and reduce glutamate receptor activ- people decline this sampling method cated by legal, ethical, social, and ity. Drugs of abuse mimic naturally fi because of cosmetic concerns and scienti c concerns. Each of these occurring neurotransmitters, such societal taboos. Drugs become trapped concerns must be taken into account that marijuana acts as anandamides, within the hair and, thus, can reflect as obstetricians, neonatologists, and opiates act as endorphins, and co- drug use over a long period of time. pediatricians work to develop proto- caine and stimulants act within the Unfortunately, using hair to determine cols for identifying prenatal drug mesolimbic dopaminergic pathways timing and quantity of exposure also exposure. For example, there is no to increase dopamine and serotonin biological specimen that, when ob- is controversial. In addition, envi- within the synapses.32 Other indirect fi ronmental contamination, natural hair tained randomly, identi es prenatal effects of drugs of abuse on the fetus drug use with 100% accuracy; hence, colors and textures, cosmetic hair include altered delivery of substrate a negative drug screening result does processing, and volume of the to the fetus for nutritional purposes, not ensure that the pregnancy was hair sample available all affect the either because of placental insuf- drug free. Targeted screening of high- rational interpretation of the results.21–24 ficiency or altered maternal health risk women is problematic, because Hair is useful for the detection of nic- behaviors attributable to the mother’s it can be biased toward women of otine, opiate, cocaine, and amphetamine addiction. These altered behaviors, racial or ethnic minorities and those exposure.16,25 which include poor nutrition, decreased who are economically disadvantaged access/compliance with health care, Other biological specimens have been or socially disenfranchised. Universal increased exposure to violence, and studied for use in the detection of in screening of pregnant women is im- increased risk of mental illness and utero drug exposure but are not practical and not cost-effective.28–30 infection, may place the fetus at commonly used in the clinical setting. Finally, testing of biological specimens risk.33 These include such specimens as cord when the maternal history is positive fl blood, human milk, amniotic uid, and for drug use increases medical costs Nicotine concentrations are higher in umbilical cord tissue.8,19,26 In the case and does not necessarily provide in- the fetal compartment (placenta, am- of umbilical cord tissue, drug class- formation that guides the medical niotic fluid, fetal serum) compared with fi – speci c immunoassays for amphet- care of the infant.31 maternal serum concentrations.34 36 amines, opiates, cocaine, and canna- Nicotine is only 1 of more than 4000 binoids appear to be as reliable as compounds to which the fetus is ex- meconium testing, with the additional MECHANISMS OF ACTION OF posed through maternal smoking. Of benefit of availability of the tissue at DRUGS ON THE FETUS these, ∼30 compounds have been as- the time of birth.27 Drugs can affect the fetus in multi- sociated with adverse health out- Beginning in the early 1980s, states ple ways. Early in gestation, during comes. Although the exact mechanisms began to enact legislation in response the embryonic stage, drugs can have by which nicotine produces adverse to the increasingly popular use of significant teratogenic effects. How- fetal effects are unknown, it is likely “crack” cocaine in our society. Such ever, during the fetal period, after that hypoxia, undernourishment of

PEDIATRICS Volume 131, Number 3, March 2013 e1011 the fetus, and direct vasoconstrictor as brain biochemistry, resulting in result in permanent changes in brain effects on the placental and umbilical decreased protein, nucleic acid, and structure and function, which can vessels all play a role.37,38 Nicotine also lipid synthesis.74,76–79 Marijuana can produce altered responsiveness to has been shown to have significant remain in the body for up to 30 days, environmental or pharmacologic chal- deleterious effects on brain devel- thus prolonging fetal exposure. In lenges later in life.98 opment, including alterations in brain addition, smoking marijuana pro- Methamphetamine is a member of metabolism and neurotransmitter sys- duces as much as 5 times the amount a group of sympathomimetic drugs tems and abnormal brain devel- of carbon monoxide as does cigarette that stimulate the central nervous opment.39–43 Additional toxicity from smoking, perhaps altering fetal oxy- system. It readily passes through the compounds in smoke, such as cyanide genation.80 placenta and the blood-brain barrier and cadmium, contribute to toxicity.44–48 In humans, opiates rapidly cross the and can have significant effects on Ethanol easily crosses the placenta placenta, with drug equilibration be- the fetus.99–101 After a single dose of into the fetus, with a significant con- tween the mother and the fetus.81 methamphetamine to pregnant mice, centration of the drug identified in the Opiates have been shown to decrease levels of substance in the fetal brain amniotic fluid as well as in maternal brain growth and cell development in were found to be similar to those and fetal blood.49,50 A variety of animals, but studies of their effects found in human infants after pre- mechanisms explaining the effects of on neurotransmitter levels and opi- natal methamphetamine exposure, alcohol on the fetus have been hy- oid receptors have produced mixed with accumulation and distribution pothesized. These include direct tera- results.82–89 of the drug most likely dependent on the monoaminergic transport sys- togenic effects during the embryonic Pharmacologic studies of cocaine in tem. It is possible that the mecha- and fetal stage of development as well animal models using a variety of nism of action of methamphetamine as toxic effects of alcohol on the pla- species have demonstrated that co- is an interaction with and alteration centa, altered prostaglandin and pro- caine easily crosses both the placenta of these neurotransmitter systems tein synthesis, hormonal alterations, and the blood-brain barrier and can in the developing fetal brain100 nutritional effects, altered neuro- have significant teratogenic effects on as well as alterations in brain transmitter levels in the brain, altered the developing fetus, directly and in- morphogenesis.102 brain morphology and neuronal de- directly.90 Cocaine’s teratogenic effects velopment, and hypoxia (thought to be most likely result from interference attributable to decreased placental with the neurotrophic roles of mono- MEDICAL ISSUES IN THE NEWBORN blood flow and alterations in vascular aminergic transmitters during brain PERIOD – tone in the umbilical vessels).51 69 development,91–94 which can signifi- Fetal Growth Although the main chemical compound cantly affect cortical neuronal devel- Fetal tobacco exposure has been a in marijuana, δ-9-tetrahydrocannabinol opment and may lead to morphologic known risk factor for low birth weight (THC), crosses the placenta rapidly, its abnormalities in several brain struc- and intrauterine growth restriction major metabolite, 11-nor-9-carboxy- tures, including the frontal cingulate for more than 50 years,103 with de- THC, does not.70 Unlike other drugs, cortex.94 It also appears that the creasing birth weight shown to be the placenta appears to limit fetal ex- development of areas of the brain related to the number of cigarettes posure to marijuana, as fetal THC that regulate attention and executive smoked.104–107 Importantly, by 24 months concentrations have been docu- functioning are particularly vulnera- of age, most studies no longer dem- mented to be lower than maternal ble to cocaine. Thus, functions such as onstrate an effect of fetal tobacco ex- concentrations in studies of various arousal, attention, and memory may posure on somatic growth parameters animal species.15,70–72 The deleterious be adversely affected by prenatal co- of prenatally exposed infants.108-114 effects of marijuana on the fetus are caine exposure.89,91,95–97 Furthermore, Growth restriction is 1 of the hall- thought to be attributable to complex insults to the nervous system dur- marks of prenatal alcohol exposure pharmacologic actions on developing ing neurogenesis, before homeostatic and must be present to establish a di- biological systems, altered uterine regulatory mechanisms are fully agnosis of fetal alcohol syndrome.3,115 blood flow, and altered maternal developed, differ from those on ma- However, even moderate amounts of health behaviors.73–75 Similar to other ture systems. Thus, cocaine exposure alcohol use during pregnancy is asso- drugs, marijuana has been shown to occurring during development of the ciated with a decrease in size at alter brain neurotransmitters as well nervous system might be expected to birth.116–119 In general, marijuana has

e1012 FROM THE AMERICAN ACADEMY OF PEDIATRICS FROM THE AMERICAN ACADEMY OF PEDIATRICS

not been associated with fetal growth limited. However, Little et al131 reported neonates. A large multicenter trial restriction, particularly after control- no increase in the frequency of major evaluating buprenorphine’s effect on ling for other prenatal drug expo- anomalies in a small sample of exposed exposed infants documented de- sures.109,120-122 Fetal growth effects are infants when compared with non- creased morphine dose, hospital reported in studies of prenatal opiate exposed infants. length of stay, and length of treat- exposure; however, confounding vari- ment.150–152 There has been no sub- ables known to be associated with Withdrawal stantiation of early reports regarding poor growth, such as multiple drug No convincing studies are available cocaine withdrawal.153 Currently, no use and low socioeconomic status, that document a neonatal withdrawal prospective studies of withdrawal in were not well controlled in many of the syndrome for prenatal nicotine expo- methamphetamine-exposed infants studies.123 Using data from the Mater- sure. Although several authors de- are available. A retrospective study nal Lifestyle Study, Bada et al124 scribe abnormal newborn behavior of by Smith et al154 reported with- reported lower birth weight in opiate- exposed infants immediately after drawal symptoms in 49% of their exposed newborn infants born at ≥33 delivery, the findings are more con- sample of 294 methamphetamine- weeks’ gestation, independent of use sistent with drug toxicity, which exposed newborn infants. However, of other drugs, prenatal care, or steadily improves over time,144,145 as only 4% required pharmacologic in- other medical risk factors. An in- opposed to an abstinence syndrome, tervention. The AAP clinical report dependent effect of prenatal cocaine in which clinical signs would escalate on neonatal drug withdrawal contains exposure on intrauterine growth has over time as the drug is metabolized in-depth information on neonatal been the most consistent finding and eliminated from the body. There is drug withdrawal, including treatment across studies of prenatally exposed 1 report of withdrawal from prenatal options.155 infants.122,125-130 Early studies on pre- alcohol exposure in infants with fetal natal methamphetamine exposure131 as alcohol syndrome born to mothers Neurobehavior well as recent studies132 reveal in- who drank heavily during preg- Abnormalities of newborn neuro- dependent effects of the drug on fetal nancy,146 but withdrawal symptoms behavior, including impaired orienta- growth. However, the literature avail- have not been reported in longitudinal tion and autonomic regulation156 and able is limited at this time. Several studies available in the extant litera- abnormalities of muscle tone,144,147,157 reviews on the effects of prenatal drug ture. Neonatal abstinence symptoms have been identified in a number of exposure on growth contain additional have not been observed in marijuana- prenatal nicotine exposure studies. details.133–135 exposed infants, although abnormal Poor habituation and low levels of newborn behavior has been reported arousal along with motor abnormali- Congenital Anomalies with some similarities to that associ- ties have been identified in women Nicotine has been associated with oral ated with narcotic exposure.147 An who drank alcohol heavily during facial clefts in exposed newborn opiate withdrawal syndrome was first their pregnancy.80,158 Prenatal mari- infants,136–140 although the data are described by Finnegan et al148 in juana exposure is associated with in- relatively weak. There is a vast liter- 1975. Neonatal abstinence syndrome creased startles and tremors in the ature on the teratogenic effects of includes a combination of physiologic newborn.120 Abnormal neurobehavior prenatal alcohol exposure after the and neurobehavioral signs that in- in opiate-exposed newborn infants is first description of fetal alcohol syn- clude such things as sweating, irrita- related to neonatal abstinence (see drome in 1973.3 The American Acad- bility, increased muscle tone and earlier section on Withdrawal). Using emy of Pediatrics (AAP) policy activity, feeding problems, diarrhea, the Brazelton Newborn Behavioral As- statement “Fetal Alcohol Syndrome and seizures. Infants with neonatal sessment Scale,159 reported effects of and Alcohol-Related Neurodevelopmental abstinence syndrome often require prenatal cocaine exposure on infants Disorders” contains more informa- prolonged hospitalization and treat- have included irritability and lability tion.141 No clear teratogenic effect of ment with medication. Methadone ex- of state, decreased behavioral and au- marijuana or opiates is documented posure has been associated with tonomic regulation, and poor alertness in exposed newborn infants.142 Origi- more severe withdrawal than has ex- and orientation.160 Recent data from nal reports regarding cocaine terato- posure to heroin.149 Early reports re- the Infant Development, Environment, genicity have not been further garding buprenorphine, a more recent and Lifestyle multicenter study on documented.133,143 Studies of fetal meth- alternative to methadone, suggest min- the effects of prenatal methamphet- amphetamine exposure in humans are imal to mild withdrawal in exposed amine exposure documented abnormal

