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CHAPTER 10 Pharmacology in Neonatal Care
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249
75. Simpson JH, Lynch R, Grant J, et al. Reducing medication
errors in the neonatal intensive care unit. Arch Dis Chil Fetal
Neonatal Ed. 2004;89(6):F480.
76. Smith PB, Cohen-Wolkowiez M, Castro LM, and the
Meropenem Study Team, et al. Population pharmacokinetics of
meropenem in plasma and cerebrospinal fluid of infants with
suspected or complicated intra-abdominal infections. Pediatr
Infect Dis J. 2011;30(10):844.
77. Smith PB, Walsh TJ, Hope W, et al. Phar macokinetics of an
elevated dosage of micafungin in premature neonates. Pediatr
Infect Dis J. 2009;28(5):412.
78. Tayman C, Rayyan M, Allegaert K. Neonatal pharmacology:
extensive interindividual variability despite limited size. J Pediatr
Pharmacol Ther. 2011;16(3):170.
79. Temple ME, Jkubecz MA, Link NA. Implementation of a
training program to improve pharmacy services for high-risk
neonatal and maternal populations. Am J Health-System Pharm.
2013;70(2):143.
80. Tetelbaum M, Finkelstein Y, Nava-Ocampo AA, et al. Back
to basics: understanding drugs in children: pharmacokinetic
maturation. Pediatr Rev. 2005;26(9):321.
81. The Joint Commission. Preventing pediatric medication errors.
Sentinel Event Alert. 2008;39.
82. The Joint Commission: national patient safety goals for 2018.
http://www.jointcommission.org/assets/1/6/2018_CAH_
NPSG_goals-final.pdf. Accessed October 2, 2018.
83. US Food and Drug Administration. FDA drug safety communication: FDA restricts use of prescription codeine pain and
cough medicines and tramadol pain medicines in children;
recommends against use in breastfeeding women. 2017 https://
www.fda.gov/Drugs/DrugSafety/ucm549679.htm. Accessed
May 11, 2017.
84. Venkatesan C, Young S, Schapiro M, Thomas C. Levetiracetam
for the treatment of seizures in neonatal hypoxic ischemic
encephalopathy. J Child Neurol. 2017;32(2):210.
85. Vieux R, Hascoet JM, Merdariu D, et al. Glomerular filtration
rate reference values in very preterm infants. An Pediatr.
2010;125(5):e1186.
86. Watterberg KL, Gerdes JS, Cole CH, et al. Prophylaxis of early
adrenal insufficiency to prevent bronchopulmonary dysplasia: a
multicenter trial. An Pediatr. 2004;114(6):1649.
87. WHO Department of Child and Adolescent Health and
Development. Breastfeeding and maternal medication:
recommendations for drugs in the eleventh WHO model list
of essential drugs. http://apps.who.int/iris/bitstream/han-
dle/10665/62435/55732.pdf; 2002, Accessed September 11,
2018.
88. Yaffe SJ, Aranda JV. Neonatal and Pediatric Phar macology.
Philadelphia: Lippincott Williams & Wilkins; 2010.
89. Zanelli S, Buck M, Fairchild K. Physiologic and pharmacologic
considerations for hypothermia therapy in neonates. J Perinatol.
2011;31(6):377.
DRUG WITHDRAWAL IN
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11
THE NEONATE
JODI JACKSON, BETSY KNAPPEN, AND STEVEN L. OLSEN
hen a neonate shows signs of withdrawal from a medication or drug
W
nancy, this does not necessarily imply that the
mother was addicted or an “addict.” Medications
may be needed for maternal health reasons that
pose a risk for withdrawal in the baby following
birth. These risks and benefits must be known and
discussed between the health care provider and
patient before being used. Nonetheless, the rising
prevalence of illicit and prescription maternal
substance use and abuse has affected pregnant
women of all demographic backgrounds.
The extent of drug use during pregnancy is often
underestimated, as are the effects on the fetus and
neonate. Estimated illicit drug use suggests an
annual prevalence of approximately 6% of pregnant women, with the highest use at 18.3% in
women 15 to 17 years of age. Illicit use decreases
to 9% in those 18 to 25 years of age and 3.4% in
those 26 to 44 years of age.
Disease Control and Prevention (CDC) reported
from 2011 to 2013 an average of 10.3% of all pregnant women 18 to 44 years of age voiced current
alcohol use, with 3.1% engaging in binge drinking.
Cigarette smoking, while decreased overall, has
remained unchanged in the pregnant woman.
The National Survey on Drug Use and Health in
2013 showed that 15.4% of pregnant women 15 to
44 years of age smoked cigarettes in the previous
month.
