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Developmental Consequences of Fetal Exposure to
Drugs: What We Know and What We Still Must Learn
Emily J Ross
1
, Devon L Graham
2
, Kelli M Money
3
and Gregg D Stanwood*
,2,4
1
Chemical & Physical Biology Program, Vanderbilt University, Nashville, TN, USA;
2
Department of Pharmacology, Vanderbilt
University, Nashville, TN, USA;
3
Neuroscience Graduate Program, Vanderbilt University, Nashville, TN, USA;
4
The Vanderbilt
Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN, USA
Most drugs of abuse easily cross the placenta and can affect fetal brain development. In utero exposures to drugs thus can
have long-lasting implications for brain structure and function. These effects on the developing nervous system, before
homeostatic regulatory mechanisms are properly calibrated, often differ from their effects on mature systems. In this review,
we describe current knowledge on how alcohol, nicotine, cocaine, amphetamine, Ecstasy, and opiates (among other drugs)
produce alterations in neurodevelopmental trajectory. We focus both on animal models and available clinical and imaging
data from cross-sectional and longitudinal human studies. Early studies of fetal exposures focused on classic teratological
methods that are insufficient for revealing more subtle effects that are nevertheless very behaviorally relevant. Modern
mechanistic approaches have informed us greatly as to how to potentially ameliorate the induced deficits in brain formation
and function, but conclude that better delineation of sensitive periods, dose–response relationships, and long-term
longitudinal studies assessing future risk of offspring to exhibit learning disabilities, mental health disorders, and limited neural
adaptations are crucial to limit the societal impact of these exposures.
Neuropsychopharmacology Reviews (2015) 40, 61–87; doi:10.1038/npp.2014.147; published online 30 July 2014
INTRODUCTION
Substance use disorders among pregnant women continues
to be a major public health concern, posing risk to the
child’s development, and imposing socioeconomic burdens
on society by increasing needs for medical and social
services. Given the crucial roles for the major protein
targets of drugs of abuse in shaping brain development
(Bhide, 2009; Bonnin and Levitt, 2011; Frederick and
Stanwood, 2009; Hohmann, 2003; Kater and Lipton, 1995;
Lauder, 1993; Money and Stanwood, 2013; Stanwood and
Levitt, 2004), it should not be surprising that fetal drug
exposures have been linked to a wide variety of brain
deficits. In this review, we will focus on: (1) what is
currently known about the likely pattern of substance use
among pregnant or women of childbearing age; (2) the
cellular and molecular pathways by which prenatal drug
exposure may influence structural and functional brain
development; (3) current studies on outcomes of exposed
individuals across various areas of functioning (neurobiol-
ogy, physical growth, intelligence, executive functioning,
behavior, and psychopathology); (4) reviews of current
experimental animal models, and (5) current limitations in
understanding and potential avenues for future research.
While beyond the scope of the current review, untreated
drug abuse/addiction also typically coincides with poor
nutrition and prenatal care, which increases the risk of
obstetric complications and disrupted developmental pro-
cesses in the fetus. Thus, beyond the specific developmental
biology of individual drugs, there are additional common
factors that can produce deficits in neurodevelopmental
trajectories.
Recent data suggest that nearly 25 million Americans aged
12 or older are current illicit drug users; this estimate
represents 9.2 percent of the population. Illicit drugs include
marijuana/hashish, cocaine (including crack), heroin, hallu-
cinogens, inhalants, or prescription-type psychotherapeutics
used non-medically (Substance Abuse and Mental Health
Services Administration, 2013). Current illicit drug use
among pregnant women aged 15–44, has remained constant
at 5.9% despite efforts of prevention and education programs
(Substance Abuse and Mental Health Services Administra-
tion, 2013). In fact, the pattern of rates of current illicit drug
use among young adolescent females has grown to where
they are now more likely than males in their age group to be
current non-medical users of psychoactive drugs.
*Correspondence: Dr GD Stanwood, Department of Pharmacology,
Vanderbilt University, 23rd Avenue South, 476 RRB, Nashville TN 37232-
6600, USA, Tel: +1 615 936 3861, Fax: +1 615 936 2202,
E-mail: gregg.stanwood@vanderbilt.edu
Received 3 March 2014; revised 29 May 2014; accepted 2 June 2014;
accepted article preview online 18 June 2014
Neuropsychopharmacology REVIEWS (2015) 40, 61– 87
&
2015 American College of Neuropsychopharmacology. All rights reserved 0893-133X/15
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Legal drugs such as alcohol and nicotine also represent a
significant hurdle regarding unintended effects on the fetus.
The 2012 NSDUH also found that among pregnant women
aged 15–44, the prevalence of reported current alcohol and
cigarette usage rates has not changed substantially in the
past decade. Although the US population as a whole is
smoking less, the past month cigarette use among pregnant
women aged 15–44 has held at B16–17% over the past
2 years (as compared with 18% in 2002–2003). An annual
average of B8.5% also reports current alcohol use during
pregnancy. As described below, legality of a drug does not
necessarily correlate with its safety profile, and as research-
ers and clinicians, we need better therapies and educational
strategies for pregnant and/or breastfeeding women.
Different drugs and biological processes are often
modeled in different animal species, each with its own
unique developmental timeline (Figure 1) and advantages/
disadvantages. This greatly complicates translatability to
humans. Rodents (mice, rats) and lagomorphs (rabbits) are
born relatively early, as compared with humans, and thus
those offspring must be treated with drugs postnatally if the
aim is to model third trimester human exposure (Figure 1).
However, this omits the transplacental transfer that is
inherent in human fetal drug exposure. Issues of accurate
dose levels, route of administration, and pharmacokinetics/
bioavailability are also often underappreciated in animal
models.
Moreover, drugs can alter fetal development through a
wide variety of mechanisms (Figure 2). For example, if the
drug crosses the placenta (and the vast majority of drugs of
abuse do cross), then it can directly act on its molecular
target in the fetus. Drugs can also act directly on the uterus
and/or placenta. These effects would include altering
placental secretory activity or uteroplacental blood flow,
for example. Finally, the drug can produce effects on the
mother’s physiology that may secondarily influence the
fetus, such as increased secretion of stress hormones or
altered maternal health behaviors attributable to the
mother’s addiction. And although it is beyond our scope
to review it here, it has recently become clear that paternal
exposures, to drugs such as cocaine, during spermatogen-
esis, can also influence offspring brain development and
neurobehavioral development through epigenetic mechan-
isms, at least in animal models (Killinger et al, 2012;
Rodgers et al, 2013; Vassoler et al, 2013). This topic is thus
extremely complicated; nevertheless, we will do our best to
review both animal models and clinical and imaging data
from longitudinal human cohorts following fetal exposure
to specific drugs of abuse.
PSYCHOSTIMULANTS
Methamphetamine
Methamphetamine (METH) is metabolized in rat and
human livers to the main metabolites, amphetamine,
and 4-hydroxymethamphetamine (Caldwell et al, 1972)
(prenatal amphetamine exposure discussed below). Due to
the addition of a methyl group, METH has a higher
lipophilicity than amphetamine, allowing more rapid
transport of the drug across the blood–brain barrier (Barr
et al, 2006). METH has a high potential for abuse and
Prenatal weeks
Prenatal days
Human
(G270)
Macaque
monkey
(G165)
Rabbit
(G31)
Mouse
(G18.5)
Rat
(G21.5)
1st trimester
1st trimester 2nd trimester
2nd trimester
3rd trimester
3rd trimester
24 28
0
012
1310 17
0
123
1512 19 1 2 3
2
2
3
3
4
912 24 38
7 8 15 18 23
13 18
Postnatal weeks
Figure 1. Major neurodevelopmental events across species. Schematic
diagram that aligns human brain development with several animal models
(monkey, rabbit, rat, and mouse) often used in studies of fetal drug
exposure. Note in particular that the rodent equivalent of third trimester
fetal development occurs postnatally.
Prenatal
substance
use
Additional risk markers
(maternal
and paternal age,
education, stressors)
Polypharmacy
exposure
(alcohol, tobacco,
marijuana)
Mental state
• Anxiety
• Depression
• Insomnia
• Memory loss
• Hallucinations
• Abnormal behavior
Increased risk
• Blood, heart, and skin
infections
• Arrhythmias
• Infectious diseases
• Seizures
• Stroke
• Hypothermia
Umbilical cord
• Drugs are passed
directly to fetus
• Tissue can be used to
detect drugs
Mother’s blood
• Increased levels of CO
2
,
CO, and blood pressure
• Anemia
• Pre-eclampsia
Breastfeeding
• Continued exposure
• Decreased prolactin
release and supply
Amniotic fluid
• Possible
accumulation of
intact drugs
Lungs
• Pulmonary edema
• Breathing problems
Uterus
• Premature birth
• Contractions
Placenta
• Vasoconstriction
• Placental insufficiency
• Placental abruption
Figure 2. Biological targets of fetal drug exposures. Drugs of abuse not
only target the developing fetal brain directly, but can exert effects
through a variety of organs with the mother, including the uterus,
placenta, heart, lungs, and brain.
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addiction compared with other amphetamine-type stimu-
lants, affecting the serotonin (5-HT) plasma membrane
transporter (SERT) and activating the psychological reward
system by triggering a cascade of the massive release of
dopamine (DA) in the brain. This release of DA occurs
by multiple mechanisms including: binding to reuptake
transporter (DAT), the displacement of vesicles and
inhibition of monoamine oxidase, and enhancing DAT-
mediated reverse transport of DA transport across the
plasma membrane (Scott et al, 2007). These targets of
METH appear by mid-gestation in the fetal brain (Bhide,
2009; Frederick and Stanwood, 2009; Malanga and
Kosofsky, 1999; Money and Stanwood, 2013).
The use of METH in the United States and in other parts
of the world still remains a serious public health concern.
According to the United Nations, 1.3% of the general
population in Central and North America use ampheta-
mine-type stimulants (UNODC, 2013). There are few studies
that have surveyed the prevalence of METH use among
pregnant women. The only large-scale investigation to
report METH prevalence for pregnant women has been the
Infant Development, Environment, and Lifestyle (IDEAL)
study. They found that B5% of women self-reported METH
use during their pregnancy (Arria et al, 2006) in areas of the
United States where METH use was of high concern.
Furthermore, over 40% of the women enrolled in the IDEAL
study continued using the drug during their third trimester,
and approximately half did not significantly change their
personal use during the course of the pregnancy (Della
Grotta et al, 2010).
Despite the fact that METH has been utilized by pregnant
women for many years, relatively little is known about
the effects of METH during early infancy and even less is
known about the long-term effects. The most common
effects noted in newborns indicate that METH use is
associated with growth restriction, decreased weight, length,
and head circumference (Little et al, 1988; Nguyen et al,
2010; Smith et al, 2003; Smith et al, 2006b). Echoencepha-
lography has revealed congenital anomalies in exposed
neonates include cardiac anomalies, cranial abnormalities,
and abnormal brain development closely resembling those
in ill, asphyxiated infants (Dixon and Bejar, 1989). Mild
withdrawal symptoms have also been noted in newborns
(Oro and Dixon, 1987; Smith et al, 2003), although these
symptoms are not as common. In animal models, increased
DNA oxidation and postnatal functional deficits in motor
coordination were documented in neonatal METH-exposed
mice (Jeng et al, 2005).
