Addictive Disorders in Women: The Impact of

Maternal Substance Use on the Fetus and Newborn

Christiana N. Oji-Mmuo, MD,* Tammy E. Corr, DO,* Kim K. Doheny, PhD*
*Division of Newborn Medicine, Department of Pediatrics, Penn State Children’s Hospital, Hershey, PA

Education Gap
Clinicians caring for newborns need to recognize the clinical features and
long-term effects of fetal exposure to maternal substance use.

Objectives After completing this article, readers should be able to:

1. Understand the nomenclature and epidemiology of licit and illicit drug use
in pregnancy.
2. Discuss the effects of maternal drug dependence on the developing fetus.
3. Recognize the clinical features and long-term effects of fetal exposure to
common licit and illicit drugs.
4. Review the current and future areas for research in maternal addiction and
neonatal abstinence syndrome.

AUTHOR DISCLOSURE Drs Oji-Mmuo, Corr,

Abstract and Doheny have disclosed no financial
relationships relevant to this article. This
Addictive disorders are rising to epidemic proportions throughout the United commentary does not contain a discussion of
States and globally, placing significant social and economic burdens on an unapproved/investigative use of a
commercial product/device.
industrialized societies. It is well-known that a high percentage of drug-dependent
individuals are women of childbearing age. Maternal substance use and abuse ABBREVIATIONS
exposes the fetus to drugs of dependence during critical periods of development, ACOG American Congress of
resulting in short- and long-term neurodevelopmental effects in infancy and Obstetricians and Gynecologists
ASAM American Society of Addiction
childhood. Neonatal abstinence syndrome (NAS) is a term that was initially used to Medicine
describe the withdrawal symptoms observed in infants who were exposed to CNS central nervous system
opioids in utero. As we have learned more about the various effects of in utero FAS fetal alcohol syndrome
FASD fetal alcohol syndrome disorder
drug exposure and the subsequent consequences, NAS has become a term that
IUGR intrauterine growth restriction
more broadly describes the signs and symptoms of withdrawal resulting from any LBW low birthweight
dependence-inducing substance consumed by a pregnant woman. The aim of this MDMA methylenedioxmethamphetamine
review is to discuss the perinatal outcome of pregnancy associated with maternal nAChrs nicotinic acetylcholine receptors
NAS neonatal abstinence syndrome
drug use. In the United States and other developed nations, the incidence of NAS
SAMHSA Substance Abuse and Mental
continues to rise, paralleling the evolution of the opioid epidemic. Chronic in utero Health Services Administration
exposures to licit and illicit drugs of dependence have fetal, neonatal, and early SSRIs selective serotonin receptor
childhood consequences and are addressed in this review. inhibitors
THC cannabis/delta-9-
tetrahydrocannabinol

