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Pharmacist's Letter
Online Training Course
Tiniest Patients – Managing Meds in the NICU
Accreditation, Goals and Objectives | Introduction | Levels of Neonatal Intensive Care
Routine Care of Healthy Newborn | Specialized Needs of Acutely Ill Newborns | The Bottom Line
Quiz Questions | References

Accreditation, Goals and Objectives

Course Accreditation Information, Goals and Objectives

Introduction

What are the different levels of neonatal intensive care? How do these differences impact pharmacists? Does your facility
have a neonatal intensive care unit? If yes, what level is your facility's neonatal intensive care unit?

Neonatal intensive care improves outcomes in high-risk infants. High-risk infants may include preterm infants or those born with serious medical
conditions that may require surgery, such as a congenital heart defect. Not every hospital has a neonatal intensive care unit (NICU), as it
requires prescribers, nurses, and other healthcare professionals with specialized training. However, many hospitals do provide some level of
neonatal care.

Pharmacists play a significant role in the care of newborns, particularly those with specialized needs. It's important for hospital pharmacists to be
aware of these needs and the medications commonly used to treat them. This knowledge will help improve pharmacists' ability to safely manage,
dispense, and monitor medications for this patient population.

Levels of Neonatal Intensive Care

There are approximately 1,500 NICUs in the United States. In fact, the number of critical care beds, in general, is growing, with a 15% increase
from 2006 to 2010.2 The need for NICUs is also increasing. From 1990 to 2010, the rates of preterm births increased by 13%. This is thought to
be a result of elective early cesarean deliveries, multiple births, advanced maternal age, and complications during pregnancy.1 There are
different levels of care provided by neonatal intensive care units as some infants have more significant problems than others. For example,
babies born with a gestational age of less than 32 weeks or with very low birth weight of less than 1,500 grams have increased mortality if they
are born in NICUs that are NOT able to provide a higher level of care.1 This is why the American Academy of Pediatrics (AAP) has provided
guidelines for four different levels of neonatal care.

Level I: Well Newborn Nursery1

Provide neonatal resuscitation at delivery.

Provide postnatal care to stable newborns with a gestational age of at least 35 weeks.

Infants with a gestational age of less than 35 weeks or who are born ill will be stabilized and transferred to a higher level of care.

Expect a level I nursery to be staffed by pediatricians, family physicians, physician assistants, nurse practitioners, and other advanced
practice registered nurses.

Level II: Special Care Nursery (provide Level I care PLUS)1

Provide care to infants with a gestational age of at least 32 weeks and weighing at least 1,500 grams who may be moderately ill but
expected to resolve rapidly and are not expected to require urgent subspecialty services.

Infants with a gestational age of less than 32 weeks or weighing less than
1,500 grams will be stabilized and transferred to a higher level of care.

Provide mechanical ventilations for brief (less than 24 hours) duration or continuous positive airway pressure or both.
Provide care to infants who were previously acutely ill requiring a higher level of care and are now recovering.
Expect a level II nursery to be staffed by pediatric hospitalists, neonatologists, and neonatal nurse practitioners or physician assistants.

Level III: Neonatal Intensive Care Unit (NICU) (provide level II care PLUS)1

Provide comprehensive care for critically ill infants, those born less than 32 weeks' gestation, or those weighing less than 1,500 grams.
Provide sustained life support, including a full range of respiratory support that may include conventional and/or high frequency ventilation
and inhaled nitric oxide.
Perform advanced imaging with interpretation on an urgent basis, such as computed tomography, MRI, and echocardiography.
Provide readily available access to pediatric medical and surgical subspecialists, pediatric anesthesiologists, and pediatric
ophthalmologists.
Expect a level III NICU to be staffed by similar personnel mentioned in a level II nursery, in addition to the pediatric specialists mentioned
in this section.

Level IV: Regional NICU (provide level III care PLUS)1

Provide surgical repair of complex congenital or acquired conditions.

Facilitate transport from other institutions for those infants requiring this higher-level care.
Provide full range of pediatric medical and surgical subspecialists and pediatric anesthesiologists on site.
Provide outreach education.
Expect a level IV regional NICU to be staffed by similar personnel mentioned in a level III NICU, in addition to pediatric surgical
subspecialties.