Several recent studies have examined the effects of METH
exposure on childhood growth patterns and behavior after
birth. Focusing on physical growth patterns, Zabaneh et al
(2012) found children exposed prenatally to METH have a
modest decrease in height during the first 3 years of life
with no observed difference in weight, head circumference,
or weight-for-length trajectories. Prenatal METH exposure
also is associated with significantly reduced caudate nucleus
volume and cortical thickness increases in perisylvian and
orbital–frontal cortices (Derauf et al, 2012; Zabaneh et al,
2012). Diffusion tensor imaging (DTI) suggests lower
diffusion and higher fractional anisotropy in METH-
exposed children at 3–4 years of age, indicating that fetal
METH may alter white matter tracts (Cloak et al, 2009).
In a magnetic resonance spectroscopy (MRS) study,
METH-exposed 3–4 year-old children exhibited higher total
creatine, N-acetyl compounds, and glutamate þglutamine
concentrations in the frontal white matter, but lower
myoinositol and myoinositol/creatine in the thalamus
(Chang et al, 2009). The higher metabolite concentrations
of N-acetyl compounds, total creatine, and glutamate þ
glutamine suggest a higher neuronal density or cellular
compactness in the white matter, whereas lower myoinositol
suggests lower glial content in the thalamus. Furthermore,
the METH-exposed children performed significantly worse
on a visual motor integration task, which correlated with
lower myoinositol in the thalamus (Chang et al, 2009).
In another magnetic resonance imaging (MRI) study on
children ranging from 3 to 16 years of age, exposed
children scored lower on measures of visual motor
integration, attention, verbal memory, and long-term spatial
memory. There were no differences among the groups in
motor skills, short delay spatial memory, or measures of
nonverbal intelligence. Despite comparable whole brain
volumes in each group, the METH-exposed children
appeared to have subtle but significant decreases in size
or volume in certain brain regions, including the putamen,
globus pallidus, and hippocampus. These reductions
correlated with poorer sustained attention and delayed
verbal memory (Chang et al, 2004). It is important to note
that although the study had an impressive age range, sample
sizes were limited.
Concentrating on long-term motor skills after birth,
Smith et al (2011) observed a subtle METH exposure effect
on fine motor performance at 1 year, with the poorest
performance observed in the most heavily exposed children.
However, by 3 years of age, no differences in fine motor
performance were observed. These findings suggest METH
exposure has modest motor effects in the first year of life,
but that this may be mostly resolved by 3 years of age. The
IDEAL study found that prenatal METH exposure was
associated with child externalizing behavioral problems at
5 years and parenting stress and psychological symptoms
experienced by primary caregivers were associated with
increased child behavioral problems; indicating these
effected children may have more difficulties negotiating
the increasing complex academic and social demands of
school-age children (LaGasse et al, 2012; Twomey et al,
2013).
Animal models may give us insight and provide correla-
tion to these studies examining the effects of prenatal
METH exposure and if these effects will remain into
adulthood. Results from mouse exposure to METH during
a time period equivalent to the third trimester of human
fetal gestation (see Figure 1) impaired weight gain, reduced
novel location recognition, and impaired novel object
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recognition in both male and female mice during adoles-
cence. In rats, neonatal exposure to METH produces deficits
in latency and memory in a Morris water maze (Vorhees
et al, 2000). Both prenatal and neonatal exposure also
caused impaired spatial learning (Slamberova et al, 2005;
Williams et al, 2003b; Williams et al, 2003d; Williams et al,
2002) and neonatal exposure altered the adrenal response to
a forced swim stressor, suggesting that the adrenal output
during learning may contribute to the spatial learning
deficits (Williams et al, 2003a). Rats exposed to METH
in utero showed changes in the mesolimbic dopaminergic
system and were more sensitive to the administration of
the acute dose of METH in adulthood (Bubenikova-
Valesova et al, 2009). This indicates that offspring exposed
to METH in utero could be more sensitive to METH
and potentially to other psychostimulants (Bubenikova-
Valesova et al, 2009).
Although relatively little is known about the effects of
METH during early infancy or the following long-term
effects, recently there have been studies attempting to
examine children exposed to METH in utero. Further
studies are important to aid in prevention programs and
treatment for these individuals. Comparing the effects of
prenatal METH exposure on infant and childhood growth
between the United States and New Zealand demonstrated
that the effects of prenatal METH differed across countries
(Abar et al, 2013). In the study, the prenatal METH-exposed
children in New Zealand fared better than exposed children
in the United States. In addition, according to the United
Nations, 1.3% of the general population in Central and
North America use amphetamine-type stimulants (UNODC,
2013). This reported use is at higher levels than the global
average of 0.7% of the general population (UNODC, 2013).
These studies suggest that the United States needs improved
prevention programs, better pre- and postnatal treatments,
and caregiver support for this exposed population.
Amphetamine
Amphetamines (alpha-methyl-phenethylamine) (AMPH),
commonly known as ‘Speed’, continue to be widely used
by women of childbearing age. The users are either legally
prescribed AMPHs for medical reasons or are nonmedical
users. For example, attention deficit hyperactivity disorder
(ADHD) affects B5% of adults (Fayyad et al, 2007) in the
United States. Although ADHD is less common in females
than males, a significant percentage of women of child-
bearing age are thus likely prescribed AMPH or other
stimulants as a treatment for ADHD. The prevalence of
women of childbearing age using non-medical AMPH is
currently unknown, and even less is known about the
frequency of use during pregnancy. Further studies are
required to determine the true frequency of illegal AMPH-
exposed pregnant and lactating women, so that appropriate
care can be provided for mother and her family.
After prenatal exposure, AMPH has been detected in
human umbilical cord (Jones et al, 2009), plasma (Dearlove
and Betteridge, 1992), and placenta as early as the first
trimester (Joya et al, 2010). The cellular actions of AMPH
are nearly identical to METH (see section above), including
increasing the levels of norepinephrine (NE), DA, and 5-HT
in the synaptic cleft via transporter reuptake inhibition.
This increased availability allows the monoamines to act
upon post-synaptic receptors. The use of AMPHs during
pregnancy increases the risk of adverse effects on the
outcome of pregnancy, such as placental hemorrhage
(Figure 2). This is mediated, at least in part, by stimulation
of contractions in the uterus and by targeting NET and
SERT in the human placenta (Cordeaux et al, 2008;
Ramamoorthy et al, 1995). These actions have been
hypothesized to contribute to preterm labor associated
with AMPH exposure (Cordeaux et al, 2008). To date, fetal
AMPH exposure has not been proven to be directly
teratogenic; however, in primary human cell cultures,
AMPH reduced folic acid uptake and this could potentially
lead to placental and/or fetal toxicity (Keating et al, 2009).
Animal studies revealed at a prepubertal age, an enhance-
ment of D1 receptors in the dorsal striatum and nucleus
accumbens (NAc) and a decrement of the D3 receptors
in NAc, olfactory tubercle, and the islands of Calleja. In
contrast, at a postpubertal age, the authors instead
measured an increase in the levels of DAT in the NAc and
striatum, and a decrease in D2 receptor expression in the
NAc shell. In addition, acute AMPH induces a marked
decrease in locomotor activity in rats following prenatal
AMPH exposure (Flores et al, 2011). These developmental
and behavioral changes in animal models associated with
in utero AMPH exposure provide insights to the mechan-
isms causing changes in affective, behavioral, and cognitive
outcomes in exposed children.
A meta-analysis of 10 studies of low-to-moderate risk
of bias submits that AMPH exposure in pregnancy is
associated with higher odds of preterm birth, low birth
weight, and small size for gestational age (Ladhani et al,
2011). Birth weight as a continuous variable was also found
to be significantly lower among exposed women. Gesta-
tional age, however, was not found to be significantly
different (Ladhani et al, 2011). The most extensive follow-
up data on affective, behavioral, and cognitive outcomes
following prenatal AMPHs are provided by Swedish
researchers who tracked a cohort of 65 AMPH-exposed
children from birth to age 14. They reported in children
with continuous AMPH exposure throughout gestation, a
variety of adverse physical, cognitive, emotional, and social
effects, including increased prevalence of ADHD, aggres-
sion, and learning difficulties attributed to deficits in
attention, memory, and motivation (Eriksson et al, 1994;
Eriksson et al, 2000). Furthermore, a relationship between
head circumference at birth and at 1 year of age predicted
language and mathematics proficiency at 14 years of age
(Eriksson et al, 2000). As with its parent drug METH,
further studies on prenatal AMPH exposure is needed
to better understand effects from prescribed AMPHs or
non-medical users (Oei et al, 2012).
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3,4-Methylenedioxymethamphetamine
3,4-Methylenedioxymethamphetamine (MDMA), commonly
known as Ecstasy, is a derivative of AMPH that has both
stimulant and hallucinogenic properties. It acts as a powerful
releasing agent of 5-HT, NE, and DA and also acts as a
reuptake inhibitor of their high-affinity transporters (de la
Torre et al, 2004; Rudnick and Wall, 1992). MDMA is actively
transported through the plasma membrane and can then
inhibit the vesicular monoamine transporter, resulting in
increased concentrations of 5-HT, NE, and DA in the
cytoplasm. MDMA can also directly bind a number of
receptors with moderate affinity, including a2-adrenergic
(adrenaline) and 5-HT2A receptors (de la Torre et al, 2004).
A single MDMA injection to pregnant rat dams results in
MDMA transfer into the fetal compartment (Campbell et al,
2006). However, emerging data also suggests key roles for
maternal and placental 5-HT in regulating brain development
(Bonnin et al, 2011; Bonnin and Levitt, 2011) (Figure 2).
In the United States, data from the 2012 National Survey
on Drug Use and Health estimate that about 6.2 percent
of individuals aged 12 or older had used Ecstasy at least
once in their lifetime. In addition, B900 000 individuals
tried Ecstasy for the first time in 2012. Although data from
pregnant women was not presented, the prevalence of at
least once in lifetime Ecstasy use in 2012 saw a significant
increase from past-year use, and past-year use for eighth
through twelfth graders remained stable (UNODC, 2013).
To date, there are only a few studies examining prenatal
exposure to MDMA in humans, despite concerns about
its potential harmful effects to the fetus (Ho et al, 2001;
McElhatton et al, 1999; Singer et al, 2012; van Tonningen-
van Driel et al, 1999). Very little is known about the
characteristics of pregnant women who use Ecstasy. Using
data collected regarding women contacting the Motherrisk
Helpline in Toronto (Ho et al, 2001), MDMA users tended
to be younger, single, Caucasian, binge drinkers, and had
a higher prevalence of psychiatric symptoms. Most of these
users discontinued MDMA once pregnancy was known,
but because the recruitment was based on contact initiated
by the mothers, the sample likely overrepresented more
‘motivated’ women. The few available studies demonstrate
that pregnant MDMA users exhibit a clustering of repro-
ductive risk factors that contribute to neurobehavioral and
teratological outcomes. A retrospective report of 136 babies
exposed to Ecstasy in utero noted premature births,
a significantly increased risk of congenital defects, cardio-
vascular anomalies, and musculoskeletal anomalies
(McElhatton et al, 1999). Another study in the Netherlands
reported congenital cardiac malformation and spontaneous
abortions (van Tonningen-van Driel et al, 1999). A recent
neurobehavioral outcome study suggests that prenatal
MDMA exposure predicts poorer infant mental and motor
development at 4 and 12 months of age in a dose-dependent
manner (Singer et al, 2012).
Only a handful of animal models of pre- and perinatal
MDMA exposure have been developed as well. A rat study
of prenatal MDMA exposure (E14–E20) described increases
in dopaminergic fibers in the prefrontal cortex, striatum,
and NAc—areas critical in novelty responses, reward,
attention, and motor behavior (Thompson et al, 2009b). It
also appears to increase NE fiber density in the prelimbic
region of the prefrontal cortex and in the hippocampus
(Thompson et al, 2012).