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INTRODUCTION
Maternal addiction is a growing public health concern. The
prevalence of drug use among women of childbearing
age is rising. Women between the ages of 15 and 44 years
continue to use illicit drugs during pregnancy with re-
ported rates of gestational abuse as high as 5.9% according
to recent data from the National Survey on Drug Use and
Health. Every 30 minutes an infant is born at risk for drug
withdrawal. (1)
Women may be dependent on licit or illicit substances,
which results in unintended consequences for the devel-
oping fetus and neonate. The care of women who are
drug-dependent is very complex, starts before pregnancy,
and should continue beyond the postpartum period. This
review will provide an overview of maternal drug use, the
subsequent fetal effects, short-term neonatal complica-
tions, and potential long-term consequences. Before
proceeding with this review, certain terms need to be
defined so the reader understands the nomenclature as
described by the American Society of Addiction Medi-
cine (ASAM).
Use: The word “use” describes sporadic intake of licit and
illicit substances with no adverse consequences as a result
of the consumption.
Abuse: This term refers to the continued use of substances
such as illegal drugs, prescription drugs, or over-the-
counter medications, leading to negative consequences
to the user.
Physical dependence: This term is used to describe a
physical condition caused by the prolonged or chronic
use of a tolerance-forming substance or drug. The
sudden discontinuation of a dependence-inducing drug
leads to a syndrome of withdrawal characterized by
somatic signs and symptoms.
Psychological dependence: In this form of dependence,
the user feels a subjective sense that he or she strongly
needs to use a particular substance. Psychological
dependence involves complex emotional-motivational
withdrawal symptoms. The user craves these sub-
stances mainly because of their positive or negative
consequences.
Addiction: ASAM defines addiction as a primary, chronic
disease of brain reward, motivation, memory, and re-
lated circuitry. The syndrome is characterized by bio-
logical, psychological, social, and spiritual features.
Addiction is described as the inability to consistently
abstain, impairment in behavioral control, and craving.
The user experiences diminished recognition of the
associated problems with his or her behaviors and
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interpersonal relationships and displays dysfunctional
emotional responses. Addiction is a lifelong disease
with recovery, replacement, and remission cycles, and
it is associated with significant morbidity and mortality.
EPIDEMIOLOGY OF SUBSTANCE USE IN
PREGNANCY AND THE BURDEN OF NEONATAL
ABSTINENCE SYNDROME
For more than a decade, the epidemic of prescription and
nonprescription opioid use has been growing, resulting
in a marked upsurge in the incidence of neonatal absti-
nence syndrome (NAS). (1)(2)(3)(4) NAS is defined as a
constellation of symptoms and signs that are noted in
the infant after birth following abrupt discontinuation
of placentally transferred drugs of addiction. Between
2000 and 2009, the rate of NAS diagnosis in the United
States increased nearly threefold, from 1.2 to 3.4 per 1,000
hospital births. By 2012, the incidence had increased still
further to 5.8 per 1,000 hospital births. (3) This more than
fourfold increase in hospital admissions for NAS from
2003 to 2012 cost nearly $316 million in the United States
in 2012. (4) NAS is not an issue isolated to the United
States. It is a global problem with increasing reports of
the syndrome noted in both developed and developing
countries. (5)
In part, the rise in NAS coincides with the increase in
maternal prescription opioid use. (1)(6) For example, in
Tennessee, 63% of cases of NAS followed maternal use of
prescription opioids as opposed to 33% resulting from
abuse of illicit substances. (6) Unfortunately, this is not
an isolated example. Nationwide, the Centers for Disease
Control and Prevention noted that around one-third of
reproductive-aged women filled an opioid prescription
in the years 2008 to 2012. (1) In turn, NAS has become
a quickly growing reason for NICU admission in the
United States, with NAS accounting for 4% of NICU days
in 2013, up from 0.6% in the previous decade. (3)
Maternal substance abuse continues to contribute to
NAS, both in the forms of prescription opioid abuse and
the use of illicit drugs such as heroin. (7) These recent
increases in opioid use and abuse have led to more mothers
requiring conversion to an opiate substitute during preg-
nancy. Although these conversions have shown improve-
ment in both medical and social outcomes for the mother
and infant, (8) the substantial increase in opioid replace-
ment programs has also been associated with the increase in
NAS.
There is a growing economic burden associated with
NAS, with a significant rise in hospital charges associated
Vol. 18 No. 10 OCTOBER 2017 e577
 with NAS between the years 2000 and 2012. (1)(3) The
majority of these costs were borne by state Medicaid
systems, suggesting additional financial considerations
for federal and state budgets. (3)
FETAL DEVELOPMENTAL BIOLOGY IN THE SETTING
OF MATERNAL SUBSTANCE USE
During the fetal period, the growing brain is vulnerable
to exogenous insults, and exposure to licit and illicit sub-
stances has been linked to neurodevelopmental deficits. (9)
Table 1 lists the common licit and illicit substances as