Routine Care of Healthy Newborn

After delivery, newborns are immediately cared for by drying them, clamping the cord, and assessing their status with a screening tool called an
Apgar score.3,4 The Apgar score provides a standardized assessment of newborns within one and five minutes after delivery. It is generally
repeated every five minutes until the newborn is stabilized. It assesses the neonate's color, heart rate, reflexes, muscle tone, and respiratory
effort. The Apgar score ranges from one to ten with a lower number indicating a poorer status.4 Apgar scores of greater than seven are
considered "reassuring" and normally mean newborns of at least 35 weeks' gestation can be reunited with their mother for initial skin to skin
contact and breastfeeding.3,4 Newborns will be continually assessed over the next 24 hours to ensure their status remains healthy. Expect
monitoring of temperature (concerning if higher than 37.5°C or lower than 35.5°C), breathing rate (concerning if faster than 60 breaths/min),
signs of jaundice, and feeding.3

Vitamin K Deficiency Bleeding

Which newborns should receive vitamin K? How many doses of vitamin K should newborns receive? Which route of
administration is recommended for vitamin K given to newborns?

Vitamin K deficiency can lead to unexpected bleeding in otherwise healthy newborns during the first week of life. Late vitamin K deficiency
bleeding, which is defined as bleeding two to twelve weeks after birth, can also occur. To prevent vitamin K deficiency bleeding, the American
Academy of Pediatrics (AAP) recommends that all newborn infants should be given an intramuscular (IM) dose of 0.5 to 1 mg of vitamin K shortly
after birth.

Oral and IM vitamin K appear to be equally effective at preventing early vitamin K deficiency bleeding, but there appears to be an increased
likelihood of late vitamin K deficiency bleeding with oral administration. This is why AAP recommends using IM rather than oral administration.
You may hear some controversy over an association between IM vitamin K and increased risk of childhood cancer. However, AAP reviewed the
information and did not feel the evidence was strong enough to support the theory. In addition, other studies evaluating this issue have NOT
found an association between IM vitamin K and childhood cancers.

Expect most newborn nursery order sets to include 0.5 to 1 mg of IM vitamin K.5 Commercially-available 1 mg vitamin K syringes are generally
marked with both a 0.5 mg and 1 mg mark so that either dose may be easily administered. Generally, very premature neonates will require the
lower dose of 0.5 mg, while term and near-term infants may receive either a 0.5 mg or 1 mg dose.

Gonococcal Ophthalmia Neonatorum

Which newborns should receive erythromycin ophthalmic ointment? How many doses of erythromycin should newborns
receive? Why is erythromycin ophthalmic ointment used in newborns? What alternatives can be used if erythromycin
ophthalmic ointment is not available?

Another medication included on newborn nursery order sets is a topical ophthalmic antibiotic to prevent gonococcal ophthalmia neonatorum.6
Ophthalmia neonatorum (ON), also known as neonatal conjunctivitis, is an acute infection occurring in the first four weeks after birth. Neonatal
conjunctivitis can be caused by chemical, bacterial, and viral pathogens. Ophthalmia neonatorum caused by Neisseria gonorrhoeae can be
severe, leading to significant complications, including corneal scarring, ocular perforation, and neonatal blindness.7,8 Unfortunately, up to 28% of
newborns born to women with gonorrheal disease will develop this infection. This is why it's important to administer prophylactic therapy to
newborns at an increased risk, such as those born to a mother with a history of sexually transmitted infections, substance abuse, or no prenatal
care. In fact, because of the risk associated with neonatal conjunctivitis caused by Neisseria gonorrhoeae and lack of harm associated with
topical therapy, the United States Preventative Services Task Force (USPSTF) and the Centers for Disease Control and Prevention (CDC)
recommend routine prophylaxis of all newborns, regardless of risk. The recommended therapy is to administer erythromycin 0.5% ophthalmic
ointment in both eyes within 24 hours after delivery.8,9 Because it is a one-time dose, make sure your pharmacy stocks the single-use tubes of
erythromycin ophthalmic ointment. Single-use tubes will prevent staff from re-using multi-dose tubes on more than one patient, which can cause
cross-contamination and possibly transmit infections to other patients. If your pharmacy also carries the multi-dose tubes (often used for
outpatient infections), be sure to separate them in the pharmacy minimize the risk of sending multi-dose tubes up for neonates. Another way to
reduce the risk is to use a "shelf shouter" to remind pharmacy staff to avoid using the multi-dose tubes in neonates.