Further studies suggest that developmental MDMA,
particularly during a time analogous to the early third
trimester, can produce persistent reductions in DA and
5-HT metabolites (Koprich et al, 2003a; Koprich et al,
2003b). Meyer et al (2004) determined that MDMA
exposure from P1 to P4 can decrease 5-HT levels in the
hippocampus on P25 and P60, and suggested that MDMA
treatment stimulates apoptotic cell death during early
postnatal development. Significant reductions in 5-HT fiber
density were observed in the cerebral cortex with a
hyperinnervation in the caudate–putamen and NAc in 9–
month-old animals, demonstrating enduring effects (Meyer
et al, 2004). The early hippocampal changes were not
observed in adulthood, suggesting a recovery of damaged
serotonergic fibers following neonatal exposure. The Meyer
lab further demonstrated that developmental MDMA
administration can lead to long-lasting functional abnorm-
alities including enhanced sensitivity to the drug later in life
(Piper et al, 2009; Piper and Meyer, 2006).
Other studies have shown few effects of MDMA exposure
in developing animal models. This could possibly be
because of time period of treatment—embryonic versus
postnatal—or doses (once again, please see Figure 1 for a
description of human and animal development timelines).
For example, when rats were exposed to MDMA twice a day
from E12 to E15, no differences were seen in hippocampal
levels of 5-HT, DA, NE, or metabolites when assayed on P21
(Winslow and Insel, 1990). In addition, no changes in 5-HT
or DA levels in various brain regions were observed in rat
offspring whose mothers were exposed to 20 mg/kg MDMA
once per day every other day beginning at E6 until birth
(Aguirre et al, 1998).
As adults, prenatal MDMA-exposed rats exhibit increased
activity, risk-taking behavior, and altered spatial learning;
however, it did not affect their feeding or food reward,
or alter cocaine self-administration behaviors or locomotor
responses (Thompson et al, 2009b). Neonatal administra-
tion of MDMA also produces impaired path integration
learning (Broening et al, 2001; Vorhees et al, 2004; Williams
et al, 2003c). Neonatal MDMA exposure alters the release of
DA and 5-HT at P70 in the striatum and hippocampus, and
reduces sucrose preference (an index of reward systems) at
P70 (Galineau et al, 2005).
The detailed mechanisms through which prenatal/peri-
natal MDMA exposure produces alterations in neurodeve-
lopmental trajectory are thus not fully understood. Heavier
use has been associated with impaired motor and intellec-
tual development in infants, but whether there are
long-lasting changes in neurobehavioral outcomes is not
yet known. A major concern is possible serotonergic
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dysfunction produced by repeated and/or high doses of the
drug. A recent animal report suggests that that the simul-
taneous abuse of alcohol and Ecstasy during pregnancy,
even for short periods of time, may cause much more
significant abnormalities in neurocognitive development than
either drug alone (Canales and Ferrer-Donato, 2014). Given
the widespread recreational use of MDMA (Ecstasy), pregnant
women should be cautioned about possible developmental
effects in offspring. Animal models need to be designed to
include relevant doses and human developmental periods to
best ascertain the developmental effects of MDMA (for an
excellent review, see Skelton et al (2008)).
Cocaine
Currently the percentage of women of childbearing age
consuming cocaine is unknown and less information is
known about the current frequency of use during preg-
nancy. According to the latest figures from (UNODC, 2013),
cocaine was the third largest abused illicit drug (Substance
Abuse and Mental Health Services Administration, 2013)
within the past year. Among women ages 12 and older,
including women of childbearing age, 0.3% were current
users of cocaine (Substance Abuse and Mental Health
Services Administration, 2013). Thus, cocaine use in women
continues to be a major public health concern. It has been
noted that prenatal cocaine exposure alone accounts for
over 26 million dollars per year in special education services
in the United States (Levine et al, 2008).
Studies of cocaine in animal models, using a variety of
species, have demonstrated cocaine easily crosses both the
placenta and blood–brain barrier and can have teratogenic
effects on the developing fetus (Mayes, 1994). The negative
outcomes and effects from neonatal exposure to cocaine
can result from the pathophysiology originating from
three possible pathways; first, cocaine directly inhibits
the reuptake of multiple monoamines at the presynaptic
junction, leading to increased concentrations of DA, 5-HT,
and NE within the synaptic cleft. Also, neonatal cocaine
exposure has been attributed to indirect vasoconstrictive
effects and higher levels of activation in the catecholami-
nergic system (Nassogne et al, 1998). In addition to the
neurochemical and vascoconstrictive effects of cocaine on
fetal development, cocaine may also act by altering genetic
programming (Lester and Padbury, 2009).
Clinical reports of the impact of prenatal cocaine have
been varied; some suggest global and severe physical
malformations, others document specific deficits in physi-
cal, cognitive, and emotional development, and yet other
studies indicate no effects. It is important to note that the
magnitude of these effects depend upon the dosage,
gestational timing, duration of exposure, and/or postnatal
care. Some of the disparities in the human literature arose
from the problem that many of the early studies were poorly
controlled and produced media hysteria around so-called
‘crack babies’. Nevertheless, well-controlled studies have
demonstrated that prenatal cocaine exposure does in fact
affect fetal physical growth, and results in an increase of
premature birth, and generalized growth retardation—
including decreased birth weight, shorter body length, and
smaller head circumference (Bigsby et al, 2011; Covington
et al, 2002; Gouin et al, 2011; Mayes et al, 2003). Abnormal
infant behavioral outcomes have also been documented;
these outcomes include abnormalities related to lower
arousal, poorer quality of movement and self-regulation,
higher excitability, jitteriness, and more non-optimal
reflexes (Lester et al, 2002; Richardson et al, 2008; Singer
et al, 2000; Tronick et al, 2005). Studies have revealed that
the behavioral outcomes observed at birth continue and
sometimes worsen after 12 months of age (Bigsby et al,
2011; Chiriboga et al, 2007; Mayes et al, 2003; Richardson
et al, 2008).
Growth restriction among prenatal cocaine exposure
children has been documented to continue well past infancy
(Minnes et al, 2006) and may persist in children as old as 10
years of age (Covington et al, 2002; Richardson et al, 2013).
While consistency exists in the reports of reduced fetal
growth and development, some follow-up studies at later
ages have suggested catch-up growth. Shankaran et al
(2011) found that children exposed to prenatal cocaine were
similar in weight to non-exposed children at 6 years of age.
Interestingly, children who had been exposed to high levels
of prenatal cocaine, and were born full-term, were reported
to have a higher body mass index and blood pressure
changes. These variable outcomes of prenatal cocaine
exposure on physical growth and development are in part
the result of important covariates such as amount of drug
use and timing throughout pregnancy. Other possible
variables are disturbances in physiological regulation, such
as the respiratory sinus arrhythmia and cardiac develop-
ment (Finger et al, 2014). Studies in animal models also
provide evidence for a programming effect resulting in
detrimental long-term changes to the heart induced by
fetal cocaine exposure (Meyer and Zhang, 2009). Overall,
additional long-term follow-up studies of children with
neonatal cocaine exposure and its effects on health
outcomes are needed to help identify mechanisms that
result in abnormal growth and development.
Although prenatal cocaine exposure alone does not
appear to lower global intelligence, there is consistent
evidence of poor cognitive performance in language skills,
behavior, and executive functioning. Longitudinal studies
have reported that prenatal cocaine is associated with
impaired language development through early adolescence
(Bandstra et al, 2011; Lewis et al, 2007; Lewis et al, 2011).
However, some studies suggest a general improvement in
receptive language starting in adolescence through age 17
(Betancourt et al, 2011). Furthermore, adoption or foster
care appears to enrich the children’s linguistic environment
and helps to protect children against some language delays
(Lewis et al, 2011).
Long-term studies have described varying effects on
executive function in exposed children. Executive function
is a set of mental processes for the management of cognitive
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operations that include attention, behavior, cognition,
working memory, and information/problem solving.
Richardson et al (2013) found that first trimester cocaine
exposure has been associated with less sociability, more
withdrawn behavioral problems, more anxious/depressed
behaviors and symptoms in the children. These behaviors
may be precursors of later psychiatric problems. By
caregiver reports, higher cocaine use was associated with
disruptive behaviors including aggression and delinquent
behavior at 9 years of age (McLaughlin et al, 2011).
Moreover, caregiver reports indicate overall issues of
executive function in 12 year-old children with higher
amounts of prenatal exposure; in particular, females had
greater problems with initiation activities, working mem-
ory, and organization (Minnes et al, 2014). Carmody et al
(2011) further documented cocaine exposure affected
the attention and inhibitory control performance of
males, but not females, in children at ages 6, 9, and 11.
The neurobiological mechanisms leading to gender-depen-
dent differences in disrupted executive function following
prenatal cocaine are not currently understood; however,
this is an important consideration for future investigation.
These longitudinal studies have described varying effects
on executive function in exposed children; however, it is
also important to know the structure, function, and
pharmacology of the brain that is possibly being altered
by the drug exposure. Neuroimaging—for example, struc-
tural MRI, functional magnetic resonance imaging (fMRI)
and DTI—is valuable in examining the underlying neural
circuitry and connectivity. Recent reports describe long-
term structural alterations in brain regions such as cortical
and limbic regions (Rando et al, 2013). Lower fractional
anisotropy in the right arcuate axons and higher mean
diffusivity in the splenium of the corpus callosum has also
been observed (Lebel et al, 2013). Cortical thickness of the
right dorsolateral prefrontal cortex appears to be thinner in
adolescents following prenatal cocaine (Liu et al, 2013), and
cocaine-exposed adolescents have reduced ventral prefron-
tal cortex activation in response to increased memory load.
Reduced structural connectivity between the ventral pre-
frontal cortex and the amygdala was also observed through
DTI measurements (Li et al, 2013).
Overall, fetal cocaine exposure can affect fetal and long-
term growth patterns, as well as cause language deficits,
behavior defects, and executive functioning abnormalities.
Animal models, across multiple species, give us further
insight on the pathophysiological mechanisms that are
possibly occurring during the developmental changes and
are not accessible to study in vivo. Animal models confirm
that prenatal cocaine exposure results in specific and long-
lasting behavioral, cellular, and molecular changes (Bhide,
2009; Dow-Edwards, 2011; Harvey, 2004; Lidow et al, 2003;
Mactutus et al, 1994; Malanga and Kosofsky, 1999; Mayes,
2002; Stanwood and Levitt, 2004). Moreover, animal models
of prenatal exposure have disrupted cortical neurogenesis
and migration during and after birth, reduction of neuronal
numbers and density in the cortex, and differences in
dopaminergic function (Crandall et al, 2004; Hamilton et al,
2010; McCarthy and Bhide, 2012; McCarthy et al, 2012;
Ren et al, 2004). Specific anatomical defects include aberrant
growth of dendrites of cortical projection and interneurons,
suggesting disruption of local circuitry, and behavioral
abnormalities that involve learning and stereotypic motor
behavior (Mayes, 2002; Stanwood et al, 2001b; Thompson
et al, 2005). Data suggest that the equivalent of the second
trimester may be the most ‘sensitive period’ for the actions
of fetal cocaine (Stanwood et al, 2001a). Alterations in the
fetal development of the monoaminergic system can affect
short- and long-term attention and cognitive development.
Perhaps a point of origin for the disturbances from the
effects of cocaine is the reduction of the coupling of the D1
receptor to its G protein-coupled receptor (Jones et al, 2000;
Stanwood et al, 2005; Zhen et al, 2001). This uncoupling is
sustained into adulthood and is specific for D1 receptors.