described by the Substance Abuse and Mental Health Ser-
vices Administration (SAMHSA). (10) Cellular and molec-
ular mechanisms are well-described as the pathophysiologic
basis for resultant patterns of injury. Transplacental transfer
is the primary mechanism for transmission of the drug to
the fetus, and exposure to these various substances can have
a direct effect on the uterus, placenta, and fetal brain. These
drugs can also alter maternal physiology, leading to condi-
tions such as preeclampsia, seizures, hypertension, and
preterm labor, which also have a direct impact on the fetus
and developing brain. (11) Placental blood flow is signifi-
cantly reduced in mothers who abuse drugs such as tobacco
and cocaine. Placental insufficiency secondary to vasocon-
striction and reduced blood flow from maternal hyperten-
sion and placental abruption contribute to decreased
nutrient supply to the developing fetus. (12) The impact
of maternal undernutrition, a commonly associated condi-
tion in drug-dependent women, can lead to fetal growth
restriction. Similarly, exposure to alcohol during pregnancy
also causes poor fetal growth.
In addition, alcohol remains the most common tera-
togenic substance of abuse to which fetuses are exposed,
such that no alcohol should be allowed during pregnancy
TABLE 1. Classification of Licit and Illicit Substances
LICIT SUBSTANCES
Tobacco
Caffeine
Alcohol
Prescription opiates
Stimulants
Amphetamines
Benzodiazepines
Substance Abuse and Mental Health Services Administration (10)
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according to the American Congress of Obstetricians
and Gynecologists (ACOG). Alcohol consumption dur-
ing pregnancy can result in low birthweight (LBW)
secondary to decreased nutrient supply to the fetus and
prematurity, and small to moderate amounts of alcohol
intake in pregnant mothers have been linked to preterm
delivery during the index pregnancy. (13) Preterm birth,
including late prematurity, is an important independent
risk factor for adverse long-term neurodevelopment out-
comes. (14) As described, maternal substance use results
in numerous fetal effects with both short- and long-term
implications for infant health. The results of drug expo-
sure on the fetus during the pregnancy depend on the
amount or dose; the timing in gestation when the expo-
sure occurs; maternal nutrition (prenatal and during preg-
nancy); and social, genetic, environmental, and epigenetic
factors.
REVIEW OF FETAL AND NEONATAL EFFECTS OF
COMMON MATERNAL LICIT SUBSTANCE USE
Caffeine
Caffeine is by far the most common licit substance that
causes psychological dependence. It is readily available
and a common ingredient in most drinks such as cof-
fee, soda, and so-called energy drinks. Dependence on
caffeine often starts before pregnancy, and preventive
measures should commence in the pregestational stage.
Caffeine crosses the placenta and leads to increased cir-
culating catecholamine levels in pregnant women. (15)
Caffeine is a popular central nervous system (CNS)
stimulant, and physical dependence has been described.
(16)
The fetal effects of caffeine consumption based on
low, moderate, and high caffeine intake among pregnant
ILLICIT SUBSTANCES
Marijuana/cannabis/hashish
Cocaine (including crack)
Heroin
Hallucinogens and inhalants
Prescription-type psychotherapeutics used
nonmedically
women have been studied. Some studies suggest that the
risk of LBW and intrauterine growth restriction (IUGR)
increases significantly with moderate to high intake (caf-
feine dose >150 mg/day). (17)(18) However, based on the
collective literature, ACOG maintains that the relationship
of caffeine to growth restriction remains undetermined.
The current ACOG statement suggests that “moderate
caffeine consumption (<200 mg/day) does not appear to
be a major contributing factor in miscarriage or preterm
birth.” (19)
Nicotine/Tobacco
Over 4,000 chemicals are produced during cigarette
smoking. Nicotine is only one of such substances, and
about 40 of these chemicals have been shown to be car-
cinogenic. (20) Tobacco use among substance-abusing
pregnant mothers is high. (21) It is the most common licit
substance of abuse among women who are pregnant and
of childbearing age. Nicotine binds to the nicotinic ace-
tylcholine receptors (nAChrs). The nAChrs are expressed
in the fetal CNS and stimulation of the nAChrs by nicotine
is known to disturb the fetal CNS through its effects on
morphogenesis, neuronal well-being, and activity. (22)
Oxygen and nutrient delivery to the developing fetus is
impaired secondary to abnormal gas exchange related to
the byproducts of cigarette smoke such as carbon mon-
oxide. Cigarette smoking also has been linked to preterm
birth, stillbirth, IUGR, and LBW. (23)(24) Neonatal nico-
tine withdrawal has been described in the literature to be
similar to neonatal opiate withdrawal with clinical signs of
irritability, tremors, stress dysregulation, and increased
muscle tone in the newborn. (25)
Alcohol
Fetal alcohol syndrome (FAS) is an antiquated term that
was historically used to describe the teratogenic effects of
in utero alcohol exposure on the fetus. The nomenclature
has changed in recent years to fetal alcohol spectrum
disorders (FASDs) to represent the range of outcomes
to fetal alcohol exposure. The classic FAS features include
distinct abnormal facies, limb anomalies, cognitive defi-
ciency, and poor growth. Alcohol-related neurodevelop-
mental disorder describes the intellectual and behavioral
issues that can be seen in isolation and the alcohol-related