Neonatal abstinence syndrome (NAS) par-
allels the national opioid epidemic. While the
CDC’s press report in 2018 shows opioid use disorder increased from 1.5 per 1000 hospital deliveries
in 1999 to 6.5 in 2014, NAS escalated accordingly.19
taken by the mother during preg-
115
The Centers for
113
25,103
115
NAS has increased from 1.2 to 5.8 per 1000 hospital births per year from 2004 to 2012.92 Many
infants are exposed to poly-substances that
compound NAS.95 The national average length
of stay for an infant requiring treatment for NAS
has increased from 16 days to 19 days.
aggregate hospital charges for NAS increased from
732 million to 15 billion, 81% attributed to state
Medicaid programs.
of Drug Abuse 2017 “Monitoring the Future” study
showed that past-year misuse of prescription opioids
over the last 15 years (2002 to 2017) among 12th
graders is declining (Vicodin dropped from 9.6%
to 2%).82 Across all grades, past-year use in 2017 of
heroin, methamphetamine, synthetic cannabinoids,
and cigarettes are at their lowest.
Providers must recognize these data as a snapshot
of these young people and that these behaviors can
change. The sequelae of both licit and illicit sub-
stance use by the mother during pregnancy must
be recognized and addressed to provide optimal
medical care of the neonate. Stereotypic biases
should not interfere with the diagnosis or treatment.
Therefore, health care providers must consider
drug exposure in any neonate who is exhibiting symptoms at birth suggestive of withdrawal
from or exposure to illicit or prescribed drugs.
Opioid use by a mother during pregnancy has
been studied in detail for decades in terms of its
effects on the woman, the fetus, and the developing
27,33,46,51,65
child.
ural or synthetic drug that has pharmacologic
properties similar to those of opium.
opiate is derived from opium or contains opium. The
diagnosis of “opioid use disorder” was introduced in
the Diagnostic and Statistical Manual of Mental Disorders
92,95,119
The National Institute
An opioid is defined as any nat-
119
19,82
27,32,46
In turn,
An
BLUE type highlights content that is particularly applicable to clinical settings.
250
CHAPTER 11 Drug Withdrawal in the Neonate
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251
(DSM 5) in 2013 and combined the two previous
diagnoses: opioid dependence and opioid abuse. The
diagnosis incorporates a wide range of illicit and
prescribed drugs of the opioid class. Because time,
circumstances, and knowledge have changed, other
factors now should be considered in treating neonates. Diagnostic data can no longer be gathered
on the assumption that one drug or substance
was used. Poly-drug use (the concurrent use of
two or more drugs) is now the norm and not
the exception. Poly-drug use also can be the
combination of illicit substances with those that
are legal or found over the counter. The effect
on the fetus and neonate is not necessarily minimized by the legality of the substance. Patterns
of abuse, purity of the illicit drug, and sometimes
potent or poisonous additions to them also may
cause catastrophic sequelae in newborns.
Iatrogenic physical dependence has been
documented in infants given intravenous fentanyl or morphine to maintain continuous
analgesia and/or sedation during extracorporeal
membrane oxygenation (ECMO) and mechanical ventilation.
118
The signs of withdrawal are
much like those reported in infants born to opioid-dependent mothers. Fifty percent to 84% of
neonates removed from fentanyl within a 24-hour
period exhibited withdrawal symptoms, and 48%
exhibited signs and symptoms with morphine
withdrawal.
118
Regardless of the agent(s) used
for sedation, once the decision is made to start
weaning the medication, careful observation of
the infant is crucial to monitor for signs and
symptoms of withdrawal.
14,118
A review of the
literature points out the importance of initiatives for
adequate analgesia in neonates, the development of
formal policies concerning intensive care sedation,
and the treatment of the withdrawal.
8,114,118
Several authors have described the use of specific
tools for documentation of the manifestations of
withdrawal including: the Lipsitz Tool (1975), the
Finnegan Scoring System (1975), and the Neonatal
Withdrawal Inventory by Zahorodny (1998).
74,80,88
The literature cites various pharmacologic agents
that have been used to alleviate the symptoms of
opioid withdrawal with methadone, buprenorphine,
oral morphine sulfate, and others.
33,45,58,64,68
Advances in neonatology have continued to
broaden the period of viability as many more
premature infants are surviving. What appears to
be decreased severity of abstinence in preterm
infants may be related to developmental immaturity of the central nervous system (CNS) or to
differences in total drug exposure. This proves to
be a problem in evaluating the severity of abstinence
signs in a smaller preterm infant because scoring
tools were developed largely for use with term or
near-term infants.
5,46,78
This chapter presents current information about
treatment issues surrounding drug-exposed neonates, with the main focus on opioid withdrawal.
The effects of other substances such as stimulants,
hallucinogens, selective serotonin reuptake inhibitors (SSRIs), nonopioid CNS depressants, tobacco,
methamphetamines, and alcohol are addressed when
symptoms deviate from those of NAS.