Behavioral changes in response to cocaine exposure have
also been reported in multiple animal models, including
deficits in attention and emotional reactivity (Gabriel et al,
2003; Garavan et al, 2000; Harvey et al, 2001; Morrow et al,
2002a, b; Stanwood and Levitt, 2003; Thompson et al, 2005;
2009a). These findings correspond with the human clinical
literature, which reports disturbances in both attention
and emotion regulation in children exposed prenatally to
cocaine. Gestational cocaine also increases the sensitivity to
the conditioned rewarding effects of cocaine in male rats and
modestly affected females (Dow-Edwards et al, 2014),
indicating alterations in the development of reward circuits.
This brief discussion of prenatal exposure to cocaine
clearly emphasizes the complexity of determining the
pathophysiological mechanisms and associated risk factors.
Given the consistently large number of affected individuals,
there is a constant need for furthering research and medical,
mental health, and educational services for this impacted
population.
OPIOIDS
Opiate receptors are G protein-coupled receptors and fall
into three groups: mu, delta, and kappa. In situ hybridiza-
tion of the adult rat brain identified mRNA for all three
receptors throughout the central nervous system as well as
numerous peripheral tissues (Wittert et al, 1996). Opioid
receptor expression (Barg and Simantov, 1989; Lenoir et al,
1984) and endogenous opioid concentrations in the fetus
and neonate differ from that in adults (Barg and Simantov,
1989). Thus, administration of opiates in utero may have
more distinctive effects compared with adult exposure
(Pertschuk et al, 1977).
Illicit opiate use has been steadily increasing in the past
decade and a large part of this increase is in the 18–25 age
bracket, which includes women of reproductive age
(Substance Abuse and Mental Health Services Admin-
istration, 2013). The probability of preeclampsia, premature
labor and rupture of membranes, placental insufficiency,
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abruptio placentae, intrauterine growth retardation, and
intrauterine death increases greatly with illicit opiate use
during pregnancy (Bashore et al, 1981; Hulse et al, 1998;
Kaltenbach et al, 1998). Even with a successful labor and
delivery, neonates often have low birthweight and smaller
head circumference as well as experience symptoms of
opiate withdrawal (Binder and Vavrinkova, 2008; Hunt et al,
2008; Kandall et al, 1976). Some clinical studies have also
suggested an increased prevalence of heart defects, auto-
nomic dysregulation (Paul et al, 2014), nystagmus (Gupta
et al, 2012), and strabismus (Gill et al, 2003) in children
exposed prenatally to opiates. At the pre- and elementary
school ages, these children show motor and cognitive
impairments (Bunikowski et al, 1998; Guo et al, 1994; Hunt
et al, 2008), inattention (Hickey et al, 1995; Ornoy et al,
1996), hyperactivity (Ornoy et al, 1996), and an increase in
ADHD when exposed prenatally to heroin (Ornoy et al,
2001). The damage of prenatal opiate exposure is debilitat-
ing and long lasting, and physicians must continue to track
cohorts of exposed children to further understand the
impact into adulthood.
Similar to human clinical studies, rodents exposed to
heroin or morphine have a lower birthweight (Eriksson and
Ronnback, 1989; Lu et al, 2012; Zagon and McLaughlin,
1977b, c) and impaired learning and memory (Steingart
et al, 2000a; Wang and Han, 2009). Numerous structural
and functional alterations have been found that could
underlie the effects of prenatal opiates on cognition,
including perturbations in dendritic length, synaptic
plasticity, neuronal proliferation, and cholinergic function.
Prenatal heroin or morphine exposure decreases dendritic
branch length in layer II/III pyramidal neurons in
somatosensory cortex, which is thought to be specific to
opiate receptor activation, as it can be blocked by co-
administration of an opiate receptor antagonist (Lu et al,
2012; Ricalde and Hammer, 1990). Long-term potentiation,
long-term depression, and proteins associated with synaptic
transmission are all attenuated with perinatal morphine
exposure (Villarreal et al, 2008; Yang et al, 2006). Decreased
proliferation in the developing striatum (Harlan and Song,
1994) and increased apoptosis in dopaminergic cell cultures
and the hippocampus have been observed with perinatal
heroin or morphine exposure (Oliveira et al, 2003; Oliveira
et al, 2002; Svensson et al, 2008; Wang and Han, 2009).
The Yanai lab has provided substantial evidence to
suggest that the deficits in spatial learning and memory
may be tied to hippocampal cholinergic alterations. They
found increased hippocampal levels of a cholinergic
receptor (muscarinic M1 receptor) and the choline trans-
porter with perinatal heroin (Steingart et al, 2000a; Steingart
et al, 2000b). In addition, they observed altered levels and
activity of protein kinase C—a signaling protein down-
stream of the M1 receptor- and enhanced inositol
phosphate induction by cholinergic agonists (Steingart
et al, 2000a; Steingart et al, 2000b; Yaniv et al, 2004).
Whether a cholinergic deficit is found in cohorts of opiate-
exposed children is unknown.
Perinatal heroin and morphine exposure also disrupt
maturation of the opiate receptor system. Postnatal
morphine exposure decreases mu opioid receptor binding
in the striatum, NAc, amygdala, hypothalamus, and spinal
cord (Hammer et al, 1991; Kirby, 1983; Tempel, 1991).
Perinatal morphine exposure also induces morphine
tolerance (Chiang et al, 2010; Eriksson and Ronnback,
1989; Hovious and Peters, 1984), although an increased
sensitivity to morphine analgesia has been reported in
female offspring (Arjune and Bodnar, 1989). Aroyewun and
Barr (1982) proposed that postnatal morphine also accel-
erates the maturation of some aspects of opiate-dependent
behaviors, such as opiate antagonist-induced anorexia, that
normally only occurs after P14. Postnatal morphine
exposure accelerated the appearance of this behavior to
P10 and 12 (Aroyewun and Barr, 1983), but the observed
hypophagia could also have been induced by the precipita-
tion of opiate withdrawal. In addition, perinatal morphine
or heroin has also been shown to alter sexual behavior
(Vathy and Katay, 1992), NE turnover and release (De Vries
et al, 1991), neuroendocrine function (Litto et al, 1983), and
several other important structures and processes that this
review cannot cover (for a comprehensive review of the
developmental effects of illicit opiates see Slamberova
(2012)).
Opiate Maintenance Therapies
The American Academy of Pediatrics and American College
of Obstetricians and Gynecologists recommend opioid
maintenance therapy as the first line of treatment for
opioid dependence during pregnancy (ACOG Committee,
2012). Untreated illicit opiate use is associated with poor
prenatal care, nutrition, and fetal health, which is improved
with opioid maintenance therapy (Binder and Vavrinkova,
2008; Kandall et al, 1976; Maas et al, 1990). Initiation of
an effective opioid maintenance therapy facilitates better
prenatal care, decreased illicit use of opiates and other
drugs, and a continuous dosing regimen that prevents
maternal/fetal withdrawal. Opiate withdrawal is not recom-
mended during pregnancy unless the mother refuses opiate
maintenance therapy due to increased likelihood of relapse
(ACOG Committee, 2012). Animal studies have demon-
strated in utero withdrawal to increase fetal activity and
perinatal mortality (Kirby and Holtzmann, 1982; Kuwahara
and Sparber, 1981; Lichtblau and Sparber, 1981).
Opioid maintenance therapies are not without substantial
risk, as they can cross the placenta and alter development.
Withdrawal from illicit or prescribed opiates incites Neo-
natal Abstinence Syndrome in neonates, which often requires
treatment with morphine, diluted tincture of opium, or
methadone with or without diazepam (Finnegan et al,1975;
Jansson et al,2009). However, incidence, peak severity
score, duration, and length of required hospital stay due to
Neonatal Abstinence Syndrome symptoms are less severe in
neonates born to women following medically controlled
maintenance therapies compared near-term mothers still
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using illicitly (Binder and Vavrinkova, 2008; Kandall et al,
1976; Maas et al, 1990).
Methadone
Methadone is considered the current gold standard opioid
maintenance therapy for pregnant women. It is a long-
acting full mu opioid receptor agonist that is distributed as
a daily dose only at licensed methadone clinics; allowing a
tightly regulated, appropriately titered dosing regimen, and
decreased abuse. Even though methadone reduces symp-
toms compared with illicit opiate use, clinical cohorts have
demonstrated that prenatal methadone exposure can lead to
increased premature birth (Cleary et al, 2012; Fajemirokun-
Odudeyi et al, 2006; Lejeune et al, 2006), decreased
birthweight (Cleary et al, 2012; Hulse et al, 1997; Kandall
et al, 1976; Sarfi et al, 2009; van Baar et al, 1994), and
smaller head circumference (Brown et al, 1998; Hans, 1989;
Rosen and Johnson, 1985; van Baar et al, 1994; Welle-Strand
et al, 2013; Wilson et al, 1981). Additional reports indicate
an increased incidence of respiratory insufficiency at birth
(Maas et al, 1990), altered corrected QT interval on
electrocardiogram during the first postnatal week (Parikh
et al, 2011), postnatal hyperphagia (Martinez et al, 1999),
disrupted auditory event related potentials (Paul et al,
2014), and myelination deficits (Walhovd et al, 2012).
However, the prevalence of cognitive impairments pro-
duced by prenatal methadone has been questioned because
some studies have not observed differences in cognitive
development (de Cubas and Field, 1993; Hans, 1989; Rosen
and Johnson, 1985) or performance (Bauman and Levine,
1986; Soepatmi, 1994; van Baar, 1990; van Baar and de
Graaff, 1994; van Baar et al, 1994). These variations may be
in part due to socioeconomic status and other variables
(Hans, 1989).
In clinical studies of opiate maintenance therapies, we are
aware of the prenatal opiate exposure dose, which allows
researchers to mimic physiologically relevant plasma
concentrations of the drug. Most animal studies do not
measure plasma concentrations, but variations in dose and
method of delivery are common issues in prenatal exposure
studies. Despite these differences, fairly consistent altera-
tions have been seen with prenatal methadone exposure
in animals. Similar to models of perinatal heroin and
morphine exposure, perinatal methadone exposure leads to
decreased birthweight (Enters et al, 1991; Ford and Rhines,
1979; McLaughlin et al, 1978; Zagon and McLaughlin, 1977a;
1983), mu opioid receptor binding (Hou et al, 2004),
hyperactivity (Hutchings et al, 1992) and reduced perfor-
mance on learning and memory tasks (Vargas et al, 1975;
Zagon and McLaughlin, 1979; Zagon et al, 1979). Decreased
brain and cerebellar weight and brain DNA content (Ford
and Rhines, 1979; McLaughlin et al, 1978; Zagon and
McLaughlin, 1977a; 1983) as well as cortical thickness (Ford
and Rhines, 1979) have also been seen. Zagon and
McLaughlin (1982) found reduced cerebellar area and
decreased number and density of internal granular neurons
in the cerebellum with perinatal methadone exposure.
A delay of developmentally timed behaviors was reported
by the same group (Zagon and McLaughlin, 1978).
Consistent with the cardiac abnormalities in neonates
by Parikh and colleagues, rodent perinatal methadone
exposure delays cellular development of the heart evident
by altered levels of polyamines (Slotkin et al, 1982).
Alterations in the levels and/or activity of multiple
neurotransmitter systems occur with perinatal methadone
exposure. Studies have shown decreased hippocampal NE
(Robinson et al, 1997), and disrupted striatal cholinergic
activity compared with controls (Guo et al, 1990; Robinson,
2002; Robinson et al, 1996; Robinson and Wallace, 2001).