birth defects include anatomic or phenotypic congenital
anomalies such as heart defects, renal, bone, hearing, and
visual problems.
The proposed mechanisms of alcohol teratogenesis
are well-described. Specifically, the L1 neural cell adhe-
sion molecule, critical for neuronal development, has
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been shown to have its function interrupted with alcohol
consumption during pregnancy in animal studies. (26)
The effects of alcohol on the developing brain have most
consistently been noted with moderate to heavy use
during pregnancy. (27) These adverse neurobehavioral
effects persist in the affected offspring through early
adulthood. (27) Mental deficiency secondary to FASD is
among the top 3 causes of intellectual disability in North
America, more than trisomy 21 and cerebral palsy. (28)
Alcohol use in pregnancy should be discouraged because
no safe limits have been determined. ACOG recommends
that “women should avoid alcohol entirely while pregnant
or trying to conceive because damage can occur in the
earliest weeks of pregnancy, even before a woman knows
that she is pregnant.” (29)
Stimulants and Amphetamines
Amphetamines are commonly used to treat attention
deficits, sleep problems, and weight issues. Ecstasy, a form
of methylenedioxmethamphetamine (MDMA) is a com-
mon illicit stimulant and poses serious consequences to
the mother and fetus. Amphetamine use in pregnancy has
been linked to poor fetal growth and preterm birth. (30)
Serious consequences such as fetal death have also been
reported. (31) A study conducted in the United Kingdom
examined the effects of MDMA or “ecstasy” during preg-
nancy and reported the presence of congenital anomalies in
15.4% of live births. Notably, congenital anomalies including
congenital heart defects and talipes deformity were com-
mon in the cohort exposed to MDMA. (32) Long-term
adverse motor and mental deficits have been reported in
cohort studies in infancy. (33)
Antipsychotics, Anxiolytics, and Antidepressants
The prevalence of mood and anxiety disorders in the
United States has been shown to be approximately 13%.
(34) Pharmacologic treatment of mental health is rela-
tively common in pregnant women, thus the fetus is at
risk of exposure to antidepressant, anxiolytic, and anti-
psychotic medications given during pregnancy. Likewise,
mental disorders are often complicated by the additional
use of illicit substances, malnutrition, and tobacco. In-
fants exposed to selective serotonin receptor inhibitors
(SSRIs) and other antidepressant medications are at in-
creased risk of withdrawal, with symptoms that are very
similar to neonatal opiate withdrawal (35)(36) including
mild CNS, motor, gastrointestinal, and respiratory symp-
toms that typically resolve by 2 weeks of age and respond
to nonmedical therapy and supportive care. (35) SSRIs
during pregnancy have not been linked to increased risk of
Vol. 18 No. 10 OCTOBER 2017 e579
 congenital malformation, and hence are used as a safe
treatment for mild depression in pregnancy. (37) A study
examining infants exposed to in utero antidepressants
(tricyclic antidepressants and fluoxetine [an SSRI]) found
that these medications did not affect global neurodevel-
opmental outcomes in preschool children. (38)
Benzodiazepines represent another class of commonly
used anxiolytics in pregnancy. Although used in preg-
nancy safely, continued use of benzodiazepines during
lactation can lead to sedation and lethargy in the infant.
(39) Due to lack of systematic reviews and limited animal
studies, the neonatal effects of antipsychotic drugs are
not well-understood. The withdrawal symptoms are seen
shortly after birth, usually in the first 24 hours. The symp-
toms are related to sedation and extrapyramidal effects
characteristic of the medications, (40) which manifest
as abnormal motor movements (jitters) and increased
muscle tone. (41)
Cannabis
Cannabis/delta-9-tetrahydrocannabinol (THC) also known
as marijuana and several products, like hashish, extracted
from the Cannabis sativa plant, represent another class of
substances commonly abused. Smoking marijuana is the
most frequent route of consumption. A recent population
study indicated that in the United States, in people older
than 12 years, about 42% report having tried or used
marijuana at some point in their life. (10) Cannabinoids
act via the cannabinoid receptor type 1 to produce their
CNS effects. Studies suggest that the CNS of the human
fetus exhibits the cannabinoid receptor type 1 as early as
14 weeks of gestation. Cannabinoids seem to disturb the
expression of genes encoding for neuron-glia cell adhe-
sion molecules. This observation supports the hypothesis
that cannabinoids may disrupt cell proliferation, neuro-
nal migration, or axonal elongation. (42)
THC is the active form of cannabis and exerts seda-
tive effects. THC readily crosses the placenta, and animal
studies suggest that exogenous cannabinoid exposure
may enact abnormal CNS effects, leading to low language
and memory scores. (43)
Synthetic marijuana, also known as “spice gold,” is
favored by some drug-dependent mothers because it can-
not be detected in standard urine or meconium toxicology
screens. It is commonly sold in herbal stores and online
within the United States.
The fetal and neonatal effects of synthetic marijuana
are yet to be fully elucidated. Medical marijuana is cur-
rently legal in some states. However, there are no indica-
tions approved by the Food and Drug Administration for
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the use of medical marijuana in pregnancy. The 2015