There may be some circumstances when a multi-dose tube could be used in neonates, such as a shortage of the single-use tubes. Shortages of
all forms of erythromycin ophthalmic ointment can lead to significant problems since it's the only treatment option available in the United States.
There is no clinical data to support other therapies. However, past shortages exhausting all erythromycin supplies did force CDC to provide
therapeutic recommendations. During a shortage in 2019, ceftriaxone 25 to 50 mg/kg given IV or IM (not exceeding 125 mg as a single dose)
was suggested for neonates at risk for exposure, especially if born to a mother at risk for gonococcal infection or with no prenatal care.10
Hopefully, erythromycin ointment shortage problems will not reoccur. If it does, refer to expert organizations such as CDC to evaluate the best
options.

Hepatitis B Prevention

Which newborns should receive the hepatitis B vaccine before discharge? Which newborns should receive hepatitis B
immune globulin? How are the hepatitis B vaccine and immune globulin administered?

Mothers infected with hepatitis B can transmit the virus to their newborns. Before routine hepatitis B vaccination programs, up to 40% of hepatitis
B chronic infections were thought to be caused by perinatal transmission or early childhood transmission. Chronic hepatitis B infections put
patients at an increased risk of developing cirrhosis and liver cancer. In addition, these patients are the main source of continued hepatitis B
transmissions.

In an effort to eliminate the transmission of the hepatitis B virus, the Advisory Committee on Immunization Practices (ACIP) recommends an
immunization strategy which includes universal vaccination of all newborns. ACIP recommends at least three hepatitis B vaccinations ideally
administered at birth, month one, and month six, but schedules may vary slightly. ACIP does recommend the initial dose to be administered
before the newborn leaves the hospital. In addition, they recommend routine screening for hepatitis B surface antigen (HBsAg) in pregnant
women to identify active infection. Newborns born to infected mothers should receive hepatitis B immune globulin (HBIG) to prevent the onset of
the infection. The strategy has been quite effective with a 94% decline in the incidence of hepatitis B among children and adolescents.11,12

ACIP provides very specific recommendations for screening pregnant women and vaccinating infants against hepatitis B. These
recommendations involve:12

HBsAg Screening of Pregnant Women

At an early prenatal visit, screen all pregnant

During admission for delivery, screen women:

Who were not screened yet

Who engaged in high-risk behaviors for developing the disease since last screening (such as multiple sexual partners,
abusing injection drugs, etc)
Who had clinical hepatitis since last screening

Vaccinating infants (and providing the immune globulin when necessary, based on the HBsAg status of the mother)12

Status of the Mother Administration of Vaccine Prior to Discharge

Born to HBsAg-positive mothers
Hepatitis B vaccine* Yes, administer within 12 hours of birth.
 Hepatitis B immune globulin (HBIG) Yes, administer within 12 hours of birth.

Born to HBsAg-unknown mothers

*For example, initial testing performed during admission and result is not back yet.
Hepatitis B vaccine* Yes, administer within 12 hours of birth.

Newborns weighing less than 2,000 grams, administer within 12

hours of birth.
Newborns weighing 2,000 grams or more AND maternal status is
Hepatitis B immune globulin unable to be obtained, administration is NOT necessary. (Some
(HBIG) institutions may still consider administration if a there is a high
suspicion of maternal hepatitis B infection.)
Newborns weighing 2,000 grams or more AND maternal status is
pending, administer as soon as maternal status is found to be
positive and no later than seven days after birth.
Born to HBsAg-negative mothers
Newborns weighing less than 2,000 grams, administer at one month
Hepatitis B vaccine* or prior to discharge (whichever occurs first).
Newborns weighing 2,000 grams or more, administer within 24 hours
of birth.
Hepatitis B immune globulin
(HBIG) No, do not give.

*Use Recombivax HB or Engerix-B for the initial dose. Pediarix cannot be administered before 6 weeks of age.

PB was admitted in early labor. Her past medical history is significant for multiple sexual partners. She has not received
regular prenatal care. PB's HBsAg status is unknown. Labs are drawn, and results are pending. PB delivers an 1,800-
gram baby girl, and names her Jessica.

What medication(s) should be given to Jessica to prevent hepatitis B? What dose(s) are appropriate for Jessica? How
soon after delivery should dose(s) be given?