McGinty and Ford found decreased DA in the forebrain
at P1 and P20 in methadone-exposed rodents (McGinty
and Ford, 1980). Prenatal only methadone exposure may
decrease striatal DA turnover whereas combined pre- and
postnatal exposure appears to increase it (Robinson et al,
1996). However, postnatal methadone exposure was
required to decrease DA turnover in the frontal cortex
(Robinson et al, 1997), which paints a complex picture of
altered DA neurotransmission in perinatal methadone
exposure. The 5-HT system shows irregularities in the
transport system in the cortex and hippocampus
(De Montis et al, 1983) and increased basal levels in the
parietal cortex with perinatal methadone (Robinson et al,
1997). Additional disruptions in monoamine oxidase B
levels (Tsang et al, 1986), METH sensitization (Wong et al,
2014), and startle response (Hutchings et al, 1993;
Zmitrovich et al, 1994) also have implications for cognition
and addiction vulnerability.
Buprenorphine
Buprenorphine is a partial mu opioid receptor agonist and
a kappa opioid receptor antagonist that is given as an
outpatient opioid maintenance therapy. Buprenorphine is
not currently the recommended prenatal opioid mainte-
nance therapy in the United States, although it is widely
used elsewhere. A recent review of double-blind rando-
mized control trials found insufficient evidence to recom-
mend buprenorphine over methadone during pregnancy
(Minozzi et al, 2013). This recommendation was largely
based on a slightly superior retention of pregnant women
in maintenance therapy with methadone, although bupre-
norphine may produce less severe neonatal abstinence
syndrome (Minozzi et al, 2013). The American College of
Obstetricians and Gynecologists has urged that buprenor-
phine be considered first-line treatment, but methadone
is likely still the gold standard due to slightly higher
adherence, more tightly controlled dosing, and insufficient
evidence that buprenorphine is superior than methadone
treatment (ACOG Committee, 2012). Observation of clinical
cohorts has suggested that prenatal buprenorphine may
produce fewer neurobehavioral problems (Coyle et al,
2012), higher birthweight, and larger head circumference
compared with methadone (Welle-Strand et al, 2013).
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Several studies have found no difference in growth patterns
between buprenorphine-exposed and non-exposed neonates
(Bakstad et al, 2009; Fischer et al, 2000; Schindler et al,
2003; Sundelin Wahlsten and Sarman, 2013). Yet, hyper-
activity, visual/motor impairment, and memory problems
(Sundelin Wahlsten and Sarman, 2013) as well as an
increase in premature birth compared with non-exposed
neonates have been observed. Therefore, although there are
still developmental perturbations observed with prenatal
buprenorphine, the risk to the fetus may be less than with
prenatal methadone, and we encourage physicians to
consider buprenorphine as a first-line maintenance therapy
with pregnant patients.
Fewer animal studies have been published for perinatal
buprenorphine than methadone and heroin/morphine, but
perinatal buprenorphine appears to produce alterations
common to opiate exposure. Like other opiates, perinatal
buprenorphine produces morphine tolerance (Chiang et al,
2010; Robinson and Wallace, 2001), delayed acquisition of
developmentally timed behaviors (Robinson and Wallace,
2001), and increased sensitization to METH (Chiang et al,
2013). Chiang et al (2013) also found decreased D1 receptor
mRNA, basal cyclic AMP, and D1 receptor induced adenylyl
cyclase activity in the NAc of buprenorphine-exposed
offspring, suggesting disrupted signal transduction may
underlie the increased METH sensitization. Although mu
opioid receptor binding is decreased at birth, it corrects by
postnatal day 7 (Belcheva et al, 1998; Belcheva et al, 1994;
Hou et al, 2004). Perinatal buprenorphine does not appear
to cause hyperactivity in animal models to date, although
this has been reported in some clinical studies (Hutchings
et al, 1996; Sundelin Wahlsten and Sarman, 2013). Effects
on striatal acetylcholine levels are dose dependent with high
doses causing a decrease at P4 and 21 but low doses
producing an increase at P21 (Guo et al, 1990; Robinson,
2002). Altered myelination, which has been observed in
clinical studies of opiate-exposed neonates (Walhovd et al,
2012), also occurs, producing increased myelinated axon
caliber with disproportionately thin myelin sheaths poten-
tially due to changes in myelin basic proteins and myelin-
associated glycosylation (Sanchez et al, 2008). Additional
observations in animal models of perinatal buprenorphine
exposure have been reviewed comprehensively by others
(Farid et al, 2008).
Naltrexone
Naltrexone is a long-acting, nonselective opioid receptor
antagonist used more commonly outside of the United
States to prevent relapse in opiate addicts due to its ability
to block the euphoric effects of opioid agonists, low
tolerance and abuse potential, and modest adverse effects
(Jones et al, 2013). Newly developed depot formulations
allow for dosing every 4–6 weeks, improving patient
adherence and making this an increasingly preferred treat-
ment option. Inadvertent exposure due to conception after
naltrexone depot implant placement in Australia, Portugal,
and the United Kingdom has been cited, showing unre-
markable neonatal and obstetric features compared with
national averages as well as improved outcomes relative to
methadone maintenance during pregnancy (Hulse and
O’Neil, 2002; Hulse et al, 2003; Hulse et al, 2004; Hulse
et al, 2001). However, these studies did not address the
complications of pain management during labor and
delivery or effects on postnatal development.
Animal studies suggest that caution should be taken with
naltrexone exposure during pregnancy. Endogenous opioid
growth factor and the zeta receptor (this was subsequently
renamed the ‘opioid growth factor receptor’) are found in
both rodents and humans developmentally and decrease
cell proliferation (Zagon et al, 1992; Zagon et al, 1999). At
supratherapeutic dosing, animal models show increased
birth weight and brain and cerebellar weight likely through
attenuation of endogenous opioid growth inhibition with no
remarkable effects on gestation (McLaughlin et al, 1997a, b;
Zagon and McLaughlin, 1984; Zagon et al, 1998). Zagon et al
(1998) supported this hypothesis by showing decreased
cerebellar proliferation with perinatal naltrexone (Zagon
and McLaughlin, 1987). Perinatal naltrexone also alters
opioid receptor expression and function (Bardo et al, 1982;
1983; Medina Jimenez et al, 1997). High perinatal doses
(50 mg/kg) also increase dendritic arbor and spine growth
in the cerebellum and hippocampus (Hauser et al, 1987;
1989). In contrast, low doses of perinatal naltrexone appear
to produce decreases in dendritic length, proliferation, and
overall growth (Farid et al, 2012; Hauser et al, 1989; Zagon
and McLaughlin, 1984, 1987). Although these data advocate
that naltrexone exposure during pregnancy may not be
harmless, dosing discrepancies with human studies con-
found interpretations. Postnatal human studies with accu-
rate measurements of dose and timing of exposures along
with neurobehavioral endpoints are needed.
Prenatal exposure to opiates thus causes long-lasting
alterations in growth, cognition, and motor and visual
abilities. Although evidence suggests that any treatment for
opiate addiction improves maternal and fetal outcomes,
each form of medical treatment brings their own risks. The
gold standard, methadone, has good patient retention but
causes a more pronounced neonatal abstinence syndrome
whereas buprenorphine has higher abuse potential but
causes a shorter, less severe neonatal abstinence syndrome.
Both of these mu opioid receptor agonists may alter
developmental trajectory and negatively impact cognition.
The increasing use of opioid antagonist (naltrexone) depot
formulations to treat opioid addiction will bring more cases
of fetal exposure to naltrexone and an increased risk of
opioid overdose and relapse during pregnancy.
CANNABIS/delta-9-tetrahydrocannabinol
Cannabis, also known as marijuana or, in its more
concentrated form, hashish, is an illicit drug derived from
the Cannabis sativa plant and is commonly smoked or, less
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frequently, ingested orally. For the purposes of this review,
we will focus on the more commonly used form, marijuana,
in its most popular route of administration, smoking.
Marijuana is the most commonly abused form of illicit drug
in the US, with over 42% of the population aged 12 years
and over trying the drug within their lifetime. Over 38% of
US females aged 12 and over will try the drug at some point
in their lives, with 5% of females using the drug within the
past month (Substance Abuse and Mental Health Services
Administration, 2013). These statistics include women of
childbearing age, and nearly 5% of pregnant women report
smoking marijuana within the first trimester of pregnancy,
although these numbers decrease in the second (2.9%) and
third trimesters (1.4%) (Substance Abuse and Mental
Health Services Administration, 2009). Given that cannabis
has been recently legalized in Washington and Colorado
and decriminalized in other states, with many others likely
to follow suit, prenatal exposure to it is of growing concern.
Marijuana elicits a sedative-like effect, primarily due to its
active ingredient, delta-9-tetrahydrocannabinol (THC).
THC binds to the cannabinoid-1 (CB-1) receptor to induce
this effect (for review, see Trezza et al (2008b)). Transcript
for the CB-1 receptor is present in the second embryonic
week in rodents (Buckley et al, 1998) and in the second
trimester in humans (Wang et al, 2003), indicating that
exposure to marijuana in the womb might have develop-
mental consequences. Furthermore, THC can cross the
placenta with reasonable efficiency (Hutchings et al, 1989),
although unlike many other drugs of abuse, the placenta
appears to limit fetal exposure to marijuana, as fetal
THC concentrations have been documented to be lower
than maternal concentrations in studies of various animal
species (Behnke and Smith, 2013). Endogenous cannabinoids
(endocannabinoids) are crucial for proper development
in utero, and exogenous cannabinoids such as marijuana
alter fetal growth trajectories (El Marroun et al, 2009), an
effect that can have long-term consequences (for review,
see Keimpema et al (2011)). Marijuana users can
become dependent on the drug. Moreover, the THC
content of marijuana has greatly increased over the years
(Mehmedic et al, 2010), causing additional concern for fetal
exposure.
Despite the overwhelming use among pregnant women,
there are relatively few clinical studies looking at the effects
of marijuana on the offspring. Studies have shown that
fetuses exposed to marijuana during gestation exhibited
stunted growth outcomes, as assessed by fetal weight and
foot length (Hurd et al, 2005). Shorter gestation lengths,
decreased birth weights, and deficits in other growth
measures have been reported (Cornelius et al, 1995;
Fergusson et al, 2002; Fried et al, 1999; Fried et al, 1984;
Linn et al, 1983), although others have shown little to no
effect on birth outcomes (Day et al, 1991; Witter and Niebyl,
1990). While the gestational and newborn growth outcomes
remain equivocal, postnatal neurobehavioral outcomes are
only slightly less so. Our understanding of the role of
prenatal marijuana exposure derives primarily from two
long-term longitudinal studies: the Ottawa Prenatal Pro-
spective Study (OPPS) and the Maternal Health Practices
and Child Development Study (MHPCD). The OPPS
study, initiated in 1978, consists of primarily ‘low-risk’
middle class subjects, while the MHPCD, begun in 1982
in Pittsburgh, focuses on ‘higher risk’ subjects of lower
socioeconomic status. As outlined below, evidence from
these studies and others suggests that prenatal marijuana
exposure has deleterious effects on exposed children in
particular domains, although these results are not definitive
(for review, see Fried and Smith (2001) and (Campolongo
et al (2009)).