ACOG statement does not endorse its use during preg-
nancy because no standard dose regimen has been estab-
lished. (44)
Cocaine
The third largest illicit drug to be abused in the United
States is cocaine, and its use accounts for 0.3% of sub-
stance addiction among women of childbearing age based
on SAMHSA data. (10) Cocaine crosses the placenta and
blood-brain barrier and is teratogenic. Prenatal cocaine
exposure accounts for more than $26 million per year
spent on special education services in the United States,
secondary to the long-term cognitive effects of maternal
cocaine use. (38) Studies show that cocaine inhibits the
reuptake of monoamines at the presynaptic junction, and
increased dopamine, serotonin, and norepinephrine in
the synaptic cleft results in vasoconstrictive effects. Fetal
growth restriction, preterm birth, LBW, microcephaly, vas-
cular accidents (placental abruption and neonatal stroke), and
poor neurodevelopmental outcomes are known effects of
fetal cocaine exposure. (45)(46)
Opioids (Heroin, Prescription Opioids, Methadone, and
Buprenorphine)
Opioid addiction among pregnant women results from
the prolonged use of heroin or prescription opioids. Obste-
tricians may become aware of this problem through the
use of a universal screening questionnaire of all preg-
nant women at the first prenatal visit. Opioid-addicted
pregnant women are commonly referred to methadone
treatment centers because methadone remains the first-
line opioid replacement therapy for illicit opioid addiction.
(47)
Neonates exposed to methadone in utero require a
significantly longer duration of treatment for NAS com-
pared with those whose mothers receive traditional opi-
ates. Methadone exposure increased the risk of preterm
birth, small size for gestational age, and NAS, including
the need for NICU admission. However, buprenorphine
may be a safe alternative for treating opioid dependency in
pregnancy with demonstrated shorter lengths of stay,
lower peak NAS scores, and lower peak morphine dose
for infants born to mothers treated with this newer med-
ication compared with those infants whose mothers re-
ceived methadone. (48)
The effects of chronic opioid use in pregnancy are well-
studied. Pregnancies affected by opioid dependence are
at risk for preeclampsia, preterm birth, fetal growth re-
striction, stillbirths, and NAS. The recent rise in opiate
use and misuse has led to the increasing incidence of
NAS. (2)(3)(4) Short- and long-term consequences of NAS
have been described.
NAS presentation is variable; affected infants have
multisystem involvement as described (Table 2). The on-
set of opiate withdrawal is 24 to 72 hours after birth, but
can appear as late as 5 to 7 days of age. About 60% of
opiate-exposed neonates become symptomatic, requir-
ing pharmacologic treatment. (48) Indicators of NAS
severity include the length of stay and the need for
pharmacologic intervention. (48)(49)
The treatment of NAS requires a multidisciplinary ap-
proach involving obstetricians, nurses, social workers,
pediatricians, and neonatologists. The first-line approach
is to correctly identify at-risk neonates. Nonpharmaco-
logic treatment should start immediately after birth for
all at-risk newborns and may suffice in cases of mild
withdrawal. (50) Nonpharmacologic treatment involves
the family; it is cheap and readily available. The therapy
includes maternal-infant care in a quiet room, sensitive
handling, swaddling, music therapy, infant massage, breast-
feeding, non-nutritive sucking (pacifiers), kangaroo care,
low lighting, and meticulous skin care.
Breastfeeding is promoted for infants with NAS as
seen in studies that show its benefits. (51) Pharmacologic
therapy is often needed when nonpharmacologic thera-
pies fail to ameliorate the symptoms of NAS. Multiple
drugs have been used in the treatment of NAS. Opioid
replacement therapy with morphine and methadone has
proven to be effective. Second-line agents such as pheno-
barbital and clonidine are sometimes needed, particularly
in the setting of polysubstance drug exposure. (52)(53)
Neonatal toxicology testing for prenatal substance expo-
sure includes urine, meconium, hair, and umbilical cord
toxicology testing. Clinicians need to maintain a high in-
dex of suspicion to appropriately capture infants who
require testing. Meconium testing is not readily avail-
able at many centers, and often, the specimen is sent to a
TABLE 2. Clinical Features of Neonatal Abstinence Syndrome
NEUROIRRITABILITY AUTONOMIC INSTABILITY
Hypertonia Yawning
Tremors Nasal stuffiness
Hyperreflexia Tachypnea
Irritability, restlessness Sweating
High-pitched cry Sneezing
Poor sleep Fever
Seizures Skin mottling
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toxicology laboratory with results returning 2 to 3 days after
initial suspicion. Meconium testing is sensitive and specific,
particularly for opioids when compared with urine toxicol-
ogy screening. A newer and promising method is umbilical
cord testing using substance-specific immunoassay. (54)
However, it is expensive and has very limited availability
at this time.
NEURODEVELOPMENTAL CONSEQUENCES OF
PRENATAL SUBSTANCE EXPOSURE
The use of licit and illicit substances is associated with adverse
neurodevelopmental outcomes. (55) Unfortunately, there is a
paucity of data on long-term follow-up of infants born to
substance-abusing mothers. Despite limited research on
this topic, the available evidence suggests that the risk of
long-term complications exists. (56) Additional studies are