PHYSIOLOGY
Because of their low molecular weight and lipid
solubility, all drugs of abuse reach the fetal circulation by crossing the placenta, causing direct
toxic effects on the fetus.
15,24,48,56
Although certain drugs may produce specific
effects, many abused drugs produce similar
manifestations of fetal and neonatal disease. In
addition, the effects of legal drugs such as tobacco,
caffeine, and alcohol may confound simple drug-effect relationships.
5,13,46,75,93
A hostile intrauterine
environment may also be caused by adverse
effects of the mother’s drug use and must be
considered when diagnosing the neonate’s problems. Examples of factors that could affect neonatal
outcome include lifestyle, homelessness, physical or
sexual abuse, prostitution, poverty, poor or no prenatal care, poly-drug abuse, intravenous drug abuse,
binge and withdrawal cycles, anorexia, poor maternal nutrition, pica, dehydration, alcoholism, sexually
transmitted diseases, dental abscesses, preexisting
medical conditions requiring pharmacologic therapy, human immunodeficiency virus (HIV)–positive
status or acquired immunodeficiency syndrome
(AIDS), and hepatitis B and hepatitis C.
5,24,52
ETIOLOGY OF NEONATAL
ABSTINENCE SYNDROME
Neonatal abstinence is described as a generalized
disorder characterized by CNS hyperirritability,
gastrointestinal dysfunction, respiratory distress,
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and autonomic dysfunction manifesting as vague
symptoms such as yawning, hiccups, sneezing,
mottled skin color, and fever.
27,33,46,64,65,122
NAS
occurs in two ways as listed in Box 11.1. Infants
exposed in utero and born to mothers using potent
narcotics; morphine derivatives, heroin, methadone,
or buprenorphine have a high incidence of NAS
(60% to 90%).30 Less potent opioids or opioid-like
agents have also been implicated in the development of NAS. Box 11.2 gives a complete list of
drugs associated with NAS.
When narcotics cross the placenta, equilibrium
is established between maternal and fetal circulations. Before birth, the drug is cleared from the fetal
BOX
11.1
• Passive exposure to opiates/opioids in utero
• Use of illegal drugs (e.g., heroin) or use of legal medications
• Use of medications that are prescribed, but not as part of a struc-
• Use of medications that are prescribed as part of a structured
• Iatrogenically, by the administration of opiates/opioids such as fen-
ETIOLOGY OF NEONATAL ABSTINENCE
SYNDROME
that are not prescribed to the user (e.g., “off the street” codeine,
hydrocodone, oxycodone, methadone, buprenorphine)
tured treatment program (e.g., short-acting narcotics for pain)
treatment program (methadone or buprenorphine).
tanyl, morphine, hydromorphone, or methadone to the neonate for
analgesia and sedation.
circulation primarily by the placenta and maternal
excretory and metabolic mechanisms.46 Multiple
investigators have described the potential genetic
contributors to variability in fetal opiate exposure,
NAS severity, and response to treatment.
21,67
A
multicenter cohort study examined the association
of OPRMI and COMT single-nucleotide polymorphisms on NAS, the infant’s length of stay, and need
for pharmacologic treatment. This study concluded
that infants with the OPRMI gene had a length of
stay 8.5 days less than those without the variation
and a better chance of not needing pharmacologic
treatment. Neonates with the COMT gene variation were in the hospital 10.8 fewer days and had
less treatment.
121
The onset of withdrawal symptoms varies
from hours after birth to 2 weeks of age, but the
majority of symptoms appear within 72 hours.
Many factors influence the onset of NAS (Boxes
11.3 and 11.4).
Once the umbilical cord has been cut, the
neonate is no longer exposed to the drug, and
monitoring of symptoms of withdrawal should
commence within 2 to 4 hours. Any symptoms
occurring before this point are likely “drug
effect” (symptoms of the drug expressing themselves in the newborn, which is the drug toxic
profile or toxidrome). These symptoms will
BOX
11.3
FACTORS INFLUENCING THE ONSET
OF IN-UTERO ACQUIRED NEONATAL
ABSTINENCE SYNDROME
BOX
11.2
DRUGS ASSOCIATED WITH NEONATAL
ABSTINENCE SYNDROME
Opioids
• Heroin
• Fentanyl
• Methadone/buprenorphine
• Morphine
• Meperidine (Demerol)
Less Potent Opioids and Opioid-like Agents
• Propoxyphene hydrochloride
• Codeine
• Pentazocine (Talwin)
• Tramadol
• Dextropropoxyphene
• Drugs used by the mother (mono- or poly-medication/drug use, nicotine exposure)
• Possible gene variations of the OPRM1 gene or COMT gene (currently under investigation)
BOX
11.4
• Prolonged opiate sedation for mechanical ventilation
• Duration of opioid analgesia use during extracorporeal membrane
• Type of opiate used
• Maturity and presence of intrinsic disease in the neonate
FACTORS INFLUENCING THE ONSET OF
IATROGENIC NEONATAL ABSTINENCE
SYNDROME
oxygenation
CHAPTER 11 Drug Withdrawal in the Neonate
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253
decrease as the drug is cleared from the newborn’s system as opposed to worsening as is seen
with true withdrawal.