Newborns exposed to marijuana exhibit sleep distur-
bances (Scher et al, 1988), a problem that persists through
age 3 (Dahl et al, 1995), as well as a shorter, high-pitched
cry (Lester and Dreher, 1989). Altered responses to visual
stimuli and increased startles and tremors were noted in
newborns exposed to marijuana (Fried, 1982; Fried and
Makin, 1987; Fried et al, 1987), with some such symptoms
lasting for at least 30 days after birth (Fried et al, 1987),
although others, also using the Brazelton Neonatal
Behavioral Assessment Scale, have shown no significant
differences on these outcomes (Tennes et al, 1985). Diffe-
rential results were also seen in the MHPCD and OPPS
cohorts using the Bayley Scales of Infant Development.
Decreased mental scores in marijuana-exposed children at
9 months of age were found in the Pittsburgh group, an
effect attributed to exposure during the third trimester,
although at 19 months, no significant differences were seen
relative to controls (Richardson et al, 1995). Meanwhile,
others have shown no significant cognitive deficits in
children ages 1–3 years that were prenatally exposed to
marijuana (Astley and Little, 1990; Fried and Watkinson,
1988; 1990). However, exposed children at 3 years of age
from the higher risk MHPCD study demonstrated attenu-
ated cognitive development, including decreased short-term
memory, verbal, and visual skills (Day et al, 1994). These
effects correlated with exposure during the first and second
trimester yet that can in some populations be ameliorated
by environmental enrichment (Day et al, 1994).
As children approach school age, additional detrimental
effects of prenatal marijuana exposure become apparent.
These deficits are not generalized to overall cognition but
are specific to higher order function, specifically, executive
function. Impairments in verbal and memory tasks become
apparent in children at age 4, despite exhibiting no such
alterations when tested at younger ages (Fried and
Watkinson, 1990). At 5–6 years of age, exposed children
showed no overall deficits in cognition or language skills
(Fried et al, 1992a), but 6–year-olds showed attention
deficits, elevated impulsivity, and hyperactivity (Fried et al,
1992b; Leech et al, 1999). Deficits in short-term memory
and verbal reasoning were apparent at this age as well
(Goldschmidt et al, 2008). Over time, attention deficits
remain and can escalate to increased delinquency and
externalizing behaviors (Goldschmidt et al, 2000). Interest-
ingly, a study on marijuana-exposed fetuses found elevated
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levels of D2 receptor transcript in the amygdala of males
(Wang et al, 2004), suggesting potential for altered
emotional regulation. Alterations in visuospatial memory
are also noted in early adolescence (Fried and Smith, 2001).
Deficits in these more complex domains were seen at ages
9–12 (Fried and Watkinson, 2000; Fried et al, 1998),
although other data indicate that deficits in visual and
abstract reasoning can be detected as early as 3 years of age
(Griffith et al, 1994). Perhaps most striking is that even in
their early 20 s, exposed individuals still have deficits in
visuospatial working memory and impulsivity (Smith et al,
2004, 2006a). Adolescents performed more poorly in some
areas of academic testing (Fried and Smith, 2001; Fried et al,
2003; Goldschmidt et al, 2012). These data indicate that
prenatal marijuana exposure has significant effects on
multiple neurobehavioral outcomes—deficits that are en-
during, particularly at the level of executive function.
Exposed children also exhibit signs of neuropsychiatric
disorders and may be more susceptible to substance abuse
(for review, see Jutras-Aswad et al (2009)). For example,
children from the MHPCD cohort presented with signs of
depression as early as 10 years of age (Gray et al, 2005).
Moreover, decreased levels of D2 receptor transcript were
found in the NAc of exposed fetuses, potentially linking
susceptibility to drug use to prenatal marijuana exposure
(DiNieri et al, 2011). Prenatally exposed children were also
more likely to experiment with marijuana at an earlier age
as well as smoke the drug more frequently (Day et al, 2006;
Goldschmidt et al, 2012). Given that drug use and psy-
chiatric disorders are burdens not only to the individual but
also to society as a whole, in total these results indicate the
prenatal marijuana exposure has persistent deleterious
effects that can have considerable consequences.
Animal models of prenatal marijuana exposure support
these findings. Exposed offspring showed reduced body
weight at birth (Abel et al, 1981; Abel et al, 1980). As with
humans, young rats exposed to THC throughout pre- and
postnatal development had increased ultrasonic vocaliza-
tions (cries) when isolated, indicative of increased anxiety
and potentially analogous to increased irritability in human
infants (Trezza et al, 2008a). In this same study, rats showed
deficits in social behaviors during adolescence and
elevated anxiety in adulthood. Increased locomotor activity
has been demonstrated as well (Borgen et al, 1971; Mereu
et al, 2003; Rubio et al, 1995), although others have shown
either no changes in locomotion or significant hypoactivity
(for review, see Navarro et al (1995); Schneider (2009)).
As previously mentioned, marijuana exposure during
human prenatal development appears to affect ‘higher
order’ facets of learning and memory. Similar results have
been found in animal models as well. Using either the CB-1
receptor agonist WIN55,212-2 (Mereu et al, 2003) or THC
(Campolongo et al, 2007), researchers found that develop-
mental exposure resulted in impairments in passive
avoidance, indicative of diminished memory retention.
Furthermore, the THC-treated group also was unable to
discriminate between a novel and a familiar rat in the social
discrimination test. These effects are not limited to a
particular phase of life, as in utero-exposed rats showed
deficits in learning and memory tasks throughout the
lifespan (Silva et al, 2012). These data and others
(Campolongo et al, 2009; Schneider, 2009) indicate that
marijuana exposure during pregnancy impacts learning and
memory. Marijuana exposure during development may also
result in increased likelihood of drug experimentation later
in life. Exposed rats exhibited decreased levels of D2
receptor expression and binding in the NAc, a key reward
center, and increased sensitivity to the rewarding properties
of opiates (DiNieri et al, 2011). Others have shown that
exposure to THC during a period equivalent to mid-
gestation in humans resulted in increased heroin-seeking
behavior in offspring (Spano et al, 2007). Following a
similar exposure paradigm, rats administered AMPH in
adulthood were less sensitive to its locomotor-stimulating
effects (Silva et al, 2012), indicative of aberrant responsive-
ness to psychostimulants. While the preclinical data support
the clinical findings, further research is needed to under-
stand the mechanism and circuitry underlying these
deficits.
TOBACCO/NICOTINE
According to the 2010 Pregnancy Risk Assessment Mon-
itoring System data from the CDC, 12.3% of pregnant
women in the US continue to smoke throughout pregnancy
(Tong et al, 2013), and these numbers might be higher
worldwide (Bloch et al, 2008). Over 7000 different chemicals
are found in cigarette smoke, many of which are toxic and/
or carcinogenic (U.S. Department of Health and Human
Services, 2010). Nicotine, the primary psychoactive compo-
nent of tobacco, and its metabolite, cotinine, readily pass
through the placenta, and fetal concentrations of these
compounds are significantly greater than those achieved by
the mother (Lambers and Clark, 1996). Nicotine is an
agonist of the nicotinic acetylcholine receptor (nAChR),
which is expressed in the first trimester in humans and by
the second gestational week in rodents (see review Dwyer
et al (2008); Dwyer et al (2009)). Acting through this
receptor, developmental exposure to nicotine disrupts the
cholinergic system, a key modulator of brain development,
and alters synaptogenesis, neuronal migration, neurotrans-
mitter release, and a host of other molecular and functional
endpoints (see review of Slotkin 2004). However, nicotine is
only 1 of more than 4000 compounds to which the fetus is
exposed through maternal smoking (Behnke and Smith,
2013).
Maternal smoking is not the only exposure to nicotine for
the fetus. Maternal exposure to secondhand smoke (SHS)
is also highly detrimental to proper fetal development and
can cause long-term neurobehavioral alterations on its own
(Chen et al, 2013). In addition, nicotine replacement
therapies (ie, lozenges, patches, gum, etc.) are prescribed
more and more to reduce fetal exposure to the additional
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compounds found in cigarette smoke (Coleman, 2008).
However, nicotine alone, based on animal studies, is highly
toxic in and of itself, and these devices should not be
considered ‘safe’ for pregnant women to use, although the
risks are significantly less compared with cigarette smoking
alone (for review, see Bruin et al (2010)). Along those same
lines, electronic cigarettes (e-cigarettes) have become in-
creasingly popular as they eliminate SHS by delivering
nicotine as an inhalable vapor. These devices should be used
with caution, as they expose not only the user, but also
passerby to aerosolized nicotine (Czogala et al, 2013).
Similarly, maternal use of smokeless (chewing) tobacco
not only decreases birth weight (England et al, 2003), a
risk factor for long-term neurobehavioral consequences
(Rosenthal et al, 2011), but also results in higher Lipsitz
scores, a neurobehavioral test used to measure drug with-
drawal symptoms such as tremor, increased muscle tone and
reflexes, and irritability in newborns (Hurt et al, 2005).
There is a wealth of data examining the effects of prenatal
exposure to tobacco in both humans and animals, and a
number of very detailed reviews exist on the consequences
of prenatal tobacco exposure (Abbott and Winzer-Serhan,
2012; Bublitz and Stroud, 2012; Cornelius and Day, 2009;
Pauly and Slotkin, 2008; Slotkin, 2008). For this review, we
will provide an overview of some of the findings pertaining
to neurobehavioral outcomes. At birth, exposed infants tend
to be smaller in body weight, height, and head circumfer-
ence, effects attributable to third and possibly second
trimester exposure (Espy et al, 2011; Himes et al, 2013).
There is also a greater likelihood of exposed infants to be
admitted into the neonatal intensive care unit relative to
unexposed controls (Adams et al, 2002). Newborns exposed
in utero to nicotine are more irritable and have poorer
attention than unexposed infants, and they exhibit hyper-
tonicity, increased tremors and startle responses, and
deficient speech processing as well (Espy et al, 2011; Fried
et al, 1987; Key et al, 2007; Mansi et al, 2007; Reijneveld
et al, 2002; Stroud et al, 2009a). Within the first month of
life, exposed infants show signs of poorer self-regulation
and require more handling by caregivers (Stroud et al,
2009b). Newborns also demonstrate an attenuated response
to auditory stimuli, an effect that can contribute to language
and learning impairments later in life (Kable et al, 2009;
Mansi et al, 2007).
Following birth, the consequences of prenatal nicotine
exposure are persistent, with some outcomes being
consistently shown by multiple independent reports.
Children age 6 and younger had decreased receptive
language skills (Fried et al, 1992a; Fried and Watkinson,
1990; Lewis et al, 2007), which can contribute to language
comprehension deficits. Exposed children also show poorer
academic achievement or cognitive scores than peers
(Agrawal et al, 2010; Fried et al, 1992a; Fried and
Watkinson, 1990). These effects are not limited to young
children. Older adolescents also exhibit cognitive deficits, as
16–18 year olds, exposed to tobacco in utero and were
current smokers themselves, showed deficits in sensory
processing (ie, visuospatial memory) when abstinent from
nicotine (Jacobsen et al, 2006). Interestingly, this effect was
absent when subjects were allowed to smoke freely,
indicating that the deficit was withdrawal-induced and that
smoking was a means to compensate for this deficit.
Furthermore, there was no difference between subjects
exposed to tobacco throughout pregnancy or during only
the first trimester, emphasizing the necessity of smoking
cessation before pregnancy. In a test of working memory
(N-back test) combined with fMRI, there was differential
activation of various brain regions following correct
responses in exposed versus unexposed adolescents, in-
dicating abnormal function or circuitry following exposure
(Bennett et al, 2013). Moreover, pallidum volume was
smaller in adolescents following prenatal tobacco exposure,
and increased impulsivity was correlated with thalamic
volume following prenatal tobacco (Liu et al, 2013).
Attention is also a key area where a great number of
deficits are seen following gestational tobacco exposure.