Hospitals caring for newborns should implement standing orders for screening of mother's HBsAg status and administration of vaccines and
HBIG. For examples, delivery admission orders should inquire about the mother's HBsAg status (or lack of screening) and presence of any risk
factors, such as multiple sex partners. Mothers with unknown HBsAg status or negative status plus risk factors for developing the disease should
automatically trigger an order for the HBsAg screening. Consistent location for documenting HBsAg status of pregnant women will improve
communication to all team members. All stable newborns weighing at least 2,000 grams should have standing orders to receive the hepatitis B
vaccine, while those weighing less than 2,000 grams should be determined by the mother's HBsAg status. It's important to document vaccine
administration and for discharge procedures to verify all necessary vaccines have been administered prior to discharge. Finally, a process needs
to be in place for ensuring follow-up with the newborn's outpatient prescriber occurs for any pending HBsAg status.13

The hepatitis B vaccine should be administered by IM injection into the anterolateral thigh muscle. The dose of the hepatitis B vaccine varies
depending upon the product used. For example, Recombivax HB is 5 micrograms compared to Engerix-B which is 10 micrograms, however both
products are 0.5 mL and considered equivalent. Other hepatitis B products are not indicated for newborns, such as an adult, two-dose hepatitis B
vaccine containing an adjuvant (Heplisav-B), the combination hepatitis B-diphtheria, tetanus, and acellular pertussis-inactivated poliovirus
(Pediarix), or combination hepatitis A and hepatitis B (Twinrix). Be familiar with the products on your formulary to prevent any confusion.12,14 All
infants, regardless of the mother's HBsAg status, should complete the recommended vaccine series as an outpatient according to the latest
guidelines. Current guidelines recommended a total of three doses for most children, including the first dose administered after birth, prior to
discharge. For infants born to HBsAg positive mothers who weigh less than 2,000 grams, a total of four doses should be given (one dose within
12 hours of birth and three additional doses beginning at one month of age.12

Hepatitis B immune globulin (HBIG) may be administered at the same time as hepatitis B in those qualifying newborns. The HBIG dose is 0.5 mL
administered by IM injection into the anterolateral thigh muscle using a different injection site (opposite leg) than the hepatitis B vaccine.12,15

Specialized Needs of Acutely Ill Newborns

Despite proper neonatal care, some infants become acutely ill and require special care or medications. These illnesses can involve infections,
such as sepsis and respiratory syncytial virus infections. In addition, specialized care is necessary in newborns with neonatal abstinence
syndrome.

Sepsis

What are risk factors for neonatal sepsis? Which organisms are common causes of neonatal sepsis? Which empiric
therapy is recommended for early- and late-onset neonatal sepsis?

Neonatal sepsis is rare, but a significant cause of morbidity and mortality in neonates. It is most commonly caused by bacterial infections with
pathogens varying depending on whether the onset is "early" or "late." Early-onset sepsis occurs within the first 72 hours after delivery. In this
case, neonates are most likely to develop infection because of transmission from the mother.16,17 For example, neonates may aspirate bacteria-
colonized amniotic fluid while in utero.

Maternal factors that increase the risk for early-onset sepsis include:16,17

Prolonged rupture of amniotic membranes (longer than 18 hours)

Maternal infections during delivery
Maternal colonization of pathogens, such as group B Streptococcus, at the time of delivery

Some institutions may use sepsis risk calculators to help ensure appropriate use of antibiotics. An example of one of
these calculators is the Kaiser Permanente Neonatal Early-Onset Sepsis Calculator.

Neonatal risk factors for early-onset sepsis include:16,17

Premature newborns (gestational age less than 37 weeks)

Low birth weight, especially very low birth weight neonates (less than 1,500 grams)
Late-onset sepsis occurs after the first 72 hours after delivery and is most often caused by environmental factors after delivery. Newborns are at
greater risk of developing late-onset sepsis with the use of invasive devices or procedures, such as central/umbilical catheters, mechanical
ventilation, and parenteral nutrition.16,17

Signs and symptoms of early- and late-onset sepsis are the same. However, a newborn is not able to tell us they don't feel well. Monitor for
neonatal signs of infection, such as temperature instability, tachycardia, and abnormalities in white blood cell count. Other signs and symptoms
include lethargy, grunting, retraction, apnea, and even seizures.16,17