PEDIATRICS Volume 131, Number 3, March 2013 e1013 neurobehavioral patterns in exposed supply and neurobehavioral effects on syndrome, it is the least sensitive newborn infants consisting of poor the infant.172–174 However, for nicotine of the diagnostic criteria.185 No in- movement quality, decreased arousal, and alcohol, the benefits of breast- dependent effect of prenatal mari- and increased stress.161 feeding in the face of limited use of juana exposure on growth has been these drugs outweigh the potential documented throughout early child- risks. Marijuana has an affinity for hood and adolescence.109,182,184 Long- Breastfeeding lipids and accumulates in human term effects on growth have not Few sources are available document- milk,175 as can cocaine26 and amphet- been documented in the opiate- ing the prevalence of drug use during amines.101,165 Although the AAP consid- exposed child.186 The available litera- breastfeeding. Lacking recent data, ers the use of marijuana, opiates, ture on the effect of prenatal cocaine the 1988 National Maternal and In- cocaine, and methamphetamine to be exposure on growth throughout child- fant Health Survey (http://www.cdc.gov/ a contraindication to breastfeeding, hood is not conclusive. Although sev- nchs/about/major/nmihs/abnmihs.htm) supervised methadone use not only eral studies document the negative revealed that the prevalence of drug is considered to be compatible with effects of prenatal cocaine exposure use during pregnancy was compara- breastfeeding, with no effect on the on postnatal growth,187–189 others do ble to the prevalence of use among infant or on lactation, but also is not.126,190,191 No studies are available women who breastfed their infants. apotentialbenefitinreducingthe linking prenatal methamphetamine Women who used various amounts of symptoms associated with neonatal exposure to postnatal growth prob- alcohol or marijuana and moderate abstinence syndrome. Several available lems. However, 1 study of unspecified amounts of cocaine during their reviews provide more detailed in- amphetamine use suggests that in pregnancy were not deterred from formationwithregardtobreastfeeding utero exposure may be associated breastfeeding their infants. Thus, the and substance abuse.162,176 The reader with poor growth throughout early pediatrician is faced with weighing is also referred to the AAP policy childhood.192 the risks of exposing an infant to statement “Breastfeeding and the Use drugs during breastfeeding against of Human Milk.”177 Behavior the many known benefits of breast- After controlling for a variety of po- feeding.162 For women who are absti- LONG-TERM EFFECTS RELATED TO tentially confounding socioeconomic, nent at the time of delivery or who are PRENATAL DRUG EXPOSURE psychosocial, family, and health vari- participating in a supervised treat- ables, a number of studies have ment program and choose to breast- Growth identified independent effects of pre- feed, close postpartum follow-up of The effects of prenatal tobacco expo- natal tobacco exposure on long-term the mother and infant are essential. sure on long-term growth are not behavioral outcomes extending from For most street drugs, including mar- clear-cut. Reports in the literature of early childhood into adulthood. For ijuana, opiates, cocaine, and meth- effects on height and weight178–181 example, impulsivity and attention amphetamine, the risks to the infant of have not been substantiated by re- problems have been identified in ongoing, active use by the mother search teams able to control for other children prenatally exposed to nico- outweigh the benefits of breastfeeding, drug use in the sample.109,117,182,183 tine.193–195 In addition, prenatal to- because most street drugs have been Recent studies, some of which include bacco exposure has been associated shown to have some effect on the adolescents, have suggested that the with hyperactivity196 and negative197 breastfeeding infant.163–166 In addition, effect on growth might be attributable and externalizing behaviors in chil- the dose of drug being used and the to a disproportionate weight for dren,198–200 which appear to continue contaminants within the drug are un- height, such that prenatally exposed through adolescence and into adult- known for most street drugs. Nicotine children were more likely to be obese hood in the form of higher rates of is secreted into human milk167,168 and as evidenced by a higher BMI, in- delinquency, criminal behavior, and has been associated with decreased creased Ponderal index, and in- substance abuse.201–206 Prenatal alco- milk production, decreased weight gain creased skinfold thickness.113,183,184 A hol exposure is linked with significant of the infant, and exposure of the infant robust and extensive literature is attention problems in offspring207–210 to environmental tobacco smoke.169–171 available documenting the effects of as well as adaptive behavior problems Alcohol is concentrated in human milk. prenatal alcohol exposure on long- spanning early childhood to adult- Heavy alcohol use has been shown to term growth. Although poor growth hood.211 Problems identified included be associated with decreased milk is 1 of the hallmarks of fetal alcohol disrupted school experiences, delinquent

e1014 FROM THE AMERICAN ACADEMY OF PEDIATRICS FROM THE AMERICAN ACADEMY OF PEDIATRICS and criminal behavior, and substance behavioral problems. However, studies alcohol exposure has been shown to abuse. Kelly et al212 published an in- of both young and older children interfere with the development and use depth review of the effects of prenatal prenatally exposed to nicotine have of language,259 possibly leading to long- alcohol exposure on social behavior. revealed abnormalities in learning and term problems in social interaction.260 Inattention and impulsivity at 10 years memory227,228 and slightly lower IQ No effect of prenatal marijuana expo- of age have been associated with scores.201,229–231 Prenatal alcohol ex- sure on language development has prenatal marijuana exposure.213 Hy- posure frequently is cited as the most been identified in children through 12 peractivity and short attention span common, preventable cause of non- years of age.227,258 Subtle language have been noted in toddlers prenatally genetic intellectual disability. Although delays have been associated with pre- exposed to opiates,214 and older ex- IQ scores are lower in alcohol-exposed natal cocaine exposure.256,261,262 Cur- posed children have demonstrated offspring,207,232 they can be variable. rently, no data are available relating the memory and perceptual problems.215 Additionally, prenatal alcohol expo- prenatal use of opiates or metham- Caregiver reports of child behavior sure has been associated with poorer phetamine to language development in problems in preschool-aged216 and memory and executive functioning exposed offspring. elementary school-aged children217,218 skills.233 Marijuana has not been have not been related to cocaine ex- shown to affect general IQ, but it posure, except in combination with has been associated with deficits in Achievement other risk factors.219–221 However, in problem-solving skills that require The literature available evaluating ac- longitudinal modeling of caregiver sustained attention and visual memory, ademic achievement is limited. In reports at 3, 5, and 7 years of age, the analysis, and integration230,231,234–236 nicotine-exposed children, Batstra multisite Maternal Lifestyles Study and with subtle deficits in learning and et al200 identified poorer performance revealed that prenatal cocaine expo- memory.237 Longitudinal studies of on arithmetic and spelling tasks that sure had an independent negative ef- prenatal opiate exposure have not were part of standardized Dutch fect on trajectories of behavior produced consistent findings with achievement tests. Howell et al232 problems.222 There have been teacher regard to developmental sequelae. Al- reported poorer performance in reports of behavior problems in pre- though developmental scores tend to be mathematics on achievement tests in natally exposed children,223 although lower in exposed infants, these differ- adolescents who had been exposed again, findings have not been consis- ences no longer exist when appropriate prenatally to alcohol. Streissguth tent across studies,190 and some have medical and environmental controls are et al263 describe a variety of signifi- been moderated by other risks.224 included in the analyses.238–240 With little cant academic and school problems There also have been reports in this exception,241 prenatal cocaine exposure related to prenatal alcohol exposure, age group of deficits in attention pro- has not predicted overall development, primarily associated with deficits in cessing190 andanincreaseinsymp- IQ, or school readiness among toddlers, reading and math skills throughout toms of attention-deficit/hyperactivity elementary school-aged children, or the school years.263–266 Prenatal mar- disorder and oppositional defiant middle school-aged children.190,242–250 ijuana exposure has been associated disorder self-reported by the ex- However, several studies have revealed with academic underachievement, posed children.217,218 To date, no alterations in various aspects of ex- particularly in the areas of reading studies are available that link pre- ecutive functioning,221,241 including and spelling.267 School achievement is natal methamphetamine exposure visual-motor ability,244 attention,251–253 not an area that has been studied with long-term behavioral problems. and working memory.254 To date, lim- adequately with regard to prenatal However, 1 study of unspecified am- ited data are available revealing an opiate exposure. Reported effects of phetamine use during pregnancy association between prenatal meth- cocaine exposure on school achieve- suggests a possible association with amphetamine exposure and IQ.255 ment are variable. In the longitudinal externalizing behaviors and peer Maternal Lifestyle Study, 7-year-old problems.225,226 children with prenatal cocaine expo- Language sure had a 79% increased odds of Poor language development in early having an individualized educational Cognition/Executive Functioning childhood after prenatal nicotine ex- plan (adjusted for IQ),268 and Morrow The link between prenatal nicotine posure has been reported,227,256,257 et al249 found 2.8 times the risk of exposure and impaired cognition is as have poor language and reading learning disabilities among children not nearly as strong as the link with abilities in 9- to 12-year-olds.258 Prenatal with prenatal cocaine exposure