needed to examine the persisting long-term effects. A
recent study suggested that at 8 years of age, polydrug-
exposed infants were at higher risk for attention-deficit
disorders than a nonexposed cohort. (57) Another study
followed infants with in utero exposure to opioids until
they were 36 months of age. The results from the Bayley
Scores of Infant Development suggested that opioid-
exposed infants had lower mean expressive language and
mental development index outcomes and scored lower
on social maturity scales compared with healthy controls.
(56)
PREVENTION OF MATERNAL DRUG ADDICTION
AND NAS
The prevention of substance use during pregnancy must
start in the preconception period. Primary preventive
efforts focusing on reducing the prevalence of illicit sub-
stance use among adolescents and women of childbearing
age remain the most likely effective means of prevention.
High school students and parents should receive periodic
GASTROINTESTINAL DISTURBANCES OTHERS
Diarrhea Diaper rash
Vomiting Skin excoriation
Poor feeding
Failure to thrive
Vol. 18 No. 10 OCTOBER 2017 e581
 counseling on the risks and hazards of substance abuse.
Prevention of unintended pregnancies in the at-risk pop-
ulation should also be made a priority. Screening of all
pregnant women for substance use is the current norm,
based on standardized questionnaires. (58) Reproductive
and mental health services should be made accessible to
at-risk women. Implementation of routine antenatal edu-
cation, allowing women to enroll in treatment facilities
without fear of prosecution is necessary. Specialized treat-
ment programs will reduce risks to the pregnant women,
thus ensuring that mothers remain in the program after
delivery, thus leading to sobriety in the long term.
FUTURE DIRECTIONS AND AREAS FOR RESEARCH
Research is needed to further understand the effects of
maternal and paternal substance use on the developing
brain. Additional animal studies are required to evaluate
the biochemical and molecular basis of in utero polydrug
exposure. Bench research is also needed to explore the
route of administration of opioids, third-trimester inter-
ventions that can be provided to the mother to mitigate
withdrawal in the offspring, and the effects of drug phar-
macokinetics in postnatal withdrawal. NAS is a highly
variable condition, with inconsistencies noted in the same
infant over time. Sex differences have been described as
well. (59) However, these differences, including epigenetic
mechanisms, have yet to be fully explored.
Early studies on the genetic basis of NAS examining
the opioid receptor genes are promising. Wachman et al
identified single nucleotide polymorphisms in the pre-
pronociceptin (PNOC) and catechol-O-methyltransferase
(COMT) genes that had an impact on outcomes in infants
with NAS, including short-term outcomes as measured
by the in-hospital length of stay. (60)
The paucity of data on long-term outcomes in NAS
remains an ongoing challenge. Longitudinal studies based
on knowledge gained from the preclinical research avail-
able and the cohort studies to date need to be further
explored in well-designed clinical studies. Barriers to
research in maternal substance use and NAS exist. Poly-
substance exposure, poor obstetrical care, maternal com-
modities, and malnutrition are some of the important
confounders making research in this field challenging.
Variation in practice regimens is an ongoing issue;
therefore, standardization of pharmacologic and nonphar-
macologic therapies among physicians is necessary. More-
over, there is a need for objective tools in the clinical
assessment of NAS. Preliminary studies are emerging
and promising. The usefulness of skin conductance in
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response to noxious stimuli in the opioid-exposed cohort
was explored recently at our institution and revealed that
infants with severe NAS symptoms had increased sympa-
thetic arousal before the need for pharmacotherapy when
compared with infants with less severe NAS symptoms. (61)
The use of vagal tone in assessing autonomic balance seen in
NAS also has been reported. (59) Methadone-exposed infants
with lower vagal tone on the first day after birth went on to
have pronounced NAS symptoms by day 3 after birth, sug-
gesting that autonomic regulation is abnormal in NAS, and is
more pronounced in male infants.
In conclusion, the current opioid epidemic has been
associated with an increasing incidence of NAS. Polysub-
stance abuse is common. The medical and socioeconomic
burden of this syndrome has created unique challenges
for clinicians, social workers, therapy centers, and law-
makers. Prevention is critical. Early recognition and treat-
ment of addicted mothers is necessary as is using strategies
to ensure that children are cared for in a safe and nurturing
environment. More research is needed in this area, partic-
ularly for assessment, treatment options, and long-term
neurodevelopmental outcomes.
American Board of Pediatrics
Neonatal-Perinatal Content
Specification
• Know the effects on the fetus and/or newborn infant of maternal
substance abuse (eg, heroin, cocaine, cannabis,
methamphetamines, tobacco).
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NeoReviews Quiz
There are two ways to access the journal CME quizzes:
1. Individual CME quizzes are available via a handy blue CME link in the Table of Contents of any issue.
2. To access all CME articles, click “Journal CME” from Gateway’s orange main menu or go directly to: http://www.
aappublications.org/content/journal-cme.