Studies have shown that children as young as 6 years old
show attention deficits, including diagnosis with ADHD, an
effect seen well into the late teens (Bennett et al, 2009;
Cornelius et al, 2011; Cornelius et al, 2007; Jacobsen et al,
2007; Kotimaa et al, 2003; Langley et al, 2007; Lindblad and
Hjern, 2010). Both second (Cornelius et al, 2007) and third
(Cornelius et al, 2011) trimester exposures have been
correlated to attention problems. Interestingly, individuals
with self-reported ADHD or attention problems were more
likely to smoke than their peers (Kollins et al, 2005), further
corroborating a link between attention disorders and
nicotine use. While gestational exposure to nicotine appears
to be a primary indicator for attention deficits, confounding
factors such as maternal diagnosis of ADHD, environmental
factors, socioeconomic status, and exposure to other drugs
are often not accounted for in these studies (Agrawal et al,
2010; Ball et al, 2010; Langley et al, 2012). Thus, more
thorough research to eliminate these factors as confounding
variables is necessary.
Conduct and behavioral disorders are other domains
frequently associated with prenatal tobacco exposure.
Children as young as 18–24 months show increases in exter-
nalizing behaviors (Stene-Larsen et al, 2009; Wakschlag
et al, 2006a) as well as internalizing and total problem
scores following prenatal tobacco exposure (Carter et al,
2008). A study of 3-year-olds exposed gestationally to
tobacco determined that increases in oppositional behavior
were correlated to third trimester exposure (Day et al,
2000). Similar behavioral issues, including aggression,
oppositional defiance, and delinquency, have been noted
in older children (6–16 years old) (Bennett et al, 2009;
Cornelius et al, 2011; Cornelius et al, 2007; Indredavik et al,
2007; Langley et al, 2007; Wakschlag et al, 2006b; Weitzman
et al, 1992). It would appear that no level of tobacco
exposure may be safe, as children aged 7–15 years, born of
non-smoking mothers with SHS exposure during preg-
nancy, showed increased externalizing behavior (Gatzke-
Kopp and Beauchaine, 2007). Moreover, children with only
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prenatal exposure to tobacco were more likely to exhibit
abnormal behaviors relative to children exposed only
during the postnatal period (Ruckinger et al, 2010), thus
emphasizing that gestation is a critical period in the
development of behavioral disorders.
In addition to the aforementioned deficits, prenatally
exposed children are more likely to develop substance use
disorders. Lotfipour et al (2009) found that exposed
children were more likely to experiment with drugs, an
effect correlated to thinning of the orbitofrontal cortex. This
same group also demonstrated that prenatal tobacco
exposure, in combination with a genetic polymorphism of
the a6 subunit of the nAChR, resulted in increased likelihood
of smoking and drug use (Lotfipour et al, 2010). The
combined environmental and genetic conditions altered
brain development as well, as affected children had larger
striatal volumes. Others have shown that exposed children
begin to smoke and become regular users earlier than
unexposed peers (Agrawal et al, 2010).
While preclinical models allow for more specific and
controlled studies, variables such as species differences,
pharmacokinetics, routes of administration, and the timing
of the developmental exposure make comparisons or
conclusions difficult. These studies, however, are invaluable
in defining critical periods and insight into the underlying
molecular mechanisms and circuitry following develop-
mental nicotine exposure. For instance, tobacco smoke
exposure in non-human primates during gestation and
lactation resulted in neuronal cell loss, increased glia, and
decreases in cell size (Slotkin et al, 2006). Following nicotine
exposure in utero, changes to spine density, dendritic
length, and dendritic branching were observed in juvenile
(Muhammad et al, 2012) and adult (Mychasiuk et al, 2013)
rats. Such changes can alter the trajectory of development
and contribute to the functional deficits seen later in life
(Pauly and Slotkin, 2008).
Changes in body weight are also found in animal models
of developmental nicotine exposure. When pregnant dams
were exposed to cigarette smoke throughout gestation,
fetuses were significantly smaller than controls (Bassi et al,
1984; Esposito et al, 2008). Differences in body weight
following other routes of administration or only postnatal
exposure (equivalent to third trimester human exposure,
see Figure 1) have been documented as well, although
results are variable (see (Abbott and Winzer-Serhan (2012))
for review). In line with the clinical data, deficits in learning
and memory and sensory processing have also been
detected. Rodents exposed in utero to nicotine performed
poorly on tests of learning and memory, including the radial
arm maze (Levin et al, 1993; Sorenson et al, 1991) and two-
way active avoidance (Vaglenova et al, 2008). Similarly,
mice exposed to nicotine via injection took longer to reach
criterion on the radial arm maze and had increased
latencies to reach the platform on the Morris water maze
(Yanai et al, 1992). Exposed mice exhibited deficits in
sensory processing, as evidenced by hypersensitive passive
avoidance (Heath et al, 2010). These researchers determined
that postnatal exposure—the equivalent of the human third
trimester—was the key critical period for this effect. A
study using a mouse model of inhaled cigarette smoke
throughout gestation through weaning (simulating expo-
sure throughout human pregnancy) resulted in deficits in
spatial and reference memory as assessed via Morris water
maze but not in route-based (egocentric) learning in the
Cincinnati water maze (Amos-Kroohs et al, 2013). These
findings bolster the clinical evidence that prenatal nicotine
exposure alters long-term learning and memory function.
Clinical data on developmental nicotine exposure fre-
quently refers to hyperactivity and attention deficits, effects
that are found in the preclinical literature as well. Schneider
et al (2011) found that rats exposed to nicotine during
gestation performed more poorly in the 5-choice serial
reaction time task in measures of sustained attention and
impulsivity (Schneider et al, 2011). These data correspond to
the clinical literature, specifically as attention deficits have
been correlated to second trimester exposure (Cornelius
et al, 2007). A similar exposure regimen in mice found that
males and females exposed to nicotine were significantly
more hyperactive than controls, especially during the dark
(awake) cycle (Zhu et al, 2012). Moreover, nicotine-exposed
mice responded to methylphenidate (MPH), a pharmacolo-
gical treatment for ADHD, with attenuated locomotor
activity. This low oral dose of MPH had no effect on control
mice, just as humans without ADHD do not respond to
MPH. Perhaps even more amazingly, the authors then
demonstrated that the prenatal nicotine-induced hyperac-
tivity can propagate transgenerationally via the maternal line
of descent (Zhu et al, 2014). These data suggest that in utero
exposure to substances even in previous generations may
have a role in the increased incidence of neurodevelop-
mental disorders in modern society.
Finally, while conduct disorders per se are difficult to
measure in animal models, comorbid conditions, such as
anxiety, can be modeled. In fact, evidence exists that
prenatal nicotine increases anxiety in rodents (Huang et al,
2007; Santiago and Huffman, 2013; Vaglenova et al, 2008),
although also see Amos-Kroohs et al (2013). Exposed
animals are more likely to self-administer nicotine later in
life (Chistyakov et al, 2010; Levin et al, 2006). Others have
shown that exposed rodents are more sensitive to the
rewarding (Harrod et al, 2012) and locomotor-stimulating
(Amos-Kroohs et al, 2013) properties of METH. Based on
these data, further research into the long-term alterations
resulting from developmental nicotine exposure, specifically
into aggression, abnormal social behavior, and substance
use disorders, is needed.
ALCOHOL
Alcohol consumption during pregnancy can result in a
long-recognized fetal alcohol syndrome (FAS), which
includes morphogenic effects on limb and facial develop-
ment, reduced brain and birth weight, and cognitive delays
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and impairments (Behnke and Smith, 2013; Foltran et al,
2011; Jones, 1986). However, even moderate exposure can
impact brain development and these effects persist at least
into young adulthood. While FAS represents the most severe
manifestation of heavy maternal alcohol consumption during
pregnancy, the term ‘fetal alcohol spectrum disorders’
(FASDs) has been applied to characterize a broad range of
deficits present in individuals with or without facial
dysmorphology who were exposed to alcohol prenatally
(Foltran et al, 2011; Hoyme et al, 2005; Nash et al, 2008; Riley
and McGee, 2005). Thus, moderate alcohol exposure during
fetal development produces significant neurobehavioral
consequences (Behnke and Smith, 2013; Day and
Richardson, 1991; 2004; Fried and Watkinson, 1988;
Jacobson and Jacobson, 1999; Jacobson et al, 1993; Nash
et al, 2013), and FASDs currently represent the leading cause
of mental retardation in North America, ahead of Down
syndrome and cerebral palsy (Nash et al, 2008). As described
in a 1996 Institute of Medicine Report to Congress—‘Of all
the substances of abuse (including cocaine, heroin, and
marijuana), alcohol produces by far the most serious
neurobehavioral effects in the fetus.’ (Institute of Medicine,
1996). It has been estimated that at least 1 per 100 (1% of live
births) are affected by FAS or FASDs (Sampson et al, 1997).
Twelve percent of pregnant women self-report alcohol use
within the past month (Substance Abuse and Mental Health
Services Administration, 2008). A recent Australian study
found that women who binged only before pregnancy were
more likely to continue (55%) rather than reduce drinking
(29%) once pregnant (Anderson et al, 2014). In 2002, the
estimated societal cost for each individual with FAS was $2.0
million ($1.6 million for medical treatment, special educa-
tion, and residential care for persons with mental retardation,
and $0.4 million for lost productivity) (Lupton et al, 2004).
The cost of FASD in the United States was last estimated at
$4–8 billion annually (Popova et al, 2011). For comparison,
the annual budget of the entire National Institute on Alcohol
Abuse and Alcoholism is substantially less than 500 million.
In addition to total quantity, patterns of alcohol drinking
can also modulate the severity of resultant deficits—for
example ‘moderate’ drinking has much more impact on
child development when the mother consumes several
drinks in a single day than when she drinks the same
quantity in doses of one to two drinks per-day over several
days (Jacobson and Jacobson, 1999). Imaging studies reveal
gray matter volume in the left cingulate gyrus, bilateral
middle frontal gyri, right middle temporal gyrus, and right
caudate nucleus following low-to-moderate exposure (De
Guio et al, 2014; Eckstrand et al, 2012; Treit et al, 2013).
Fetal alcohol has also been associated with a host of
cognitive and behavioral impairments, including deficits in
attention, memory, verbal fluency, executive functioning,
reaction time, and motor learning (Coles et al, 2002; Howell
et al, 2006; Mattson et al, 1998; Richardson et al, 2002; Riley
and McGee, 2005; Willford et al, 2004). Maternal and fetal
alcohol dehydrogenase polymorphisms also modulate risk
(Warren and Li, 2005).