PEDIATRICS Volume 131, Number 3, March 2013 e1015 compared with their peers who were Mounting clinical data support an in- Alcohol remains the most widely not exposed to drugs prenatally. creased risk of ethanol abuse later in studied prenatal drug of abuse, and However, other studies do not support life after prenatal exposure.275,277 the evidence is strong for fetal growth significant cocaine effects on school Prenatal marijuana exposure has problems, congenital anomalies, and achievement.190,269 No data are available been associated with an increased abnormal infant neurobehavior. There for the effects of methamphetamine on risk for marijuana and cigarette use has been no convincing evidence of school achievement. Cernerud et al270 in exposed offspring.273 Insufficient a neonatal withdrawal syndrome. reported on 65 children prenatally ex- data are available to draw any con- Ongoing longitudinal studies con- posed to amphetamines. At 14 to 15 clusions relative to the affects of tinue to document long-term effects years of age, the children in their co- prenatal opiate, cocaine, or metham- on growth, behavior, cognition, lan- hort scored significantly lower on phetamine exposure on the risk for guage, and achievement, and alcohol mathematics tests than did their tobacco, problem alcohol, or illicit is the most common identifiable te- classmates who were not exposed to drug use later in life. ratogenassociatedwithintellectual amphetamines prenatally and had disability. a higher rate of grade retention than SUMMARY the Swedish norm. Although there have been studies re- Although methodologic differences vealing subtle abnormalities in infant Predisposed to Own Drug Use between studies and limited data in neurobehavior related to prenatal A limited number of studies are the extant literature make general- marijuana exposure, there have been available that have investigated the ization of the results for several of the no significant effects documented for fi association between prenatal sub- drugs dif cult, some summary state- fetal growth, congenital anomalies, or ments can be made by using the stance exposure and subsequent drug withdrawal. Long-term studies reveal current knowledge base (Table 2). abuse in exposed offspring. These effects of prenatal exposure on be- studies did not document cause and The negative effect of prenatal nicotine havior, cognition, and achievement but effect, and it remains to be determined exposure on fetal growth has been not on language or growth. how much of the association can be known for decades; however, longitu- fi linked to prenatal exposure versus dinal studies do not reveal a consistent The most signi cant effect of prenatal opiate exposure is neonatal absti- socioeconomic, environmental, and effect on long-term growth. Clinical genetic influences. Studies available studies have failed to reach a consen- nence syndrome. There have been for prenatal nicotine exposure suggest sus regarding congenital anomalies, documented effects on fetal growth an increased risk of early experi- and there is no evidence of a with- (but not on long-term growth) and mentation271 and abuse of nicotine drawal syndrome in the newborn infant neurobehavior as well as long- in exposed offspring.272,273 Brennan infant. Recent studies document term effects on behavior. There is et al274 reported an association of a negative effect of prenatal exposure not a consensus as to the effects of prenatal nicotine exposure with on infant neurobehavior as well as on prenatal opiate exposure on cognition, higher rates of hospitalization for long-term behavior, cognition, lan- and few data are available regarding substance abuse in adult offspring. guage, and achievement. language and achievement.

TABLE 2 Summary of Effects of Prenatal Drug Exposure Nicotine Alcohol Marijuana Opiates Cocaine Methamphetamine Short-term effects/birth outcome Fetal growth Effect Strong effect No effect Effect Effect Effect Anomalies No consensus on effect Strong effect No effect No effect No effect No effect Withdrawal No effect No effect No effect Strong effect No effect * Neurobehavior Effect Effect Effect Effect Effect Effect Long-term effects Growth No consensus on effect Strong effect No effect No effect No consensus on effect * Behavior Effect Strong effect Effect Effect Effect * Cognition Effect Strong effect Effect No consensus on effect Effect * Language Effect Effect No effect * Effect * Achievement Effect Strong effect Effect * No consensus on effect * * Limited or no data available.

e1016 FROM THE AMERICAN ACADEMY OF PEDIATRICS FROM THE AMERICAN ACADEMY OF PEDIATRICS

Prenatal cocaine exposure has a neg- LEAD AUTHORS COMMITTEE ON FETUS AND ative effect on fetal growth and subtle Marylou Behnke, MD NEWBORN, 2012–2013 effects on infant neurobehavior. How- Vincent C. Smith, MD Lu-Ann Papile, MD, Chairperson Jill E. Baley, MD ever, there is little evidence to support COMMITTEE ON SUBSTANCE ABUSE, William Benitz, MD an association with congenital anom- 2012–2013 Waldemar A. Carlo, MD James J. Cummings, MD alies or withdrawal. There is not Sharon Levy, MD, Chairperson Eric Eichenwald, MD a consensus regarding the effects of Seth D. Ammerman, MD Praveen Kumar, MD Pamela Kathern Gonzalez, MD prenatal cocaine exposure on either Richard A. Polin, MD Sheryl Ann Ryan, MD long-term growth or achievement; Rosemarie C. Tan, MD, PhD Lorena M. Siqueira, MD, MSPH Kasper S. Wang, MD however, there are documented long- Vincent C. Smith, MD term effects on behavior and subtle FORMER COMMITTEE MEMBER effects on language. Although there is PAST COMMITTEE MEMBERS Kristi L. Watterberg, MD little evidence to support an effect on Marylou Behnke, MD Patricia K. Kokotailo, MD, MPH overall cognition, a number of studies LIAISONS Janet F. Williams, MD, Immediate Past Chair- have documented effects on specific fi – person CAPT Wanda D. Bar eld, MD, MPH Centers for areas of executive function. Disease Control and Prevention – Studies on prenatal methamphet- Ann L. Jefferies, MD Canadian Pediatric Society LIAISON George A. Macones, MD – American College of amine exposure are still in their in- Vivian B. Faden, PhD – National Institute on Obstetricians and Gynecologists fancy. Early studies have documented Alcohol Abuse and Alcoholism Erin L. Keels APRN, MS, NNP-BC – National – an effect of prenatal exposure on fetal Deborah Simkin, MD American Academy of Association of Neonatal Nurses Child and Adolescent Psychiatry – growth and infant neurobehavior but Tonse N. K. Raju, MD, DCH National Institutes of Health no association with congenital anom- STAFF alies and no data regarding infant Renee Jarrett STAFF withdrawal or any long-term effects. James Baumberger Jim Couto, MA

REFERENCES

1. Becker RF, Little CR, King JE. Experi- 7. Fried PA. Postnatal consequences of ma- in relation to neurobehavioral outcome. mental studies on nicotine absorption in ternal marijuana use in humans. Ann N Y Pediatrics. 2002;109(5):815–825 rats during pregnancy. 3. Effect of sub- Acad Sci. 1989;562:123–132 14. Kwong TC, Shearer D. Detection of drug cutaneous injection of small chronic 8. Eyler FD, Behnke M, Wobie K, Garvan CW, use during pregnancy. Obstet Gynecol Clin doses upon mother, fetus, and neonate. Tebbett I. Relative ability of biologic North Am. 1998;25(1):43–64 Am J Obstet Gynecol. 1968;100(7):957– specimens and interviews to detect pre- 15. Lee MJ. Marihuana and tobacco use in 968 natal cocaine use. Neurotoxicol Teratol. pregnancy. Obstet Gynecol Clin North Am. 2. Jones KL, Smith DW. Recognition of the 2005;27(4):677–687 1998;25(1):65–83 fetal alcohol syndrome in early infancy. 9. Harrell AV. Validation of self-report: the 16. Lozano J, García-Algar O, Vall O, de la Lancet. 1973;302(7836):999–1001 research record. NIDA Res Monogr. 1985; Torre R, Scaravelli G, Pichini S. Biological 3. Jones KL, Smith DW, Ulleland CN, Streissguth 57:12–21 matrices for the evaluation of in utero P. Pattern of malformation in offspring of 10. Maisto SA, McKay JR, Connors GJ. Self- exposure to drugs of abuse. Ther Drug chronic alcoholic mothers. Lancet. 1973;1 report issues in substance abuse: state Monit. 2007;29(6):711–734 (7815):1267–1271 of the art and future directions. Behav 17. Chiu HT, Isaac Wu HD, Kuo HW. The re- 4. Finnegan LP. Pathophysiological and Assess. 1990;12(1):117–134 lationship between self-reported tobacco behavioural effects of the transplacental 11. Day NL, Wagener DK, Taylor PM. Mea- exposure and cotinines in urine and blood transfer of narcotic drugs to the foetuses surement of substance use during preg- for pregnant women. Sci Total Environ. and neonates of narcotic-dependent nancy: methodologic issues. NIDA Res 2008;406(1-2):331–336 mothers. Bull Narc. 1979;31(3-4):1–58 Monogr. 1985;59:36–47 18. Lester BM, ElSohly M, Wright LL, et al. The 5. Chasnoff IJ, Burns WJ, Schnoll SH, Burns 12. Magura S, Moses B. Assessing Risk and Maternal Lifestyle Study: drug use by KA. Cocaine use in pregnancy. N Engl J Measuring Change in Families: The Family meconium toxicology and maternal self- Med. 1985;313(11):666–669 Risk Scales. Washington, DC: Child Welfare report. Pediatrics. 2001;107(2):309–317 6. Oro AS, Dixon SD. Perinatal cocaine and League of America; 1987 19. Casanova OQ, Lombardero N, Behnke M, methamphetamine exposure: maternal 13. Jacobson SW, Chiodo LM, Sokol RJ, Eyler FD, Conlon M, Bertholf RL. Detection and neonatal correlates. J Pediatr. 1987; Jacobson JL. Validity of maternal report of cocaine exposure in the neonate. 111(4):571–578 of prenatal alcohol, cocaine, and smoking Analyses of urine, meconium, and