1. An infant born at term is noted to have hypertonia and jitteriness on the second day after NOTE: Learners can take
delivery. There is suspicion for neonatal abstinence syndrome (NAS). Which of the NeoReviews quizzes and
following statements regarding NAS is correct? claim credit online only
at: http://Neoreviews.org.
A. Over the past 20 years, the rate of NAS diagnosis in the United States has remained
stable at 1 per 1,000 hospital births.
B. In regions of the country where NAS has increased in frequency, the etiology To successfully complete
exclusively has been illicit abuse. 2017 NeoReviews articles
C. The Centers for Disease Control and Prevention reported that one-third of for AMA PRA Category 1
reproductive-age women filled an opioid prescription in the years 2008 to 2012. CreditTM, learners must
D. The implementation of conversion programs from heroin to opiate substitutes has demonstrate a minimum
led to a substantial decrease in incidence of NAS. performance level of 60%
E. The phenomenon of NAS is limited to developed countries where relevant drugs or higher on this
have become more prevalent in recent years. assessment, which
measures achievement of
2. A pregnant woman is attending a prenatal care visit. She is noted to be using alcohol, the educational purpose
tobacco, and amphetamines on a regular basis. Which of the following effects of these and/or objectives of this
substances is appropriately described? activity. If you score less
than 60% on the
A. Tobacco is the most common teratogenic substance of abuse to which fetuses are assessment, you will be
exposed. given additional
B. Placental blood flow is significantly reduced in mothers who use tobacco. opportunities to answer
C. According to the American Congress of Obstetricians and Gynecologists (ACOG), questions until an overall
mild alcohol use during the third trimester is permissible. 60% or greater score is
D. Amphetamine use, in conjunction with mild tobacco use, is associated with large achieved.
for gestational age birth.
E. The impact of these 3 substances on the fetus are all mediated by alteration of the
placenta, without direct effect on the fetus. This journal-based CME
activity is available
3. A woman enters prenatal care at an estimated gestational age of 8 weeks. She is noted to through Dec. 31, 2019,
drink about 2 cups of coffee per day. Which of the following effects of caffeine on however, credit will be
pregnancy and the fetus is described correctly? recorded in the year in
which the learner
A. The current ACOG statement suggests that moderate caffeine consumption (<200
completes the quiz.
mg/day) does not appear to be a major contributing factor in miscarriage or
preterm birth.
B. Although not prescribed universally, women who are at risk for preterm birth may
benefit from reducing risk of early delivery by receiving a daily dose of caffeine
during the second trimester.
C. Caffeine does not cross the placenta, but can have fetal effects due to altering
circulating maternal hormones.
D. Regular caffeine use during pregnancy may prevent intrauterine growth restriction
in women at risk of decreased placental blood flow.
E. Although caffeine may not have direct effect on fetal development, it has been
associated with later development of childhood leukemia and other cancers in
infancy.