46
Neonatal withdrawal from psychoactive sub-
stances that the fetus is exposed to occurs
in varying degrees. Because most opioids are
short-acting and not stored by the fetus in appreciable amounts, neonatal abstinence is usually
apparent within the first 24 to 72 hours of life.
The onset of clinical NAS symptoms depends
on which opioids the pregnant woman used.
For example, with heroin, NAS may occur in the
first 24 hours, whereas with methadone, it may not
develop until after 2 to 5 days.
27,46,61,74
Symptoms
of NAS in heroin-exposed infants occur earlier
than in infants of methadone-maintained mothers because of heroin’s shorter half-life.
Withdrawal may be mild, transient, and delayed
in onset, or it may increase stepwise in severity.
Symptoms may be present intermittently or
follow a biphasic course characterized by acute
NAS signs, followed by improvement, and then
the onset of a subacute withdrawal reaction.
33,46
Whether drug dose and period of expo-
sure influence the degree of withdrawal seen
in affected neonates is unclear. While some
researchers report that NAS is more severe in infants
whose mothers have taken large amounts of drugs
for an extended period, other researchers have not
confirmed this finding.
46,74,122
Usually the origin of NAS lies in the abnormal
intrauterine environment. A series of steps appear to
be necessary for the onset of NAS and thus the recovery of the infant. The growth and ongoing survival of
the fetus are threatened by the continuing or episodic
transfer of noxious substances from the maternal to
the fetal circulation. During this time, the fetus goes
through a biochemical adaptation to the abnormal
element. At delivery, abrupt removal of the drug
is the catalyst needed to start the onset of symptoms. The newborn continues to metabolize and
excrete the substance, so that withdrawal signs occur
when critically low tissue levels have been reached.
Recovery from NAS is gradual and occurs as the
infant’s metabolism is reorganized to adjust to
the absence of the offending drug.
33,46
Studies of the relationship between maternal
dose of methadone and severity of NAS have
yielded inconsistent results: 50% of the studies
find a relationship, whereas 50% find no relationship.
11,30,33,46,108
Use of adequate maternal
BOX
11.5
• Reduces illegal opiate use and use of other drugs, diminishing the
• Helps remove the opiate-dependent woman from the drug-seeking
• Eliminates illegal behavior, including prostitution
• Prevents fluctuation of the maternal drug level that may occur
• Decreases mortality and severe maternal morbidity
• Permits a more stable intrauterine environment for the fetus,
• Increases retention in substance abuse treatment
• Stabilized mothers on methadone more likely to retain custody of
• Children can be monitored by methadone clinic staff
• Provides opportunity for parenting education and other life skills
• No association between neonatal abstinence syndrome severity and
• Maternal methadone dose
• Trimester of methadone initiation
• Duration and amount of methadone exposure
• Duration of maternal drug use before pregnancy
Modified from Substance Abuse and Mental Health Services Administration (SAMHSA).
Pregnant, Substance-Using Women (TIP2) BKD127 Guideline 4. U.S. Department of
Health and Human Services; 1995.
EFFECT OF MATERNAL METHADONE
MAINTENANCE ON THE MOTHER AND
CHILD
risk for hepatitis, HIV/AIDS, and other sexually transmitted diseases
environment
throughout the day
decreasing chances of hypoxia; increases birth weight
their children
the following:
methadone for therapeutic effect may decrease
concomitant drug use and fetal risk; there is no
compelling evidence to reduce maternal dosing
to avoid NAS.
4,30
Box 11.5 outlines the effect of
maternal methadone maintenance on mother
and newborn.
Neonates experience a physiologic tolerance
and withdrawal from medications and drugs
they are exposed to in utero, but do not experience “addiction,” and cannot be classified as
“addicts.” Addiction implies a psychological
component of dependence that is not part of the
newborn experience.
Maternal Exposure to Opioid
Substances
When drugs such as heroin, methadone, morphine,
buprenorphine, and meperidine cross the placenta, the fetus may become passively dependent.
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Morphine, the major metabolite of heroin, methadone, as well as buprenorphine and its metabolite
have been identified and measured in amniotic fluid,
cord blood, breast milk,
meconium.
46,55,68,79
1,35,38
neonatal urine, and
Non-opioid CNS depressants
(e.g., benzodiazepines, barbiturates) and the other
opiates/opioids (e.g., codeine, hydrocodone, oxycodone, hydromorphone, pentazocine, propoxyphene)
all have been identified in neonatal urine and
meconium.