PEDIATRICS Volume 131, Number 3, March 2013 e1017 amniotic fluid from mothers and infants 33. Bauer CR, Shankaran S, Bada HS, et al. 47. Aaronson LS, Macnee CL. Tobacco, alcohol, exposed to cocaine. Arch Pathol Lab Med. The Maternal Lifestyle Study: drug expo- and caffeine use during pregnancy. 1994;118(10):988–993 sure during pregnancy and short-term J Obstet Gynecol Neonatal Nurs. 1989;18 20. Köhler E, Avenarius S, Rabsilber A, Gerloff maternal outcomes. Am J Obstet Gyne- (4):279–287 C, Jorch G. Assessment of prenatal to- col. 2002;186(3):487–495 48. Floyd RL, Zahniser SC, Gunter EP, Kendrick bacco smoke exposure by determining 34. Mosier HD, Jr, Jansons RA. Distribution JS. Smoking during pregnancy: preva- nicotine and its metabolites in meconium. and fate of nicotine in the rat fetus. Ter- lence, effects, and intervention strategies. Hum Exp Toxicol. 2007;26(6):535–544 atology. 1972;6(3):303–311 Birth. 1991;18(1):48–53 21. Bailey DN. Drug screening in an un- 35. Luck W, Nau H, Hansen R, Steldinger R. 49. Brien JF, Clarke DW, Smith GN, Richardson conventional matrix: hair analysis. [edi- Extent of nicotine and cotinine transfer to B, Patrick J. Disposition of acute, multiple- torial; comment] JAMA. 1989;262(23):3331 the human fetus, placenta and amniotic dose ethanol in the near-term pregnant 22. Joseph RE, Jr, Su TP, Cone EJ. In vitro fluid of smoking mothers. Dev Pharmacol ewe. Am J Obstet Gynecol. 1987;157(1): binding studies of drugs to hair: influence Ther. 1985;8(6):384–395 204–211 of melanin and lipids on cocaine binding 36. Koren G. Fetal toxicology of environmental 50. Szeto HH. Kinetics of drug transfer to the to Caucasoid and Africoid hair. J Anal tobacco smoke. Curr Opin Pediatr. 1995;7 fetus. Clin Obstet Gynecol. 1993;36(2):246– Toxicol. 1996;20(6):338–344 (2):128–131 254 23. Jurado C, Kintz P, Menéndez M, Repetto M. 37. Lehtovirta P, Forss M. The acute effect of 51. Sulik KK, Johnston MC, Webb MA. Fetal Influence of the cosmetic treatment of smoking on intervillous blood flow of the alcohol syndrome: embryogenesis in hair on drug testing. Int J Legal Med. placenta. Br J Obstet Gynaecol. 1978;85 a mouse model. Science. 1981;214(4523): 1997;110(3):159–163 (10):729–731 936–938 24. Henderson GL, Harkey MR, Zhou C, Jones 38. Ahlsten G, Ewald U, Tuvemo T. Maternal 52. West JR, Hodges CA, Black AC Jr. Prenatal RT, Jacob P III. Incorporation of iso- smoking reduces prostacyclin formation exposure to ethanol alters the organiza- topically labeled cocaine into human hair: in human umbilical arteries. A study on tion of hippocampal mossy fibers in rats. race as a factor. J Anal Toxicol. 1998;22(2): strictly selected pregnancies. Acta Obstet Science. 1981;211(4485):957–959 156–165 Gynecol Scand. 1986;65(6):645–649 53. Kennedy LA. The pathogenesis of brain 25. Jacqz-Aigrain E, Zhang D, Maillard G, Luton 39. Joschko MA, Dreosti IE, Tulsi RS. The ter- abnormalities in the fetal alcohol syndrome: D, André J, Oury JF. Maternal smoking atogenic effects of nicotine in vitro in rats: an integrating hypothesis. Teratology. 1984; during pregnancy and nicotine and coti- a light and electron microscope study. 29(3):363–368 nine concentrations in maternal and Neurotoxicol Teratol. 1991;13(3):307–316 54. Fisher SE. Selective fetal malnutrition: the neonatal hair. BJOG. 2002;109(8):909–911 40. Lichtensteiger W, Schlumpf M. Prenatal fetal alcohol syndrome. J Am Coll Nutr. 26. Winecker RE, Goldberger BA, Tebbett IR, nicotine exposure: biochemical and neu- 1988;7(2):101–106 et al. Detection of cocaine and its roendocrine bases of behavioral dys- 55. Hoff SF. Synaptogenesis in the hippocam- metabolites in breast milk. J Forensic Sci. function. Dev Brain Dysfunc. 1993;6(4–5): pal dentate gyrus: effects of in utero 2001;46(5):1221–1223 279–304 ethanol exposure. Brain Res Bull. 1988;21 27. Montgomery D, Plate C, Alder SC, Jones M, 41. Seidler FJ, Albright ES, Lappi SE, Slotkin (1):47–54 Jones J, Christensen RD. Testing for fetal TA. In search of a mechanism for 56. Clarren SK, Astley SJ, Bowden DM, et al. exposure to illicit drugs using umbilical receptor-mediated neurobehavioral tera- Neuroanatomic and neurochemical ab- cord tissue vs meconium. J Perinatol. togenesis by nicotine: catecholamine re- normalities in nonhuman primate infants 2006;26(1):11–14 lease by nicotine in immature rat brain exposed to weekly doses of ethanol dur- 28. Hansen RL, Evans AT, Gillogley KM, Hughes regions. Brain Res Dev Brain Res. 1994;82 ing gestation. Alcohol Clin Exp Res. 1990; CS, Krener PG. Perinatal toxicology (1-2):1–8 14(5):674–683 screening. J Perinatol. 1992;12(3):220–224 42. Slotkin TA. Fetal nicotine or cocaine ex- 57. Druse MJ, Tajuddin N, Kuo A, Connerty M. 29. Behnke M, Eyler FD, Conlon M, Woods NS, posure: which one is worse? J Pharmacol Effects of in utero ethanol exposure on Casanova OQ. Multiple risk factors do not Exp Ther. 1998;285(3):931–945 the developing dopaminergic system in identify cocaine use in rural obstetrical 43. Hellström-Lindahl E, Seiger A , Kjaeldgaard rats. J Neurosci Res. 1990;27(2):233–240 patients. Neurotoxicol Teratol. 1994;16(5): A, Nordberg A. Nicotine-induced alter- 58. Jollie WP. Effects of sustained dietary 479–484 ations in the expression of nicotinic ethanol on the ultrastructure of the visceral 30. Ellsworth MA, Stevens TP, D’Angio CT. In- receptors in primary cultures from hu- yolk-sac placenta of the rat. Teratology. fant race affects application of clinical man prenatal brain. Neuroscience. 2001; 1990;42(5):541–552 guidelines when screening for drugs of 105(3):527–534 59. Michaelis EK. Fetal alcohol exposure: cel- abuse in newborns. Pediatrics. 2010;125 44. Holsclaw DS, Jr, Topham AL. The effects of lular toxicity and molecular events in- (6). Available at: www.pediatrics.org/cgi/ smoking on fetal, neonatal, and childhood volved in toxicity. Alcohol Clin Exp Res. content/full/125/6/e1379 development. Pediatr Ann. 1978;7(3):201– 1990;14(6):819–826 31. Behnke M, Eyler FD, Conlon M, Casanova 222 60. Schenker S, Becker HC, Randall CL, Phillips OQ, Woods NS. How fetal cocaine exposure 45. Abel EL. Smoking and pregnancy. J Psy- DK, Baskin GS, Henderson GI. Fetal alcohol increases neonatal hospital costs. Pedi- choactive Drugs. 1984;16(4):327–338 syndrome: current status of pathogene- atrics. 1997;99(2):204–208 46. Hazelhoff Roelfzema W, Roelofsen AM, sis. Alcohol Clin Exp Res. 1990;14(5):635– 32. Stahl SM. Essential Psychopharmacology: Copius Peereboom-Stegeman JH. Light 647 Neuroscience Basis and Practical Appli- microscopic aspects of the rat placenta 61. West JR, Goodlett CR, Bonthius DJ, Hamre cation, 2nd ed. New York, NY: Cambridge after chronic cadmium administration. KM, Marcussen BL. Cell population de- Press; 2000 Sci Total Environ. 1985;42(1-2):181–184 pletion associated with fetal alcohol brain