Ethanol has diverse cellular targets, and produces wide-
ranging effects depending on the dose, duration, and timing
of exposure. Current evidence suggests that alcohol pro-
duces many of its damaging effects by exerting specific
actions on molecules that regulate key developmental
processes (eg, L1 cell adhesion molecule, alcohol dehydro-
genase, catalase), interfering with trophic factors that
regulate neurogenesis and cell survival, and/or inducing
excessive cell death via oxidative stress or activation of
caspase-3 proteases (Conti et al, 2009; Farber et al, 2010;
Goodlett et al, 2005; Ungerer et al, 2013). Several studies
have identified effects of low amounts of alcohol exposure
on the development of serotonergic neurons (Sari and Zhou,
2004; Zhou et al, 2003; Zhou et al, 2005), and suggested that
these types of defects in the ontogeny of a specific
neurotransmitter system may underlie the more ‘subtle’
deficits observed in human children diagnose with Alcohol
Related Neurodevelopmental Disorder, rather than full-
blown FAS (Zhou et al, 2003). Ethanol exposure disrupts
the proliferation of glia and neuronal precursors in the
developing central nervous system (Luo and Miller, 1998;
Miller, 2007; Miller and Hu, 2009; Powrozek and Miller,
2009) and can dramatically alter behavior (Hellemans et al,
2010; Valenzuela et al, 2012). Transcriptional analyses of
gene products regulated by fetal ethanol exposure in both
mouse and human cells also highlight genes related to neural
development, such as cell proliferation, neuronal migration,
and differentiation (Hashimoto-Torii et al, 2011; Hicks et al,
2010). Emerging data also implicate microRNAs and
epigenetic mechanisms (Balaraman et al, 2013; Mantha
et al, 2014; Pappalardo-Carter et al, 2013; Ungerer et al,
2013). For example, fetal alcohol results in alterations in
DNA methylation and microRNA expression and function
(Pappalardo-Carter et al, 2013). An intriguing hypothesis
suggests that fetal alcohol may induce a dual state of central
nervous system insulin resistance and oxidative stress and
proposes that adverse effects may be prevented or treated by
treatment with peroxisome-proliferated activated receptor
agonists (de la Monte and Wands, 2010).
Alcohol exposure continues to have potent effect on brain
development postnatally in rodents, demonstrated by
studies showing dramatic effects on the number of layer
2/3 cortical pyramidal neurons, on the branching patterns
of their basilar dendrites (Granato et al, 2003; Granato and
Van Pelt, 2003), and on dendritic excitability (Granato et al,
2012). The same group has gone on to also implicate
distinct alterations in cerebral cortical and striatal inter-
neuron distribution and morphology (De Giorgio et al,
2012; Granato, 2006). Rodent postnatal alcohol exposure
also leads to a persistent disruption in ocular dominance
plasticity, which can be treated, at least in part, with
overexpression of serum response factor or inhibition of a
phosphodiesterase (Medina et al, 2006; Paul et al, 2010).
Once again, these time periods are most similar to late
prenatal development in humans (Figure 1).
Finally, although we focus here on fetal exposures, of
great additional interest is the suggestion that adolescents
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respond differentially to the acute cognitive, sensorimotor,
and behavioral effects of alcohol consumption than adults
(Spear, 2014; Spear and Varlinskaya, 2005). For example,
studies from Brunell and Spear (2006) indicate that
adolescents exhibit bimodal behavioral responses to alcohol,
with both hypo- and hyperresponsive systems (Doremus
et al, 2003; Long et al, 1992; Varlinskaya and Spear, 2002).
These findings have important implications for the risks
associated with recreational drinking in adolescents and
young adults.
Taken together, alcohol exposure during development
induces behavioral, cognitive, and neural alterations that
are specific, replicable, persistent and highly dependent on
the timing of the exposure. Given the staggering socio-
economic toll of prenatal alcohol exposures, new strategies
to prevent exposures must be considered, and better
mechanistic understandings are needed to facilitate poten-
tial ameliorative therapies.
CAFFEINE
There have been few studies about the effects of the
naturally occurring adenosine receptor antagonist caffeine,
which is ubiquitously consumed in coffee, tea, and cocoa-
containing foods. Caffeine is likely the psychostimulant
substance most consumed worldwide. Although considered
a fairly innocuous drug, a recent animal study has provided
compelling mechanistic data suggesting that developmental
caffeine exposure transiently antagonizes adenosine recep-
tor signaling resulting in discrete but persistent alterations
in hippocampal structure and function (Silva et al, 2013).
An accompanying editorial expressed concern that ‘We
must now heed the wake-up call sounded by Silva et al
(2013) that exposure to psychoactive substances, even a
seemingly innocuous, socially well-integrated substance
like caffeine, before or soon after birth can alter brain
development’ (Kabir et al, 2013). Another team has
suggested that embryonic caffeine exposure produces an
increase in body weight (B10%), alters cardiac function
and morphology, and produces long-lasting alterations in
DNA methylation (Buscariollo et al, 2014). A third group
has focused on the neuroendocrine consequences and found
that prenatal caffeine ingestion induces an increased
susceptibility to metabolic syndrome with alterations of
glucose and lipid metabolic phenotypes that then propagate
transgenerationally (Katayama et al, 1987; Xu et al, 2012a;
Xu et al, 2012b).
These recent studies join a larger body of work also
suggestive of caffeine-induced changes in developmental
trajectories (for review, see Porciuncula et al (2013)).
Gressens et al (2001) have documented caffeine-induced
acceleration of the evagination of neuroepithelium into
telencephalic vesicles (Sahir et al, 2000) and upregulation of
sonic hedgehog (Sahir et al, 2004). Gestational caffeine also
downregulates central adenosine receptors (Leon et al, 2005;
Lorenzo et al, 2010), reduces NMDA antagonist-induced
locomotor activity (da Silva et al, 2005), and affects
respiratory control (Bodineau et al, 2003; Saadani-Makki
et al, 2004). Cognitive and motor deficits have also been
reported in adult rodents exposed in caffeine during
gestation and/or early postnatal life (Bjorklund et al, 2008;
Soellner et al, 2009), although some impairments may be
paradigm specific (Soellner et al, 2009).
The metabolism of caffeine and other methylxanthines is
impaired in pregnant women, fetuses and neonates, leading
to reduced clearance and potentially higher circulating
levels (Aden, 2011). Several clinical studies have focused on
concerns regarding caffeine-induced fetal growth restriction
and have led to suggestions that women should reduce
caffeine intake before conception and throughout preg-
nancy (Bracken et al, 2003; CARE Study Group, 2008).
Other studies have failed to find an association (reviewed in
Brent et al, 2011). Regarding more subtle changes in
developmental trajectories, a recent study from the
Netherlands did not find significant effects of prenatal
caffeine on neurobehavioral functions at 5–6 years of age
(Loomans et al, 2012), although data on caffeine intake was
obtained only once during the B16th week of gestation.
In contrast, a Norwegian prospective study has reported a
small but significant association between maternal
caffeine intake and inattention/overactivity based on the
Child Behavior Check List (Bekkhus et al, 2010). Given the
fairly dramatic range in caffeine metabolism rates among
individual women (based on CYP1A expression and
activity), it seems crucial that future studies employ
pharmacogenomics strategies and caffeine metabolite
measurements, rather than simple self-report of intake.
And when combined with a still-evolving literature
implicating adenosine A1 and A2A receptors in establishing
neuronal homeostasis, tuning the ability of synapses to
undergo plasticity, and in modulating neurotoxicity (Dias
et al, 2013), these data suggest that expanded study of this
topic is sorely needed.
FUTURE DIRECTIONS AND CLINICAL
IMPLICATIONS
In summary, fetal exposure to drugs of abuse often produces
long-lasting changes in brain structure and function (see
Figure 3). These (mal)adaptations are regardless of whether
the drugs are legal or illicit; it is in fact arguable that alcohol
and nicotine produce more dramatic deficits than ‘harder’
drugs like cocaine. Adolescence encompasses another
sensitive period of development; given that this is when
illicit drug use typically begins, detailed research on how
drugs of abuse alter relatively late-developing processes in
the brain is also essential. Importantly, the molecular targets
of psychoactive drugs sometimes have quite different actions
in early development, as compared with their adult roles as
synaptic modulators. In some cases, transgenerational
effects via epigenetic changes have been documented. In
addition, studies have repeatedly pointed out the crucial
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covariates of postnatal environment and socioeconomic
status. The developing brain is extremely plastic and
adaptable; we continue to discover new and better strategies
for intervention.
Surprisingly, research in this area is still in its formative
stages, and more precise and mechanistic work will be
necessary to characterize the extent of neurobehavioral
alterations and how developmental timing, dosages, and
genetics affect these processes. When costs for special
education, long-term medical management, and lost pro-
ductivity across the lifespan are considered, the socio-
economic impact is truly staggering. Moreover, societal
responses continue to be misguided. For example, the state
of Tennessee passed legislation in 2014 allowing women to
be charged with assault if they have a pregnancy complica-
tion after using narcotics illegally. The desire to guard fetal
health and outcomes is understandable; however, pregnant
women who fear prosecution and the potential loss of their
children will rarely seek essential prenatal and medical care.
We already discovered the negative consequences of such
practices during the peak of maternal cocaine exposures
in South Carolina from 1989–1994, before their prosecution
of these women was forced to cease (Annas, 2001; Budetti,
1993; Ferguson v. City of Charleston, 2001; McKnight v.
State of South Carolina, 2008; Poland et al, 1993). Physicians
and scientists need to better engage and educate the public
on these complex issues.
We do not claim to have all the answers, or even all of the
questions. But as a field, we must do a better job of bridging
the translational gap. Basic scientists must design their
animal models with consideration to (a) whether the route
of administration (to the dam or the pup) is the same as in
human users, (b) whether pharmacokinetics and biotrans-
formation of the drug differ between humans and the
animal model, (c) whether the model encompasses the
entirety of fetal development, and (d) how well the outcome
measures being tested in the animals conform to relevant
outcome measures in the clinical literature. Given that
women rarely, if ever, begin using an abused drug during
the third trimester of their pregnancy, postnatal-only
administration in rodents will usually be inadequate
(Figure 1). Given the great prevalence of polysubstance
use in drug-abusing women (and men), more models of
prenatal polydrug exposure seem warranted. Interactions
between fetal drug exposure and other environmental
variables, including toxicants and stressors, are also crucial
(Graf et al, 2013). Clinicians must also make better use of
the preclinical findings and predictions about the kinds of
deficits to be expected in people who have been exposed to
substances prenatally (Figure 3). Particular focus should be
Figure 3. Schematic summary of effects of distinct drug classes on offspring development. A wide variety of significant structural and neurobehavioral
deficits are induced by fetal exposures to abused substances. As described in the text, the drug class, timing, dose, and pattern of intake all substantially
determine the long-term effects on the developing child.
Prenatal effects of drugs of abuse
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paid when diverse types of models (species, dosing, timing,
etc.) produce congruent effects on functional domains (even
if the precise cellular mechanisms differ)—these are the
maladaptations that will likely be most prevalent in the
human population. The ability of animal data to potentially
predict future health issues should also not be overlooked—
for example, aging studies in animal models predict that
prenatal exposure to cocaine or nicotine (Abreu-Villaca
et al, 2004; Lawrence et al, 2008; Lloyd et al, 2006; Meyer
et al, 2009) may produce higher risks or expression
of cell death and/or neurodegenerative diseases later in life.
While only time will tell, we will likely be facing additional
societal and medical burdens as drug-exposed children
continue to age—better animal models will allow us to
predict and treat later-in-life disorders in these populations
as they emerge.
FUNDING AND DISCLOSURE
We are currently supported by RO1MH086629 (GDS),
R21DA035588 (GDS), the Vanderbilt Conte Center (GDS
and EJR), the Peter F. McManus Charitable Trust (DLG),
and the Vanderbilt Brain Institute. The authors declare no
conflicts of interest.
ACKNOWLEDGEMENTS
We are grateful to innumerable colleagues who have helped
to shape our views on these topics, including Drs Pat Levitt,
Jeremy Veenstra-Vanderweele, Gale Richardson, Charles
Vorhees, Randy Blakely, Barbara Thompson, and Pradeep
Bhide. We also thank the reviewers who provided
substantial feedback and very helpful suggestions on an
earlier draft of this review. We are currently supported by
RO1MH086629 (GDS), the Vanderbilt Conte Center (GDS
and EJR), the McManus Foundation (DLG), and the
Vanderbilt Brain Institute.
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