46,73
Ethanol and its primary metabolite,
acetaldehyde, have been identified in placental tissue
and amniotic fluid.
22,46,74
Human and animal studies have shown that use
of opioids during pregnancy directly affects
fetal growth. Heroin is associated with intrauter-
ine growth restriction (IUGR), with only a slight
reduction in gestational length, although the mechanism through which heroin inhibits growth is not
known.29 Early speculation reported that maternal
heroin use during pregnancy accelerated fetal lung
maturity, but this has not been borne out when formally studied. Additionally, no plausible mechanism
through which heroin exposure resulted in this has
been elucidated, although the associated growth
restriction and chronic stress has been suggested.
43
Older studies comparing methadone-exposed
with non-exposed infants have found that methadone-exposed infants had lower birth weights.
However, infants born to methadone-maintained
women have been reported to have higher
birth weights than those born to women using
heroin, while decreased head circumference has
been an inconsistent finding. A meta-analysis of
illicit drug use and neonatal outcomes found birth
weights of newborns born to mothers using heroin
were lower than those of newborns whose mothers used methadone alone, and those of newborns
whose mothers used both heroin and methadone
during their pregnancy.
106
A mean reduction of 483
g (about 1 pound) in birth weight and a relative
risk for low birth weight were associated with any
opiate use during pregnancy. Uncertainty remains
regarding the teratogenicity of opioids. One
systematic review found some association with
oral clefts, ventricular septal defects/atrial septal defects, and clubfoot with prenatal opioid
68
use.
Methadone maintenance had been an accepted
treatment strategy for opioid dependence for more
than 40 years. Beginning in 2010, reports were
published using buprenorphine for the treatment of
maternal opioid use and opioid use disorder as well
the effect on NAS.
*
Buprenorphine in Comparison to
Methadone
Buprenorphine and methadone both act on the
μ-opioid receptor; however, each has a unique
pharmacology. Whereas methadone has approx-
imately 90% oral bioavailability, buprenorphine
has approximately 50% oral bioavailability.
This is because methadone is a full μ-agonist and
buprenorphine is a partial μ-agonist and κ-agonist.
Buprenorphine has higher receptor affinity and a
longer duration of action than methadone.
The MOTHER Study, an eight-site, international, double-blind, double-dummy, flexible-dosing trial compared buprenorphine and methadone
in a comprehensive care environment, enrolling
175 opioid-dependent pregnant women, of whom
131 delivered while on the study. Among the
women who completed the study, there were no
significant differences between the buprenorphine and methadone groups with respect to
any baseline characteristics. There also were
no significant differences between the groups in
primary outcomes (i.e., percentage of neonates
requiring NAS treatment, peak NAS scores, and
head circumference). However, there were sig-
nificant differences in two primary outcome
measures: (1) the total amount of morphine
needed for NAS treatment (mean dose 1.1 mg
vs. 10.4 mg) and (2) the length of hospital
stay (4.1 days vs. 9.9 days). On average, the
buprenorphine-exposed neonates required 89%
less morphine and spent 43% less time in the
hospital than those exposed to methadone.
Table 11.1 compares methadone and buprenor-
phine for the management of women with opioid
use and opioid use disorder in pregnancy. Since
the MOTHER study, investigators continue to
compare the effects of methadone versus buprenorphine for maternal treatment in regard to infant
outcomes. In a study environment, or retrospective
review, methadone and buprenorphine are likely
comparable, but there are some possible advantages
to buprenorphine.
59,83,89,124
However, concerns
remain regarding confounders in these evaluations,
as well as the structure in which buprenorphine is
used in the natural environment.
* References 36,46,48,51,53,54,106,124.
18,50,66,89
51,53
51,53
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TABLE
11.1
Issue Only available through tightly regulated
Risks
Benefits
Issue
Risks
Benefits
Issue
Risks
Benefits
Issue Psychosocial supports mandated Psychosocial supports often not available
Risks
Benefits
Issue
A COMPARISON OF METHADONE AND BUPRENORPHINE FOR THE MANAGEMENT OF WOMEN WITH
OPIOID USE AND OPIOID USE DISORDER IN PREGNANCY
METHADONE BUPRENORPHINE
Available through registered individual providers
programs
Stigma attached to the program.
Limited number of programs, many exclude
pregnancy, difficult for women to access on
short notice because of waiting lists
Carefully regulated with psychosocial
supports and wraparound services; higher
rates of retention in some populations
Dose given either daily or at tightly
regulated time only through the program
Difficult for low-resource or gainfully employed
women to get to the clinic daily
Dosing controlled; patient unable to vary dosing.