Early-Onset Sepsis

The two most common bacteria causing early-onset sepsis, accounting for about 70% of the cases, include group B Streptococcus and
Escherichia coli. Both of these organisms can colonize a woman's gastrointestinal and genitourinary tract, which can lead to newborn
contamination. Other causative organisms can include Listeria monocytogenes, Streptococcus pyogenes and viridians, Streptococcus
pneumonia, Haemophilus influenzae, Staphylococcus aureus, enterococci, and Pseudomonas aeruginosa.16,17

Empiric antibiotic regimens usually include ampicillin in addition to an aminoglycoside. You may also see a cephalosporin used (ceftazidime,
cefepime, etc) used as an alternative or in addition to aminoglycosides, especially when good cerebrospinal fluid penetration is needed. Cultures
should be drawn PRIOR to starting antibiotics and followed to evaluate therapy. If the culture remains negative at 48 hours and the patient is
clinically stable without signs or symptoms of sepsis, it's recommended to discontinue therapy. If a pathogen is identified, tailor the antibiotic
regimen to these results. The duration of antibiotic therapy will vary depending on the pathogen and original source of the infection. For example,
bacteremia without an identifiable source may be treated for seven to 10 days compared to at least 21 days for gram-negative meningitis.16,17

Prevention of Group B Streptococcal Disease

Group B streptococcal (GBS) disease is the leading cause of morbidity and mortality among infants. Newborns with early-onset group B
streptococcal disease normally experience respiratory distress and pneumonia, sepsis, and sometimes meningitis within the first 24 to 48 hours
after birth. GBS disease is caused by the transmission from mothers to their newborn prior to or during delivery. Because of this, CDC
recommends routine screening of all pregnant women prior to delivery. Women identified at risk will receive intrapartum (during delivery)
antibiotic prophylaxis with penicillin or ampicillin to prevent the transmission to their newborn. Cefazolin is recommended for women with mild
penicillin allergies, such as rash. Adequate intrapartum prophylaxis is considered administration of penicillin (every four hours), ampicillin (every
four hours), or cefazolin (every eight hours) until delivery. For women with significant allergic reactions, such as angioedema or respiratory
compromise, clindamycin is recommended for susceptible GBS. If the susceptibility is unknown or it's resistant, then vancomycin (1 gram given
every 12 hours until delivery) is the recommended alternative. The use of prophylactic antibiotics has reduced mortality associated with GBS
disease from 50% in the 1970's to 4% to 6% after intervention.18

Indications for prophylactic antibiotics in pregnant women to prevent neonatal group B Streptococcus include:18

Previous infant with invasive GBS disease

GBS isolated from urine during pregnancy, including those with symptomatic or asymptomatic urinary tract infections which were treated
Positive screening (screening normally performed during weeks 35 to 37 of pregnancy)
Unknown GBS status at the onset of labor (culture not performed yet, results unknown, etc) AND any of the following risk factors:

Delivery sooner than 37 weeks' gestation

Amniotic membrane rupture for 18 hours or more
Intrapartum temperature 100.4 F (38 C) or higher
Intrapartum nucleic acid amplification test is positive for GBS

Note: prophylactic antibiotics are not indicated if a cesarean delivery is performed prior to the onset of labor with an intact amniotic membrane.
However, even women planning on having a cesarean delivery will have GBS screening and risk factors collected. This information needs to be
available to determine antibiotic prophylaxis needs depending on the status of the delivery.18

Late-Onset Sepsis

The most common pathogen to cause late-onset sepsis is coagulase-negative Staphylococcus accounting for about 50% of the infections. Other
pathogens can include Staphylococcus aureus, Enterococcus species, GBS, and gram-negative bacteria such as Escherichia coli, Klebsiella,
Pseudomonas, Enterobacter, and Serratia.16,19

Empiric antibiotic regimens commonly include gentamicin or a third-generation cephalosporin plus either vancomycin or ampicillin, depending on
the susceptibility patterns for the common gram-positive pathogens for the hospital or presumed source of infection. Some institutions may use
nafcillin/oxacillin rather than ampicillin to cover for Staphylococcal infections. Just like with early-onset sepsis, the duration of antibiotic therapy
will vary depending upon source and pathogen. Follow-up on culture results to tailor therapy or potentially discontinue antibiotics if cultures
remain negative after 48 hours.16,19

Methods to prevent late-onset sepsis include using aseptic technique during placement of invasive devices and while compounding IV
formulations, such as parenteral nutrition. In addition, it's important to follow the hospital's infection prevention policies and processes to prevent
the onset of hospital-acquired infections.16,19

Respiratory Syncytial Virus

What are the symptoms of respiratory syncytial virus (RSV) infections? What treatments are available for RSV? Which
patients should receive palivizumab? How is palivizumab use restricted to ensure appropriate use?