e1018 FROM THE AMERICAN ACADEMY OF PEDIATRICS FROM THE AMERICAN ACADEMY OF PEDIATRICS

damage: mechanisms of BAC-dependent prenatal dosing in rats. Life Sci. 1989;44 in dissociated and organotypic cultures of cell loss. Alcohol Clin Exp Res. 1990;14 (11):697–701 mouse central nervous system: critical (6):813–818 73. Murthy NV, Melville GN, Wynter HH. Con- periods and target specificity. Brain Res 62. Wigal SB, Amsel A, Wilcox RE. Fetal ethanol tractile responses of uterine smooth mus- Dev Brain Res. 1991;62(2):245–255 exposure diminishes hippocampal beta- cle to acetylcholine and marihuana extract. 88. Zagon IS, McLaughlin PJ. The perinatal adrenergic receptor density while sparing Int J Gynaecol Obstet. 1983;21(3):223–226 opioid syndrome: laboratory findings and muscarinic receptors during development. 74. Dalterio SL. Cannabinoid exposure: effects clinical implications. In: Sonderegger TB, Brain Res Dev Brain Res. 1990;55(2):161– on development. Neurobehav Toxicol Teratol. ed. Perinatal Substance Abuse: Research 169 1986;8(4):345–352 Findings and Clinical Implications. Balti- 63. Brien JF, Smith GN. Effects of alcohol 75. Fisher SE, Atkinson M, Chang B. Effect of more, MD: Johns Hopkins University – (ethanol) on the fetus. J Dev Physiol. 1991; delta-9-tetrahydrocannabinol on the in Press; 1992:207 223 15(1):21–32 vitro uptake of alpha-amino isobutyric 89. Malanga CJ, III, Kosofsky BE. Mechanisms 64. Ledig M, Megias-Megias L, Tholey G. Ma- acid by term human placental slices. of action of drugs of abuse on the de- ternal alcohol exposure before and dur- Pediatr Res. 1987;21(1):104–107 veloping fetal brain. Clin Perinatol. 1999; 26(1):17–37, v–vi ing pregnancy: effect on development of 76. Walters DE, Carr LA. Changes in brain neurons and glial cells in culture. Alcohol catecholamine mechanisms following peri- 90. Mayes LC. Neurobiology of prenatal co- Alcohol. 1991;26(2):169–176 natal exposure to marihuana. Pharmacol caine exposure effect on developing 65. Miller MW, Nowakowski RS. Effect of pre- Biochem Behav. 1986;25(4):763–768 monoamine systems. Infant Ment Health J. 1994;15(2):121–133 natal exposure to ethanol on the cell 77. Morgan B, Brake SC, Hutchings DE, Miller N, cycle kinetics and growth fraction in the Gamagaris Z. Delta-9-tetrahydrocannabinol 91. Dow-Edwards DL. Developmental toxicity proliferative zones of fetal rat cerebral during pregnancy in the rat: effects on of cocaine: mechanisms of action. In: Lewis M, Bendersky M, eds. Mothers, cortex. Alcohol Clin Exp Res. 1991;15(2): developmentofRNA,DNA,andproteinin – Babies, and Cocaine: The Role of Toxins 229 232 offspring brain. Pharmacol Biochem Behav. in Development. Hillsdale, NJ: Lawrence 66. Smith GN, Patrick J, Sinervo KR, Brien JF. 1988;31(2):365–369 Erlbaum Associates Inc; 1995:5–17 Effects of ethanol exposure on the 78. Walters DE, Carr LA. Perinatal exposure to 92. Levitt P, Harvey JA, Friedman E, Simansky embryo-fetus: experimental considerations, cannabinoids alters neurochemical de- K, Murphy EH. New evidence for neuro- mechanisms, and the role of prostaglandins. velopment in rat brain. Pharmacol Bio- – transmitter influences on brain de- Can J Physiol Pharmacol. 1991;69(5):550 chem Behav. 1988;29(1):213–216 569 velopment. Trends Neurosci. 1997;20(6): 79. Rodríguez de Fonseca F, Cebeira M, Fernández- 269–274 67. Gressens P, Lammens M, Picard JJ, Evrard Ruiz JJ, Navarro M, Ramos JA. Effects of pre- 93. Whitaker-Azmitia PM. Role of the neuro- P. Ethanol-induced disturbances of glio- and perinatal exposure to hashish extracts trophic properties of serotonin in the genesis and neuronogenesis in the de- on the ontogeny of brain dopaminergic delay of brain maturation induced by co- veloping murine brain: an in vitro and neurons. Neuroscience. 1991;43(2-3):713– in vivo immunohistochemical and ultra- caine. Ann N Y Acad Sci. 1998;846:158–164 723 structural study. Alcohol Alcohol. 1992;27 94. Harvey JA. Cocaine effects on the de- 80. Chiriboga CA. Fetal alcohol and drug (3):219–226 veloping brain: current status. Neurosci effects. Neurologist. 2003;9(6):267–279 68. Kotch LE, Sulik KK. Experimental fetal al- Biobehav Rev. 2004;27(8):751–764 81. Gerdin E, Rane A, Lindberg B. Trans- cohol syndrome: proposed pathogenic 95. Lauder JM. Discussion: neuroteratology of placental transfer of morphine in man. J basis for a variety of associated facial and cocaine relationship to developing mono- Perinat Med. 1990;18(4):305–312 brain anomalies. Am J Med Genet. 1992;44 amine systems. NIDA Res Monogr. 1991; (2):168–176 82. Zagon IS, McLaughlin PJ, Weaver DJ, Zagon 114:233–247 E. Opiates, endorphins and the developing 69. Miller MW, Robertson S. Prenatal expo- 96. Woods JR Jr. Adverse consequences of organism: a comprehensive bibliography. sure to ethanol alters the postnatal de- prenatal illicit drug exposure. Curr Opin – velopment and transformation of radial Neurosci Biobehav Rev. 1982;6(4):439 479 Obstet Gynecol. 1996;8(6):403–411 glia to astrocytes in the cortex. J Comp 83. Lee CC, Chiang CN. Maternal-fetal transfer 97. Mayes LC. Developing brain and in utero Neurol. 1993;337(2):253–266 of abused substances: pharmacokinetic cocaine exposure: effects on neural on- 70. Bailey JR, Cunny HC, Paule MG, Slikker W and pharmacodynamic data. NIDA Res togeny. Dev Psychopathol. 1999;11(4):685– – Jr. Fetal disposition of delta 9-tetrahy- Monogr. 1985;60:110 147 714 drocannabinol (THC) during late preg- 84. Wang C, Pasulka P, Perry B, Pizzi WJ, 98. Stanwood GD, Levitt P. Drug exposure nancy in the rhesus monkey. Toxicol Appl Schnoll SH. Effect of perinatal exposure to early in life: functional repercussions of Pharmacol. 1987;90(2):315–321 methadone on brain opioid and alpha 2- changing neuropharmacology during 71.AbramsRM,CookCE,DavisKH,Niederreither adrenergic receptors. Neurobehav Toxicol sensitive periods of brain development. – K, Jaeger MJ, Szeto HH. Plasma delta-9- Teratol. 1986;8(4):399 402 Curr Opin Pharmacol. 2004;4(1):65–71 tetrahydrocannabinol in pregnant sheep 85. Hammer RP, Jr, Ricalde AA, Seatriz JV. 99. Burchfield DJ, Lucas VW, Abrams RM, and fetus after inhalation of smoke from Effects of opiates on brain development. Miller RL, DeVane CL. Disposition and a marijuana cigarette. Alcohol Drug Res. Neurotoxicology. 1989;10(3):475–483 pharmacodynamics of methamphetamine 1985-1986;6(5):361–369 86. Ricalde AA, Hammer RP Jr. Perinatal opiate in pregnant sheep. JAMA. 1991;265(15): 72. Hutchings DE, Martin BR, Gamagaris Z, treatment delays growth of cortical den- 1968–1973 Miller N, Fico T. Plasma concentrations drites. Neurosci Lett. 1990;115(2-3):137–143 100. Won L, Bubula N, McCoy H, Heller A. of delta-9-tetrahydrocannabinol in dams 87. Hauser KF, Stiene-Martin A. Characteriza- Methamphetamine concentrations in fetal and fetuses following acute or multiple tion of opioid-dependent glial development and maternal brain following prenatal

PEDIATRICS Volume 131, Number 3, March 2013 e1019 exposure. Neurotoxicol Teratol. 2001;23(4): 113. Fried PA, Watkinson B, Gray R. Growth 127. Zuckerman B, Frank DA, Hingson R, et al. 349–354 from birth to early adolescence in off- Effects of maternal marijuana and co- 101. Golub M, Costa L, Crofton K, et al. NTP-CERHR spring prenatally exposed to cigarettes caine use on fetal growth. N Engl J Med. Expert Panel Report on the reproductive and marijuana. Neurotoxicol Teratol. 1999; 1989;320(12):762–768 and developmental toxicity of amphetamine 21(5):513–525 128. Zuckerman B, Frank DA. Prenatal cocaine and methamphetamine. Birth Defects Res B 114. Fenercioglu AK, Tamer I, Karatekin G, exposure: nine years later. [editorial; Dev Reprod Toxicol. 2005;74(6):471–584 Nuhoglu A. Impaired postnatal growth of comment] J Pediatr. 1994;124(5 pt 1):731– 102. Cui C, Sakata-Haga H, Ohta K, et al. Histo- infants prenatally exposed to cigarette 733 logical brain alterations following pre- smoking. Tohoku J Exp Med. 2009;218(3): 129. Richardson GA. Prenatal cocaine expo- – natal methamphetamine exposure in rats. 221 228 sure. A longitudinal study of development. Congenit Anom (Kyoto). 2006;46(4):180– 115. Mills JL, Graubard BI, Harley EE, Rhoads Ann N Y Acad Sci. 1998;846:144–152 187 GG, Berendes HW. Maternal alcohol con- 130. Bauer CR, Langer JC, Shankaran S, et al. 103. Simpson WJ. A preliminary report on sumption and birth weight. How much Acute neonatal effects of cocaine expo- cigarette smoking and the incidence of drinking during pregnancy is safe? JAMA. sure during pregnancy. Arch Pediatr 1984;252(14):1875–1879 prematurity. Am J Obstet Gynecol. 1957;73 Adolesc Med. 2005;159(9):824–834 (4):807–815 116. Streissguth AP, Martin DC, Martin JC, Barr 131. Little BB, Snell LM, Gilstrap LC III. Meth- HM. The Seattle longitudinal prospective 104. Yerushalmy J. The relationship of amphetamine abuse during pregnancy: study on alcohol and pregnancy. Neuro- parents’ cigarette smoking to outcome of outcome and fetal effects. Obstet Gynecol. behav Toxicol Teratol. 1981;3(2):223–233 – pregnancy—implications as to the prob- 1988;72(4):541 544 ’ lem of inferring causation from observed 117. Fried PA, O Connell CM. A comparison of 132. Nguyen D, Smith LM, Lagasse LL, et al. associations. Am J Epidemiol.1971;93(6): the effects of prenatal exposure to to- Intrauterine growth of infants exposed to bacco, alcohol, cannabis and caffeine on 443–456 prenatal methamphetamine: results from birth size and subsequent growth. Neu- the infant development, environment, and 105. Persson PH, Grennert L, Gennser G, rotoxicol Teratol. 1987;9(2):79–85 lifestyle study. J Pediatr. 2010;157(2):337– Kullander S. A study of smoking and preg- 118. Greene T, Ernhart CB, Sokol RJ, et al. 339 nancy with special references to fetal Prenatal alcohol exposure and preschool growth. Acta Obstet Gynecol Scand Suppl. 133. Bauer CR. Perinatal effects of prenatal physical growth: a longitudinal analysis. 1978;78(S78):33–39 drug exposure. Neonatal aspects. Clin Alcohol Clin Exp Res. 1991;15(6):905–913 Perinatol. 1999;26(1):87–106 106. Olsen J. Cigarette smoking in pregnancy 119. Jacobson JL, Jacobson SW, Sokol RJ. and fetal growth. Does the type of tobacco 134. Cornelius MD, Day NL. The effects of to- Effects of prenatal exposure to alcohol, bacco use during and after pregnancy on play a role? Int J Epidemiol. 1992;21(2): smoking, and illicit drugs on postpartum exposed children. Alcohol Res Health. 279–284 somatic growth. Alcohol Clin Exp Res. 2000;24(4):242–249 107. Zarén B, Lindmark G, Gebre-Medhin M. – 1994;18(2):317 323 135. Nordstrom-Klee B, Delaney-Black V, Maternal smoking and body composition 120. Fried PA. Marijuana use during pregnancy: Covington C, Ager J, Sokol R. Growth from of the newborn. Acta Paediatr. 1996;85(2): consequences for the offspring. Semin birth onwards of children prenatally ex- 213–219 Perinatol. 1991;15(4):280–287 posed to drugs: a literature review. Neu- 108. Hoff C, Wertelecki W, Blackburn WR, 121. English DR, Hulse GK, Milne E, Holman CD, rotoxicol Teratol. 2002;24(4):481–488 Mendenhall H, Wiseman H, Stumpe A. Bower CI. Maternal cannabis use and 136. Wyszynski DF, Duffy DL, Beaty TH. Maternal Trend associations of smoking with ma- birth weight: a meta-analysis. Addiction. cigarette smoking and oral clefts: a meta- ternal, fetal, and neonatal morbidity. 1997;92(11):1553–1560 analysis. Cleft Palate Craniofac J. 1997;34 – Obstet Gynecol. 1986;68(3):317 321 122. Eyler FD, Behnke M, Conlon M, Woods NS, (3):206–210 109. Day N, Cornelius M, Goldschmidt L, Wobie K. Birth outcome from a pro- 137. Wyszynski DF, Wu T. Use of US birth cer- Richardson G, Robles N, Taylor P. The spective, matched study of prenatal tificate data to estimate the risk of ma- effects of prenatal tobacco and marijuana crack/cocaine use: I. Interactive and dose ternal cigarette smoking for oral clefting. use on offspring growth from birth effects on health and growth. Pediatrics. Cleft Palate Craniofac J. 2002;39(2):188– through 3 years of age. Neurotoxicol Ter- 1998;101(2):229–237 192 atol. 1992;14(6):407–414 123. Hulse GK, Milne E, English DR, Holman CD. 138. Lammer EJ, Shaw GM, Iovannisci DM, Van 110. Barnett E. Race differences in the pro- The relationship between maternal use of Waes J, Finnell RH. Maternal smoking and portion of low birth weight attributable to heroin and methadone and infant birth the risk of orofacial clefts: Susceptibility maternal cigarette smoking in a low- weight. Addiction. 1997;92(11):1571–1579 with NAT1 and NAT2 polymorphisms. Epi- income population. Am J Health Promot. 124. Bada HS, Das A, Bauer CR, et al. Gesta- demiology. 2004;15(2):150–156 – 1995;10(2):105 110 tional cocaine exposure and intrauterine 139. Little J, Cardy A, Arslan MT, Gilmour M, 111. Lightwood JM, Phibbs CS, Glantz SA. Short- growth: maternal lifestyle study. Obstet Mossey PA; United Kingdom-based case- term health and economic benefits of Gynecol. 2002;100(5 pt 1):916–924 control study. Smoking and orofacial smoking cessation: low birth weight. Pe- 125. Chouteau M, Namerow PB, Leppert P. The clefts: a United Kingdom-based case- diatrics. 1999;104(6):1312–1320 effect of cocaine abuse on birth weight control study. Cleft Palate Craniofac J. 112. DiFranza JR, Aligne CA, Weitzman M. Pre- and gestational age. Obstet Gynecol. 1988; 2004;41(4):381–386 natal and postnatal environmental to- 72(3 pt 1):351–354 140. Little J, Cardy A, Munger RG. Tobacco bacco smoke exposure and children’s 126. Amaro H, Zuckerman B, Cabral H. Drug smoking and oral clefts: a meta-analysis. health. Pediatrics. 2004;113(suppl 4): use among adolescent mothers: profile of Bull World Health Organ. 2004;82(3):213– 1007–1015 risk. Pediatrics. 1989;84(1):144–151 218