Unable to sell doses and/or take more or less
than prescribed
Mandated regular drug screening
Inability to obtain an accurate specimen.
Women fail to come for dosing if worried about
other medications/drugs appearing in the drug
screen
If patient uses other drugs, her supports can
be adjusted to help her maintenance on the
program
Some patients may fail to enroll because of
their aversion to group or individual therapy
Addiction is treated as a multifaceted disease,
not just a physiologic dependence on drugs/
medications
Payment for program: some are state
subsidized, in over one-half of the states.
Medicaid or private insurance provides
coverage.
More likely to receive the medication
covered by insurance because it is dispensed
as part of the program.
87,89,93,112
Not carefully regulated
More easily available to more people
More private and less stigma
Prescription given, often for months at a time with multiple doses
dispensed
Patients can vary their dosing as desired (which may contribute to
increased NAS).
Patients can share or sell dosing and take less or more as desired.
Patients do not have to make a trip for medication at regular intervals
No required drug screening
Patients can use other legal or illegal substances without understanding the
consequences of an increase in NAS
Less expensive program
Addiction not treated as a multifaceted disease; only treats physiologic
dependence on drugs/medications.
Greater risk of relapse postpartally because the underlying disease is not treated.
Patients who would not enroll in a methadone program will seek a provider for
buprenorphine and regulate the exposure of the substance to the fetus, which has
the potential to increase the risk of NAS (from erratic dosing of other substances)
if taken as prescribed without continued use of other drugs/medications.
Payment for program and medication: often not paid for by private
insurance or Medicaid because the drug is dispensed by an “outside
pharmacy.”
Many providers have a “cash-and-carry” model and will not bill
insurance.
50
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Maternal Exposure to Nonopioid
Substances
COCAINE
Although still controversial, the neonatal effects of
maternal cocaine use, especially on fetal growth, is
consistently observed. Researchers hypothesize that
cocaine reduces fetal growth through maternal
vasoconstriction, reduced uteroplacental transfer, and direct effect on fetal metabolism interfering with fat deposition.
placenta by simple diffusion. This occurs because
of its high lipid solubility, low molecular weight,
and low ionization at physiologic pH. In addition,
the low level of plasma esterases in the fetus and
the relatively low pH of fetal blood (cocaine is a
weak base) enhance the accumulation of cocaine
in fetal compartments.79 Taking advantage of the
fact that cocaine and its metabolite benzoylecgonine
(BE) accumulate and can be detected months after
exposure in maternal and neonatal hair, an analytic
test for cocaine and BE has been developed. The
investigators looked at the characteristics of maternal and neonatal hair cocaine as biomarkers of fetal
exposure.37 Cocaine in hair and BE concentrations
are not normally distributed, and there was no correlation between maternal hair cocaine concentration and the baby-to-mother cocaine ratio, which
ruled out a dose-dependent mechanism. However,
the positive correlation between cocaine concentrations in maternal and neonates’ hair
corroborates previous reports showing transplacental transfer of cocaine.
a significant vasoconstrictive property, which
decreases blood flow to the placenta and fetus,
contributing to IUGR and hypoxia.
Accumulated evidence from well-designed
prospective investigations has revealed less severe
sequelae in the majority of infants exposed to
cocaine than originally anticipated. Unlike opioids,
which may produce NAS and neurobehavioral deficits, cocaine exposure appears to be associated
with significant but subtle decrements in neurobehavioral, cognitive, and language function.
Maternal cocaine abuse has been shown to
produce infants of lower birth weight and birth
length, and infants who were significantly more
likely to require medical support or resuscitation.34 Another study revealed children with
intrauterine exposure to cocaine had lower mean
cortical gray matter, lower total parenchymal brain
105
Cocaine crosses the
37,79
Cocaine has
37
8
volumes, and smaller mean head circumferences
than comparison children.
100
The most important
central action of cocaine is its stimulation of the
CNS by inhibiting the reuptake of norepinephrine, serotonin, and dopamine. In the neonatal
period, cocaine, unlike opiates, does not produce
an abstinence syndrome.
As part of the Maternal Lifestyle Study, Bada
et al. used multivariate regression models with more
than 11,000 mother-infant dyads to try to estimate
the effects of cocaine exposure on intrauterine
growth and to investigate when fetal growth deviation would manifest itself in the woman’s gestation.7
After controlling for confounders, at 40 weeks of
gestation, cocaine exposure was estimated to be
associated with decreases of 151 g in birth weight,
0.71 cm in length, and 0.43 cm in head circumference. Investigators concluded that in utero
cocaine exposure was associated with growth
deceleration that becomes more pronounced as
gestation advances.
ALCOHOL
7
Alcohol is the most common teratogen that
fetuses are exposed to in Western societies, and
unlike other teratogens, ethanol has no receptor but
affects cellular activity.