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections. Almost all children are infected with RSV by the
time they reach two years of age. RSV infections normally present as a cold-like illness with runny nose, sneezing, cough, fever, and nasal
congestion. This may not be that severe in some young patients. However, in premature infants or those with chronic diseases, such as cardiac
or pulmonary disease, RSV can be quite severe.20,21 Many infants with RSV infection will develop bronchiolitis, which is inflammation, swelling,
and mucous build-up in the bronchioles. Up to two out of every 100 children younger than six months of age infected with RSV may need to be
hospitalized.21 In fact, RSV is the most common cause of acute lower respiratory infection in children and is the most common cause of
hospitalization in infants.22

Palivizumab is a monoclonal antibody with anti-RSV activity. It is indicated to prevent serious respiratory tract infections in high-risk children.
Palivizumab is administered monthly during RSV season via IM injections, with the first injection given prior to the onset of RSV season. RSV
season varies depending on location. In the United States, RSV season typically occurs sometime between November and April. It's
recommended to provide a maximum of five monthly injections during RSV season.23 For example, if prophylaxis is initiated in October, then the
fifth and final dose would be given in February. Infants born during the season will likely require fewer than five doses. For example, infants born
in January would receive their last dose in March or April, depending on the RSV season in their area.

Hospitals should provide the initial dose for newborns born with risk factors during RSV season prior to discharge or ensure follow-up with
administration within 48 hours of discharge. Because the indication for palivizumab is fairly broad with limited data supporting its ability to reduce
hospitalizations, the American Academy of Pediatrics (AAP) has provided guidance to help promote where this agent may be best utilized.24
With the cost of palivizumab exceeding $1,000 per dose, expect most hospitals to have restrictive criteria for this medication to ensure it's being
used according to this expert guidance.25

AAP recommends palivizumab in the following high-risk patients during RSV season:24,26

Preterm infants born before 29 weeks' gestation who are less than 12 months old at the start of RSV season

Not recommended in their second year of life without additional risk factors

Preterm infants born before 32 weeks' gestation with chronic lung disease (which is defined as requiring more than 21% oxygen beyond
the first 28 days after birth) and who are less than 12 months old at the start of RSV season

Only recommended in their second year of life if still requiring medical therapy to treat their lung disease for 6 months prior to RSV
season

Infants with hemodynamically significant heart disease, require medication for heart failure, or who have pulmonary hypertension who are
less than 12 months old at the start of RSV season

Not recommended in their second year of life, with the exception of children who undergo cardiac transplantation in the first two
years of life

Infants with neuromuscular disease or congenital abnormality preventing them from being able to remove secretions from their upper
airway who are less than 12 months old
Infants who are profoundly immunocompromised, such as hematopoietic stem cell transplant patients, who are less than 24 months old
at the start of RSV season
There's insufficient data to recommend palivizumab prophylaxis for infants with cystic fibrosis or Down syndrome

It's important to point out that palivizumab is not indicated for treatment of RSV. In addition, palivizumab is not recommended to control outbreaks
of RSV infection in hospitals. There are no data to support its efficacy. The best method to prevent healthcare-associated RSV infections is to
follow the hospital's infection prevention policies and procedures.24

When indicated, recommend palivizumab 15 mg/kg given monthly via IM injections with the first dose given prior to hospital discharge.
Palivizumab should be administered into the outside of the middle/upper part of the thigh (anterolateral). Adverse effects with palivizumab are
rare. Serious adverse reactions that may occur include anaphylactic-type reactions, injection-related reactions, and possible severe
thrombocytopenia.23

Neonatal Abstinence Syndrome

What is neonatal abstinence syndrome? What are common signs and symptoms associated with neonatal abstinence
syndrome? Which medications are typically used to treat neonatal abstinence syndrome? How are medications adjusted
in treating neonatal abstinence syndrome?