e1020 FROM THE AMERICAN ACADEMY OF PEDIATRICS FROM THE AMERICAN ACADEMY OF PEDIATRICS

141. American Academy of Pediatrics, Com- methamphetamine exposure on fetal infants exposed via passive smoking or mittee on Substance Abuse and Commit- growth and drug withdrawal symptoms in milk from smoking mothers. J Pediatr. tee on Children With Disabilities. Fetal infants born at term. J Dev Behav Pediatr. 1985;107(5):816–820 alcohol syndrome and alcohol-related 2003;24(1):17–23 170. Schwartz-Bickenbach D, Schulte-Hobein B, neurodevelopmental disorders. Pediat- 155. Hudak ML, Tan RC; American Academy of Abt S, Plum C, Nau H. Smoking and passive rics. 2000;106(2 pt 1):358–361 Pediatrics, Committee on Drugs, Commit- smoking during pregnancy and early in- 142. Astley SJ, Clarren SK, Little RE, Sampson tee on Fetus and Newborn. Clinical report: fancy: effects on birth weight, lactation PD, Daling JR. Analysis of facial shape in neonatal drug withdrawal. Pediatrics. period, and cotinine concentrations in children gestationally exposed to mari- 1998;101(6):1079–1088 mother’s milk and infant’s urine. Toxicol – juana, alcohol, and/or cocaine. Pediatrics. 156. Picone TA, Allen LH, Olsen PN, Ferris ME. Lett. 1987;35(1):73 81 1992;89(1):67–77 Pregnancy outcome in North American 171. Hopkinson JM, Schanler RJ, Fraley JK, 143. Behnke M, Eyler FD, Garvan CW, Wobie K. women. II. Effects of diet, cigarette smoking, Garza C. Milk production by mothers of The search for congenital malformations stress, and weight gain on placentas, and on premature infants: influence of cigarette in newborns with fetal cocaine exposure. neonatal physical and behavioral character- smoking. Pediatrics. 1992;90(6):934–938 Pediatrics. 2001;107(5). Available at: www. istics. Am J Clin Nutr. 1982;36(6):1214–1224 172. Cobo E. Effect of different doses of ethanol pediatrics.org/cgi/content/full/107/5/e74 157. Dempsey DA, Hajnal BL, Partridge JC, et al. on the milk-ejecting reflex in lactating 144. Law KL, Stroud LR, LaGasse LL, Niaura R, Tone abnormalities are associated with women. Am J Obstet Gynecol. 1973;115(6): Liu J, Lester BM. Smoking during preg- maternal cigarette smoking during preg- 817–821 nancy and newborn neurobehavior. Pedi- nancy in in utero cocaine-exposed infants. 173. Little RE, Anderson KW, Ervin CH, Worthington- atrics. 2003;111(6 pt 1):1318–1323 Pediatrics. 2000;106(1 pt 1):79–85 Roberts B, Clarren SK. Maternal alcohol 145. Godding V, Bonnier C, Fiasse L, et al. Does 158. Streissguth AP, Barr HM, Martin DC. Ma- use during breast-feeding and infant in utero exposure to heavy maternal ternal alcohol use and neonatal habitua- mental and motor development at one – smoking induce nicotine withdrawal tion assessed with the Brazelton scale. year. N Engl J Med. 1989;321(7):425 430 symptoms in neonates? Pediatr Res. 2004; Child Dev. 1983;54(5):1109–1118 174. Anderson PO. Alcohol and breastfeeding. J 55(4):645–651 – 159. Brazelton TB. Neonatal Behavioral As- Hum Lact. 1995;11(4):321 323 146. Pierog S, Chandavasu O, Wexler I. With- sessment Scale, 2nd ed. Philadelphia, PA: 175. Jakubovic A, Tait RM, McGeer PL. Excretion drawal symptoms in infants with the fetal JB Lippincott Co; 1984 of THC and its metabolites in ewes’ milk. alcohol syndrome. J Pediatr. 1977;90(4): Toxicol Appl Pharmacol. 1974;28(1):38–43 160. Eyler FD, Behnke M. Early development of 630–633 infants exposed to drugs prenatally. Clin 176. American Academy of Pediatrics Commit- 147. Fried PA, Makin JE. Neonatal behavioural Perinatol. 1999;26(1):107–150, vii tee on Drugs. Transfer of drugs and other correlates of prenatal exposure to mari- chemicals into human milk. Pediatrics. 161. Smith LM, Lagasse LL, Derauf C, et al. huana, cigarettes and alcohol in a low 2001;108(3):776–789 Prenatal methamphetamine use and neo- risk population. Neurotoxicol Teratol. natal neurobehavioral outcome. Neuro- 177. Gartner LM, Morton J, Lawrence RA, et al; 1987;9(1):1–7 toxicol Teratol. 2008;30(1):20–28 American Academy of Pediatrics Section 148. Finnegan LP, Connaughton JF, Jr, Kron RE, on Breastfeeding. Breastfeeding and the 162. Howard CR, Lawrence RA. Breast-feeding Emich JP. Neonatal abstinence syndrome: use of human milk. Pediatrics. 2005;115 and drug exposure. Obstet Gynecol Clin assessment and management. Addict Dis. (2):496–506 North Am. 1998;25(1):195–217 1975;2(1-2):141–158 178. Dunn HG, McBurney AK, Ingram S, Hunter 163. Cobrinik RW, Hood RT, Jr, Chusid E. The effect 149. Chasnoff IJ, Hatcher R, Burns WJ. Polydrug- CM. Maternal cigarette smoking during of maternal narcotic addiction on the new- and methadone-addicted newborns: a con- pregnancy and the child’s subsequent born infant; review of literature and report tinuum of impairment? Pediatrics. 1982;70(2): development: I. Physical growth to the age – 210–213 of 22 cases. Pediatrics. 1959;24(2):288 304 of 6 1/2 years. Can J Public Health. 1976; 150. Fischer G, Johnson RE, Eder H, et al. 164. Perez-Reyes M, Wall ME. Presence of 67(6):499–505 Treatment of opioid-dependent pregnant delta9-tetrahydrocannabinol in human 179. Naeye RL. Influence of maternal cigarette – women with buprenorphine. Addiction. milk. N Engl J Med. 1982;307(13):819 820 smoking during pregnancy on fetal and 2000;95(2):239–244 165. Steiner E, Villén T, Hallberg M, Rane A. childhood growth. Obstet Gynecol. 1981;57 151. Johnson RE, Jones HE, Fischer G. Use of Amphetamine secretion in breast milk. (1):18–21 – buprenorphine in pregnancy: patient man- Eur J Clin Pharmacol. 1984;27(1):123 124 180. Rantakallio P. A follow-up study up to the agement and effects on the neonate. Drug 166. Chasnoff IJ, Lewis DE, Squires L. Cocaine age of 14 of children whose mothers Alcohol Depend. 2003;70(suppl 2):S87–S101 intoxication in a breast-fed infant. Pediat- smoked during pregnancy. Acta Paediatr 152. Jones HE, Kaltenbach K, Heil SH, et al. rics. 1987;80(6):836–838 Scand. 1983;72(5):747–753 Neonatal abstinence syndrome after 167. Ferguson BB, Wilson DJ, Schaffner W. De- 181. Fogelman KR, Manor O. Smoking in preg- methadone or buprenorphine exposure. N termination of nicotine concentrations in nancy and development into early adult- Engl J Med. 2010;363(24):2320–2331 human milk. Am J Dis Child. 1976;130(8): hood. BMJ. 1988;297(6658):1233–1236 153. Eyler FD, Behnke M, Garvan CW, Woods NS, 837–839 182. Day NL, Richardson GA, Geva D, Robles N. Wobie K, Conlon M. Newborn evaluations 168. Steldinger R, Luck W, Nau H. Half lives of Alcohol, marijuana, and tobacco: effects of of toxicity and withdrawal related to pre- nicotine in milk of smoking mothers: prenatal exposure on offspring growth natal cocaine exposure. Neurotoxicol Ter- implications for nursing. J Perinat Med. and morphology at age six. Alcohol Clin atol. 2001;23(5):399–411 1988;16(3):261–262 Exp Res. 1994;18(4):786–794 154. Smith L, Yonekura ML, Wallace T, Berman 169. Luck W, Nau H. Nicotine and cotinine 183. Vik T, Jacobsen G, Vatten L, Bakketeig LS. N, Kuo J, Berkowitz C. Effects of prenatal concentrations in serum and urine of Pre- and post-natal growth in children of