4. A pregnant woman who is addicted to heroin enters prenatal care. The obstetrician and
the woman discuss various options for care regarding her drug use. Which of the following
statements regarding opioid addiction during pregnancy and appropriate care for the
mother and infant is correct?

Vol. 18 No. 10 OCTOBER 2017 e585

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 A. To avoid severe withdrawal symptoms in the mother and adverse reactions in the
fetus/infant, the mother should continue low doses of heroin until she delivers her
infant.
B. Buprenorphine can be used only as a postnatal replacement therapy for the
mother, because it has been shown to have teratogenic effects.
C. Naloxone should be administered to the mother during active phase of labor and
subsequently to the infant shortly after delivery.
D. The first-line treatment for opioid-addicted pregnant women is hydrocodone.
E. Methadone exposure in utero has been associated with significantly longer
duration of treatment for NAS than those exposed to traditional opiates.
5. An infant who was born to a mother with chronic heroin use is being monitored after birth.
Which of the following correctly describes the presentation and treatment of NAS?
A. About 90% of opiate-exposed neonates become symptomatic and require
treatment.
B. Breastfeeding is contraindicated regardless of maternal drug use status.
C. The onset of opiate withdrawal is 24 to 72 hours after birth, but can appear as late as
5 to 7 days after delivery.
D. The initial presenting symptoms include hypotonia, hyporeflexia, and lethargy.
E. For confirmatory toxicology testing, urine screening is more sensitive and specific
than meconium testing.

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Addictive Disorders in Women: The Impact of Maternal Substance Use on the
Fetus and Newborn
Christiana N. Oji-Mmuo, Tammy E. Corr and Kim K. Doheny
NeoReviews 2017;18;e576
DOI: 10.1542/neo.18-10-e576

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http://neoreviews.aappublications.org/content/18/10/e576#BIBL
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Addictive Disorders in Women: The Impact of Maternal Substance Use on the
Fetus and Newborn
Christiana N. Oji-Mmuo, Tammy E. Corr and Kim K. Doheny
NeoReviews 2017;18;e576
DOI: 10.1542/neo.18-10-e576

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/18/10/e576

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