110
In both recent prospective
and retrospective studies of animals and mammals,
ethanol has been shown to cause multiple problems
during gastrulation and organogenesis that includes
cellular growth, differentiation, and migration.
110,120
These cellular effects can be seen with both ethanol
and acetaldehyde and are instrumental in inducing
fetal malformations.
Early exposure to alcohol, whose effects
are globally referred to as fetal alcohol spectrum disorders (FASD) are well-known causes
of mental deficit.
120
FASD is an umbrella term
describing the range of effects that can occur in
an individual who was prenatally exposed to alcohol. These effects may include physical, mental,
behavioral, and/or learning disabilities with lifelong
implications. FASD is not a diagnostic term. It refers
to specific conditions, such as fetal alcohol syndrome (FAS), alcohol-related neurodevelopmental
disorder (ARND), and alcohol-related birth defects
(ARBDs).
111
Research documenting deleterious
outcomes for children prenatally exposed to
even small amounts of alcohol (0.5 drink per
day) has led to a realization that a threshold
(or critical dose effect) has not been identified.
CHAPTER 11 Drug Withdrawal in the Neonate
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257
Current research has also found a genomic effect
that is different in all individuals.
110
When ethanol
exposure is held constant, genetic factors modulate
the risk for cardiac, craniofacial, skeletal, and central
nervous system defects in the developing fetus.
110
In light of these facts, health care professionals
should counsel all women not to drink any
alcohol while pregnant.
97,98
When women consume cocaine and alcohol
together, they compound the danger. Researchers
have found that the human liver combines cocaine
and alcohol to produce a unique metabolite, cocaethylene, which intensifies cocaine’s euphoric effects.
Cocaethylene is associated with a greater risk for
sudden death than cocaine alone.81 Discussions in
the 1990s surrounding the use of cocaine and
alcohol together suggested that cocaethylene
was reported to be 10 times more potent than
cocaine alone and more toxic to the growing
fetus. No current studies further our understanding
of this toxic metabolite.
AMPHETAMINES
Amphetamines and methamphetamines known
as crystal, ice, or crank are abused by pregnant
women in many geographic areas in the United
States with the same frequency as cocaine. Like
cocaine and “crack,” the amphetamines are potent
stimulants, and effects on the fetus and neonate
are similar; also like cocaine the preponderance of
available data would suggest little or no effect of
amphetamine on organogenesis.44 Early research
has shown how in utero amphetamine exposure
can lead to congenital brain lesions, including hemorrhage, infarction, or cavitary lesions. Investigators
also described the sites of these lesions as frontal
lobes, basal ganglia, posterior fossa, or generalized
atrophy; the effects of the lesions are not exhibited
until the child is older. In the neonatal period, neurologic abnormalities including decreased arousal,
poor state control, difficulty with habituation,
tremors, hyperactive neonatal reflexes, abnormal
cry, increased stress, drowsiness, poor feeding, and
seizures have been reported.
109
Outcome effects
of prenatal exposure to amphetamines have yet to
be isolated from the effects of alcohol and nicotine, the two drugs most often used with the
methamphetamines.
81
A review of the literature documents lack of
prenatal care as the hallmark of maternal cocaine
and amphetamine use with an increase in maternal
morbidity and mortality as its consequence.
The use of these stimulants is reported to be
toxic to the fetal brain, and there may be
an increase in sudden infant death syndrome
(SIDS). Stimulants (amphetamines and cocaine)
have been found in breast milk in extremely
high levels, and may produce an acute neurotoxic syndrome with hypertonia, tremors,
apnea, and seizures.
MARIJUANA
7,37,46,105,109
Marijuana, one of the most popular illicit drugs
used by pregnant women,33 has been studied for
many years with conflicting data. Accumulating
evidence in animals and humans indicate that prenatal exposure may result in harm to the developing
fetus. Cannabinoids mediate their effects through
the endocannabinoid receptors, which form very
early in fetal life and have critical function in fetal
and postnatal brain development, neuronal connectivity, and glial cell differentiation.
16,49,102
prospective cross-sectional study that included fullterm infants born to adolescent mothers who used
marijuana, de Moraes et al. found that marijuana
was detected in both the mother’s and the infant’s
hair and that the exposure during pregnancy altered
the neurobehavioral performance of the term newborns when assessed with the neonatal intensive
care unit (NICU) Network Neurobehavioral Scale
(NNNS).
24,46
Other recent studies have highlighted
the long-term effects of marijuana use in pregnancy
on the neonate and child and reveal conflicting
data. While some studies show a correlation with
prenatal marijuana use and increased hyperactivity, impulsivity, inattention symptoms, and
delinquency,81 other studies have reported minimal effects on cognition, language, and motor
development.