PEDIATRICS Volume 131, Number 3, March 2013 e1021 women who smoked in pregnancy. Early 197. Brook JS, Brook DW, Whiteman M. The in- 209. Streissguth AP, Bookstein FL, Sampson PD, Hum Dev. 1996;45(3):245–255 fluence of maternal smoking during Barr HM. Attention: prenatal alcohol and 184. Fried PA, James DS, Watkinson B. Growth pregnancy on the toddler’s negativity. Arch continuities of vigilance and attentional and pubertal milestones during adoles- Pediatr Adolesc Med. 2000;154(4):381–385 problems from 4 through 14 years. Dev cence in offspring prenatally exposed to 198. Day NL, Richardson GA, Goldschmidt L, Psychopathol. 1995;7(3):419–446 cigarettes and marihuana. Neurotoxicol Cornelius MD. Effects of prenatal tobacco 210. Coles CD, Platzman KA, Raskind-Hood CL, Teratol. 2001;23(5):431–436 exposure on preschoolers’ behavior. J Dev Brown RT, Falek A, Smith IE. A comparison 185. Davies JK, Bledsoe JM. Prenatal alcohol Behav Pediatr. 2000;21(3):180–188 of children affected by prenatal alcohol and drug exposures in adoption. Pediatr 199. Wakschlag LS, Hans SL. Maternal smoking exposure and attention deficit, hyperac- Clin North Am. 2005;52(5):1369–1393, vii during pregnancy and conduct problems tivity disorder. Alcohol Clin Exp Res. 1997; 186. Shankaran S, Lester BM, Das A, et al. Im- in high-risk youth: a developmental 21(1):150–161 pact of maternal substance use during framework. Dev Psychopathol. 2002;14(2): 211. Streissguth AP, Bookstein FL, Barr HM, pregnancy on childhood outcome. Semin 351–369 Sampson PD, O’Malley K, Young JK. Risk Fetal Neonatal Med. 2007;12(2):143–150 200. Batstra L, Hadders-Algra M, Neeleman J. factors for adverse life outcomes in fetal 187. Hurt H, Brodsky NL, Betancourt L, Braitman Effect of antenatal exposure to maternal alcohol syndrome and fetal alcohol LE, Malmud E, Giannetta J. Cocaine-exposed smoking on behavioural problems and effects. J Dev Behav Pediatr. 2004;25(4): children: follow-up through 30 months. J academic achievement in childhood: pro- 228–238 Dev Behav Pediatr. 1995;16(1):29–35 spective evidence from a Dutch birth co- 212. Kelly SJ, Day N, Streissguth AP. Effects of 188. Covington CY, Nordstrom-Klee B, Ager J, hort. Early Hum Dev. 2003;75(1-2):21–33 prenatal alcohol exposure on social be- Sokol R, Delaney-Black V. Birth to age 7 201. Naeye RL. Cognitive and behavioral ab- havior in humans and other species. growth of children prenatally exposed to normalities in children whose mothers Neurotoxicol Teratol. 2000;22(2):143–149 drugs: a prospective cohort study. Neu- smoked cigarettes during pregnancy. 213. Goldschmidt L, Day NL, Richardson GA. rotoxicol Teratol. 2002;24(4):489–496 J Dev Behav Pediatr. 1992;13(6):425–428 Effects of prenatal marijuana exposure on 189. Minnes S, Robin NH, Alt AA, et al. Dys- 202. Fergusson DM, Horwood LJ, Lynskey MT. child behavior problems at age 10. Neu- morphic and anthropometric outcomes in Maternal smoking before and after preg- rotoxicol Teratol. 2000;22(3):325–336 6-year-old prenatally cocaine-exposed nancy: effects on behavioral outcomes in 214. Rosen TS, Johnson HL. Long-term effects children. Neurotoxicol Teratol. 2006;28(1): middle childhood. Pediatrics. 1993;92(6): of prenatal methadone maintenance. NIDA 28–38 815–822 Res Monogr. 1985;59:73–83 190. Richardson GA, Conroy ML, Day NL. Pre- 203. Fergusson DM, Woodward LJ, Horwood LJ. 215. Lifschltz MH, Wilson GS. Patterns of natal cocaine exposure: effects on the Maternal smoking during pregnancy and growth and development in narcotic- development of school-age children. Neu- psychiatric adjustment in late adoles- exposed children. NIDA Res Monogr. rotoxicol Teratol. 1996;18(6):627–634 cence. Arch Gen Psychiatry. 1998;55(8): 1991;114:323–339 191. Kilbride H, Castor C, Hoffman E, Fuger KL. 721–727 216. Warner TD, Behnke M, Hou W, Garvan CW, Thirty-six-month outcome of prenatal co- 204. Williams GM, O’Callaghan M, Najman JM, Wobie K, Eyler FD. Predicting caregiver- caine exposure for term or near-term et al. Maternal cigarette smoking and reported behavior problems in cocaine- infants: impact of early case manage- child psychiatric morbidity: a longitudinal exposed children at 3 years. J Dev Behav ment. J Dev Behav Pediatr. 2000;21(1):19– study. Pediatrics. 1998;102(1). Available at: Pediatr. 2006;27(2):83–92 26 www.pediatrics.org/cgi/content/full/102/ 217. Accornero VH, Anthony JC, Morrow CE, Xue 192. Eriksson M, Jonsson B, Steneroth G, 1/e11 L, Bandstra ES. Prenatal cocaine exposure: Zetterström R. Cross-sectional growth of 205. Räsänen P, Hakko H, Isohanni M, Hodgins an examination of childhood externalizing children whose mothers abused amphet- S, Järvelin MR, Tiihonen J. Maternal and internalizing behavior problems at amines during pregnancy. Acta Paediatr. smoking during pregnancy and risk of age 7 years. Epidemiol Psichiatr Soc. 2006; 1994;83(6):612–617 criminal behavior among adult male off- 15(1):20–29 193. Kristjansson EA, Fried PA, Watkinson B. spring in the Northern Finland 1966 Birth 218. Linares TJ, Singer LT, Kirchner HL, et al. Maternal smoking during pregnancy Cohort. Am J Psychiatry. 1999;156(6):857– Mental health outcomes of cocaine- affects children’s vigilance performance. 862 exposed children at 6 years of age. Drug Alcohol Depend. 1989;24(1):11–19 206. Weissman MM, Warner V, Wickramaratne J Pediatr Psychol. 2006;31(1):85–97 194. Fried PA, Watkinson B, Gray R. A follow-up PJ, Kandel DB. Maternal smoking during 219. Sood BG, Nordstrom Bailey B, Covington C, study of attentional behavior in 6-year-old pregnancy and psychopathology in off- et al. Gender and alcohol moderate care- children exposed prenatally to mari- spring followed to adulthood. J Am Acad giver reported child behavior after pre- huana, cigarettes, and alcohol. Neuro- Child Adolesc Psychiatry. 1999;38(7):892– natal cocaine. Neurotoxicol Teratol. 2005; toxicol Teratol. 1992;14(5):299–311 899 27(2):191–201 195. Thapar A, Fowler T, Rice F, et al. Maternal 207. Nanson JL, Hiscock M. Attention deficits in 220. Bendersky M, Bennett D, Lewis M. Ag- smoking during pregnancy and attention children exposed to alcohol prenatally. gression at age 5 as a function of prenatal deficit hyperactivity disorder symptoms in Alcohol Clin Exp Res. 1990;14(5):656–661 exposure to cocaine, gender, and envi- offspring. Am J Psychiatry. 2003;160(11): 208. Streissguth AP, Sampson PD, Olson HC, ronmental risk. J Pediatr Psychol. 2006;31 1985–1989 et al. Maternal drinking during pregnancy: (1):71–84 196. Kotimaa AJ, Moilanen I, Taanila A, et al. attention and short-term memory in 14- 221. Dennis T, Bendersky M, Ramsay D, Lewis Maternal smoking and hyperactivity in year-old offspring—a longitudinal pro- M. Reactivity and regulation in children 8-year-old children. J Am Acad Child Ado- spective study. Alcohol Clin Exp Res. 1994; prenatally exposed to cocaine. Dev Psy- lesc Psychiatry. 2003;42(7):826–833 18(1):202–218 chol. 2006;42(4):688–697

e1022 FROM THE AMERICAN ACADEMY OF PEDIATRICS FROM THE AMERICAN ACADEMY OF PEDIATRICS

222. Bada HS, Das A, Bauer CR, et al. Impact of 12-year olds prenatally exposed to ciga- in preschool children with prenatal drug prenatal cocaine exposure on child be- rettes and marihuana. Neurotoxicol Ter- exposure. Child Neuropsychol. 2004;10(2): havior problems through school age. Pe- atol. 1998;20(3):293–306 89–101 diatrics. 2007;119(2). Available at: www. 235. Fried PA, Smith AM. A literature review of 247. Singer LT, Minnes S, Short E, et al. Cogni- pediatrics.org/cgi/content/full/119/2/e348 the consequences of prenatal marihuana tive outcomes of preschool children with 223. Delaney-Black V, Covington C, Templin T, exposure. An emerging theme of a de- prenatal cocaine exposure. JAMA. 2004; et al. Teacher-assessed behavior of chil- ficiency in aspects of executive function. 291(20):2448–2456 dren prenatally exposed to cocaine. Pedi- Neurotoxicol Teratol. 2001;23(1):1–11 248. Frank DA, Rose-Jacobs R, Beeghly M, Wilbur M, atrics. 2000;106(4):782–791 236. Fried PA, Watkinson B. Differential effects Bellinger D, Cabral H. Level of prenatal 224. Nordstrom Bailey B, Sood BG, Sokol RJ, on facets of attention in adolescents cocaine exposure and 48-month IQ: im- et al. Gender and alcohol moderate pre- prenatally exposed to cigarettes and portance of preschool enrichment. Neu- natal cocaine effects on teacher-report of marihuana. Neurotoxicol Teratol. 2001;23 rotoxicol Teratol. 2005;27(1):15–28 – child behavior. Neurotoxicol Teratol. 2005; (5):421 430 249. Morrow CE, Culbertson JL, Accornero VH, – 27(2):181 189 237. Richardson GA, Ryan C, Willford J, Day NL, Xue L, Anthony JC, Bandstra ES. Learning 225. Eriksson M, Billing L, Steneroth G, Goldschmidt L. Prenatal alcohol and disabilities and intellectual functioning in Zetterström R. Health and development of marijuana exposure: effects on neuro- school-aged children with prenatal co- 8-year-old children whose mothers psychological outcomes at 10 years. Neu- caine exposure. Dev Neuropsychol. 2006; – abused amphetamine during pregnancy. rotoxicol Teratol. 2002;24(3):309 320 30(3):905–931 Acta Paediatr Scand. 1989;78(6):944–949 238. Lifschitz MH, Wilson GS, Smith EO, Des- 250. Hurt H, Betancourt LM, Malmud EK, et al. 226. Billing L, Eriksson M, Jonsson B, Steneroth mond MM. Factors affecting head growth Children with and without gestational co- fl G, Zetterström R. The in uence of envi- and intellectual function in children of caine exposure: a neurocognitive systems – ronmental factors on behavioural prob- drug addicts. Pediatrics. 1985;75(2):269 analysis. Neurotoxicol Teratol. 2009;31(6): lems in 8-year-old children exposed to 274 334–341 amphetamine during fetal life. Child 239. Kaltenbach K, Finnegan LP. Children ex- 251. Leech SL, Richardson GA, Goldschmidt L, Day Abuse Negl. 1994;18(1):3–9 posed to methadone in utero: assessment NL. Prenatal substance exposure: effects 227. Fried PA, O’Connell CM, Watkinson B. 60- and of developmental and cognitive ability. Ann on attention and impulsivity of 6-year-olds. 72-month follow-up of children prenatally N Y Acad Sci. 1989;562:360–362 Neurotoxicol Teratol. 1999;21(2):109–118 exposed to marijuana, cigarettes, and al- 240. Kaltenbach KA, Finnegan LP. Prenatal 252. Bandstra ES, Morrow CE, Anthony JC, cohol: cognitive and language assessment. narcotic exposure: perinatal and de- Accornero VH, Fried PA. Longitudinal in- J Dev Behav Pediatr. 1992;13(6):383–391 velopmental effects. Neurotoxicology. vestigation of task persistence and sus- 228. Cornelius MD, Ryan CM, Day NL, Goldschmidt 1989;10(3):597–604 tained attention in children with prenatal L, Willford JA. Prenatal tobacco effects on ’ 241. Bennett DS, Bendersky M, Lewis M. Childrens cocaine exposure. Neurotoxicol Teratol. neuropsychological outcomes among intellectual and emotional-behavioral 2001;23(6):545–559 preadolescents. J Dev Behav Pediatr. 2001; adjustment at 4 years as a function of 253. Savage J, Brodsky NL, Malmud E, 22(4):217–225 cocaine exposure, maternal character- Giannetta JM, Hurt H. Attentional func- 229. Olds DL, Henderson CR, Jr, Tatelbaum R. istics, and environmental risk. Dev Psychol. tioning and impulse control in cocaine- Intellectual impairment in children of 2002;38(5):648–658 exposed and control children at age ten women who smoke cigarettes during 242. Wasserman GA, Kline JK, Bateman DA, years. J Dev Behav Pediatr. 2005;26(1):42–47 pregnancy. Pediatrics. 1994;93(2):221–227 et al. Prenatal cocaine exposure and 230. Fried PA. Adolescents prenatally exposed school-age intelligence. Drug Alcohol De- 254. Mayes L, Snyder PJ, Langlois E, Hunter N. to marijuana: examination of facets of pend. 1998;50(3):203–210 Visuospatial working memory in school- aged children exposed in utero to cocaine. complex behaviors and comparisons with 243. Hurt H, Malmud E, Betancourt LM, Brodsky Child Neuropsychol. 2007;13(3):205–218 the influence of in utero cigarettes. J Clin NL, Giannetta JM. A prospective compari- Pharmacol. 2002;42(suppl 11):97S–102S son of developmental outcome of children 255. Chang L, Smith LM, LoPresti C, et al. 231. Fried PA, Watkinson B, Gray R. Differential with in utero cocaine exposure and con- Smaller subcortical volumes and cogni- effects on cognitive functioning in 13- to trols using the Battelle Developmental In- tive deficits in children with prenatal 16-year-olds prenatally exposed to ciga- ventory. J Dev Behav Pediatr. 2001;22(1): methamphetamine exposure. Psychiatry rettes and marihuana. Neurotoxicol Ter- 27–34 Res. 2004;132(2):95–106 atol. 2003;25(4):427–436 244. Arendt RE, Short EJ, Singer LT, et al. Chil- 256. Delaney-Black V, Covington C, Templin T, 232. Howell KK, Lynch ME, Platzman KA, Smith dren prenatally exposed to cocaine: de- et al. Expressive language development of GH, Coles CD. Prenatal alcohol exposure velopmental outcomes and environmental children exposed to cocaine prenatally: and ability, academic achievement, and risks at seven years of age. J Dev Behav literature review and report of a pro- school functioning in adolescence: a lon- Pediatr. 2004;25(2):83–90 spective cohort study. J Commun Disord. gitudinal follow-up. J Pediatr Psychol. 245. Messinger DS, Bauer CR, Das A, et al. The 2000;33(6):463–480, quiz 480–481 2006;31(1):116–126 maternal lifestyle study: cognitive, motor, 257. Fried PA, Watkinson B. 36- and 48-month 233. Kodituwakku PW, Kalberg W, May PA. The and behavioral outcomes of cocaine- neurobehavioral follow-up of children effects of prenatal alcohol exposure on exposed and opiate-exposed infants prenatally exposed to marijuana, ciga- executive functioning. Alcohol Res Health. through three years of age. Pediatrics. rettes, and alcohol. J Dev Behav Pediatr. 2001;25(3):192–198 2004;113(6):1677–1685 1990;11(2):49–58 234. Fried PA, Watkinson B, Gray R. Differential 246. Pulsifer MB, Radonovich K, Belcher HM, 258. Fried PA, Watkinson B, Siegel LS. Reading effects on cognitive functioning in 9- to Butz AM. Intelligence and school readiness and language in 9- to 12-year olds prenatally

PEDIATRICS Volume 131, Number 3, March 2013 e1023 exposed to cigarettes and marijuana. Neu- 265. Goldschmidt L, Richardson GA, Stoffer DS, factor for early tobacco experimentation? rotoxicol Teratol. 1997;19(3):171–183 Geva D, Day NL. Prenatal alcohol exposure Nicotine Tob Res.2000;2(1):45–52 259. Mattson SN, Riley EP. A review of the and academic achievement at age six: 272. Buka SL, Shenassa ED, Niaura R. Elevated neurobehavioral deficits in children with a nonlinear fit. Alcohol Clin Exp Res. 1996; risk of tobacco dependence among off- fetal alcohol syndrome or prenatal expo- 20(4):763–770 spring of mothers who smoked during sure to alcohol. Alcohol Clin Exp Res. 1998; 266. Olson HC, Streissguth AP, Sampson PD, pregnancy: a 30-year prospective study. 22(2):279–294 Barr HM, Bookstein FL, Thiede K. Associa- Am J Psychiatry. 2003;160(11):1978–1984 260. Coggins TE, Timler GR, Olswang LB. A state tion of prenatal alcohol exposure with 273. Porath AJ, Fried PA. Effects of prenatal of double jeopardy: impact of prenatal behavioral and learning problems in early cigarette and marijuana exposure on adolescence. J Am Acad Child Adolesc alcohol exposure and adverse environ- drug use among offspring. Neurotoxicol Psychiatry. 1997;36(9):1187–1194 – ments on the social communicative abili- Teratol. 2005;27(2):267 277 ties of school-age children with fetal 267. Goldschmidt L, Richardson GA, Cornelius 274. Brennan PA, Grekin ER, Mortensen EL, alcohol spectrum disorder. Lang Speech MD, Day NL. Prenatal marijuana and al- Mednick SA. Relationship of maternal cohol exposure and academic achieve- Hear Serv Sch. 2007;38(2):117–127 smoking during pregnancy with criminal ment at age 10. Neurotoxicol Teratol. 2004; arrest and hospitalization for substance 261. Bandstra ES, Morrow CE, Vogel AL, et al. 26(4):521–532 abuse in male and female adult offspring. Longitudinal influence of prenatal cocaine 268. Levine TP, Liu J, Das A, et al. Effects of Am J Psychiatry. 2002;159(1):48–54 exposure on child language functioning. prenatal cocaine exposure on special ed- 275. Baer JS, Barr HM, Bookstein FL, Sampson Neurotoxicol Teratol. 2002;24(3):297–308 ucation in school-aged children. Pediat- PD, Streissguth AP. Prenatal alcohol ex- 262. Lewis BA, Singer LT, Short EJ, et al. Four- rics. 2008;122(1). Available at: www. posure and family history of alcoholism in year language outcomes of children ex- pediatrics.org/cgi/content/full/122/1/e83 the etiology of adolescent alcohol prob- posed to cocaine in utero. Neurotoxicol 269. Hurt H, Brodsky NL, Roth H, Malmud E, lems. J Stud Alcohol. 1998;59(5):533–543 Teratol. 2004;26(5):617–627 Giannetta JM. School performance of 276. Yates WR, Cadoret RJ, Troughton EP, 263. Streissguth AP, Barr HM, Sampson PD. children with gestational cocaine expo- Stewart M, Giunta TS. Effect of fetal alco- Moderate prenatal alcohol exposure: sure. Neurotoxicol Teratol. 2005;27(2):203– hol exposure on adult symptoms of nico- effects on child IQ and learning problems 211 tine, alcohol, and drug dependence. at age 7 1/2 years. Alcohol Clin Exp Res. 270. Cernerud L, Eriksson M, Jonsson B, Alcohol Clin Exp Res. 1998;22(4):914–920 – 1990;14(5):662 669 Steneroth G, Zetterström R. Amphetamine 277. Alati R, Al Mamun A, Williams GM, 264. Coles CD, Brown RT, Smith IE, Platzman KA, addiction during pregnancy: 14-year O’Callaghan M, Najman JM, Bor W. In utero Erickson S, Falek A. Effects of prenatal follow-up of growth and school perfor- alcohol exposure and prediction of alco- alcohol exposure at school age. I. Physical mance. Acta Paediatr. 1996;85(2):204–208 hol disorders in early adulthood: a birth and cognitive development. Neurotoxicol 271. Cornelius MD, Leech SL, Goldschmidt L, Day cohort study. Arch Gen Psychiatry. 2006;63 Teratol. 1991;13(4):357–367 NL. Prenatal tobacco exposure: is it a risk (9):1009–1016

e1024 FROM THE AMERICAN ACADEMY OF PEDIATRICS