16,76
There are also conflicting data
in regard to fetal growth and birth complications,
with few studies citing lower birth weight, others
concluding an increase in NICU admissions, and
still others reporting an increased risk of neonatal
morbidity.
16,76
The only finding that seems consis-
tent across studies is that marijuana does not cause
structural anatomic defects in humans.16 In
summary, there are no randomized controlled trials
on the effect of marijuana use by pregnant and lactating women, and the available longitudinal studies
must be viewed with caution given the potential
confounding of the effect of marijuana during pregnancy by other licit and illicit substances, as well as
46,106
In a
UNIT TWO Support of the Neonate258
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sociodemographic and environmental risk factors.
Given that the evidence about the effects of marijuana use during pregnancy and fetal-related complications and child development is inconclusive,
continued counseling to abstain from marijuana
use during pregnancy needs to be conveyed.
102
Further research is critical to understand the specific
risks to the developing fetus and growing child.
BENZODIAZEPINES
123
Benzodiazepines have hypnotic, muscle-relaxant,
and anticonvulsant properties. They can be used to
treat anxiety, insomnia, panic disorder, seizures, and
agitation, and for sedation.
The data regarding the use of the benzodiazepines (including clonazepam, alprazolam, lorazepam,
and diazepam) during pregnancy are insufficient.
There is some suggestion that there may be an
increased risk of cleft lip and palate associated
with first-trimester exposure to these medications.85 Risk does not seem to be influenced by the
dosage of medication taken by the mother.
There is further concern regarding drug effect
(toxidrome) and withdrawal for the baby exposed
to benzodiazepines in utero. Symptoms of toxic-
ity have been reported in newborns, and these
include sedation, hypotonia, and breathing
problems, as could be seen in anyone exposed to
these medications. Withdrawal symptoms include
irritability, sleep disruption, and, less commonly, seizure. Onset ranges from 12 hours to
3,6,71,115
days.
BARBITURATES
Barbiturates, a type of sedative-hypnotic, are used
to treat anxiety, seizures, and insomnia. Barbiturates
are no longer routinely prescribed for pregnant
women because of concern for birth defects, but
remain a substance of abuse. The drug effect or
toxidrome of barbiturates is similar to those of benzodiazepines described earlier. Withdrawal symptoms
include irritability, tremors, hyperacusis, excessive crying, vasomotor instability, diarrhea, restlessness, increased tone, hyperphagia, vomiting,
and disturbed sleep. Onset can occur during the
first 24 hours, but as late as 10 to 14 days of life.
INHALANTS
3,6,115
No well-controlled, prospective studies have been
done on maternal inhalant use (huffing)—often
substances of abuse in poor and underprivileged
communities because they are widely available (e.g.
acetone), legal, and relatively inexpensive. Organic
solvents are chemical compounds used to dissolve
substances, and although their chemical structures
widely differ, they share some common features:
low molecular weight, lipophilia, and volatility at
room temperature.
73,107
Inhalants are classified into
four groups: volatile solvents, aerosols, gases, and
73,75,107
nitrites.
Inhalants may produce a variety of rapid neuropsychiatric effects with euphoria or drowsiness occurring
within seconds to minutes. Case reports and follow-up
studies of children of inhalant/solvent-abusing mothers are available. Inhalant/solvent-abusing mothers
give birth to babies who are small for gestational
age (SGA) and who have developmental delays,
craniofacial deformities, and an alcohol-like withdrawal syndrome.
ANTIDEPRESSANT USE IN PREGNANT
WOMEN AND OCCURRENCE OF
NEONATAL ABSTINENCE SYNDROME
Psychopharmacology for pregnant women with
coexisting mental health diagnoses are also of concern.42 As many as 70% of pregnant women
experience some symptoms of depression, with
10% to 16% of pregnant women meeting diagnostic criteria for a major depressive disorder.
116
The typical or atypical antipsychotic drugs all pass
the maternal blood–placenta barrier, with significant
difference among compounds.99 Continuing treatment throughout pregnancy, at the lowest effective
dose, may be necessary to prevent relapse and to
prevent potential harmful effects on the mother-fetal dyad. Case reports, adverse drug reaction reports,
and prospective studies have linked third-trimester
use of SSRIs in pregnant women to a constellation
of neonatal signs indicating an altered neonatal
adaptation to extrauterine life. These include
continuous crying, irritability, jitteriness, and/or
restlessness; shivering; fever; tremors; hypertonia or rigidity; tachypnea or respiratory distress;
feeding difficulty; sleep disturbance; hypoglycemia; and seizures. The onset of these signs ranged
from several hours to several days after birth and
usually resolved within 1 to 2 weeks. Biochemical
studies that correlate serial serum SSRI concentrations and markers of CNS serotonin activity
support a drug toxicity phenomena rather than
a drug withdrawal state as the cause of the clinical signs.
46,57,58
A mother on treatment with an
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