Neonatal abstinence syndrome (NAS) may occur in neonates after maternal use of certain substances, such as opioids, during pregnancy. The
neonate will generally undergo withdrawal 24 to 72 hours after birth due to an abrupt discontinuation of exposure to the substance post-
delivery.27 Onset may present later (five days after birth) for those born to mothers on longer acting opioids like methadone. The incidence of
neonatal abstinence syndrome is increasing. Approximately 8.5% of women abuse illicit drugs during their pregnancy.28 However, it's important
to note that neonatal abstinence syndrome is not only seen in neonates born to women abusing drugs. This may occur in any neonate whose
mother is taking medications that may be more appropriately titrated prior to discontinuation. Some examples include opioids used for the
management of sickle cell disease or barbiturates or benzodiazepines used for seizure disorders, etc.

The signs of neonatal abstinence syndrome can range from irritability and excessive crying to more severe symptoms such diarrhea causing
dehydration and electrolyte imbalances, tremors, and even seizures. Some signs, such as temperature instability, tachypnea, and nasal
stuffiness, can be confused with other complications, such as respiratory distress, and will require a full work-up to evaluate the diagnosis. GI
side effects, such as regurgitation and vomiting, are common and can lead to poor weight gain in newborns.27

Ask the mother about any and all medications used during pregnancy. Keep in mind, some mothers may not admit to the use of illicit substances.
Document all medications (prescribed, over-the-counter [OTC], or illicit). If any medications associated with neonatal abstinence syndrome are
identified, monitor for known complications. If newborns are exhibiting signs and symptoms, toxicology screening should be considered. This can
be done by performing an analysis of the neonate's initial urine, meconium (their first dark green stool), or umbilical cord.27

The onset, duration, and severity of the withdrawal depend on what substance the mother was using, how much she used, and the timing of her
last exposure to the drug. If the newborn is showing signs of withdrawal, it's important to work closely with the mother to gather as much
information as possible to optimize the treatment plan.27

Non-pharmacological therapy will be attempted first. This includes swaddling the newborn and reducing stimulation, such as noise and light, to
try to decrease their agitation and promote sleep. It's recommended to provide frequent feeds with breastmilk or high calorie formulas to meet
their metabolic demands. The newborn's feeding, weight gain, and sleep should be monitored closely to ensure the newborn is progressing in
the right direction. There are tools that provide scores for various withdrawal symptoms to help determine the severity and monitor for
improvement once treatment has been started. For example, the modified Finnegan Neonatal Abstinence Scoring Tool is a commonly used
scoring system.27

An infant, LF, exposed to opioids in utero, is experiencing severe neonatal abstinence syndrome (NAS). LF weighs 3 kg.
He is in severe withdrawal, based on his modified Finnegan score. What treatment options should be considered? What
monitoring should be done?

Medications may be necessary for those newborns with more severe withdrawal interfering with their feeding, sleep, development, movements,
or behavior. Mediation is recommended when:27

Withdrawal signs and symptoms are severe. For example infants with seizures or significant nausea and vomiting leading to dehydration.
Supportive therapy fails to control withdrawal signs and symptoms.

Since neonatal abstinence syndrome can be caused by exposure to a variety of substances, there is no standardized treatment option. It's
recommended to avoid opioid antagonists, such as naloxone, since it may precipitate seizures. Morphine and methadone are two commonly
used medications for NAS due to opioid exposure.27,29 Due to its shorter half-life, expect to see morphine dosed every three to four hours
compared to every six to twelve hours with methadone. After initial doses are chosen, the dose may be increased as needed to control
withdrawal symptoms with the ultimate goal of titrating off the medication while maintaining symptom control.27

Example morphine protocol for neonatal abstinence syndrome:27

Step 1: Start medication and monitor newborn with modified Finnegan scoring every three to four hours during the first 24
hours

Step 2: Determine severity to decide if medication should be started

If scores remain less than 8 after birth, continue monitoring every three to four hours for the next three to five days
(Monitoring may need to be extended up to seven days if infants were exposed to meds with a longer half-life,
such as methadone).
If infant remains stable, may consider discharge with close follow-up
If scores worsen, may need to start pharmacological therapy
If severe scores are obtained (two consecutive scores of 12 or higher or three consecutive scores of eight or
higher):

Start morphine 0.05 mg/kg/dose enterally every 3 hours

Step 3: If medication is started, will need to monitor and potentially adjust dose:

Increase dose by 10% if scores remain elevated; consider rescue doses for two consecutive scores of at least 12
Titrate to a maximum dose of 1.3 mg/kg/day
Consider adjunct therapy with clonidine or phenobarbital if maximum dose reached without symptom control
After the patient remains stable (scores less than 8) for 24 to 48 hours, consider weaning the dose as tolerated by
10% to 20% every 24 to 48 hours; continue to monitor scores every 4 hours

Phenobarbital may also be used as an adjunct to morphine or methadone in severe withdrawal, especially those exposed to multiple substances.
Clonidine may also be used as an adjunct to methadone and morphine; however, monitor for side effects such as hypotension and
bradycardia.27

Helpful example dosing information for meds used for neonatal abstinence syndrome:27,29
Medication Dose Notes
Morphine Initial dose: 0.05 to 0.2 mg/kg Short half-life (9 hours)
Dosing frequency: every 3 to 4 Recommend using a standard dilution to 0.4
hours mg/mL
Titrate by: 0.05 mg/kg
Suggested max dose: 1.3
mg/kg/day
Methadone Initial dose: 0.05 to 0.1 mg/kg Long half-life (26 hours)
Dosing frequency: every 12 Alcohol is an ingredient in the liquid
hours formulation
Titrate by: 0.05 mg/kg
Suggested max dose: 1
mg/kg/day
Buprenorphine Initial dose: 4 to 5 mcg/kg Short half-life (12 hours)
Dosing frequency: every 8 hours Alcohol is an ingredient used when
Titrate by: 4 mcg compounding the liquid formulation
Max dose: 60 mcg/kg/day
Phenobarbital Loading dose: 10 to 16 mg/kg Long half-life
followed by maintenance dose 24 (45 to 100 hours)
hours later Monitor levels
Maintenance dose: 1 to 2.5 Alcohol is an ingredient in the liquid
mg/kg/dose every 12 hours formulation
Max maintenance dose: 5
mg/kg/day
Clonidine Initial dose: 0.5 to 1 mcg/kg Long half-life
Dosing frequency: every 4 to 6 (44 to 72 hours)
hours Hypotension and bradycardia
Titrate by: 0.5 mcg/kg Abrupt discontinuation may cause
Max dose: 4 to 6 mcg/kg/day hypertension and tachycardia

It's important to make sure your pharmacy has standardized oral liquid concentrations and treatment protocols for neonatal abstinence
syndrome. Many hospital pharmacies will send the patient-specific dose drawn up in a unit dose syringe for the infant. This makes keeping up
with daily titrations, especially the controlled substances, challenging. This is why hospital pharmacies may include safety checks, such as
independent verification of the dose, prior to sending the dose to the floor. In addition, it's important to be aware of your controlled substance
policies to ensure the documentation for any dose changes occur. For example, if the morphine dose decreases, then the pharmacist may need
to adjust the dose in the syringe and waste some of the morphine. Make sure proper documentation of waste occurs, such as having a second
person witness and document the waste.

Let's go back to our patient case:

An infant, LF, exposed to opioids in utero, is experiencing severe neonatal abstinence syndrome. The infant weighs 3 kg.
His modified Finnegan scores are consistently above 8 and morphine is started.

LF is started on 0.3 mg (0.1 mg/kg/dose) of morphine every four hours. Your hospital's standardized pediatric morphine
liquid concentration is a dilution of 0.5 mg/mL.

The hospital procedure is to draw up patient-specific doses. What volume should be drawn into the syringe? What size
syringe should be used?

0.3 mg of morphine liquid 0.4 mg/mL = 0.75 mL

It's best to use the smallest syringe size possible since future small titrations may be needed in the dose.
Consider using a 1 mL syringe.
 The following day the dose was reduced by 10% to 0.27 mg every 4 hours. What is volume should be drawn up to
achieve this dose?

0.27 mg of morphine liquid 0.4 mg/mL = 0.675 mL

This example emphasizes how complicated treatment can be and the importance of adding procedures to prevent errors. Strategies, such as
independent verification, may seem time consuming, but it's so important to ensure accuracy for these complex regimens. Pharmacists can play
a significant role in ensuring patients receive the care they need in the safest way possible.

The Bottom Line

Pharmacists play an important role in the medication management of neonates. All newborns require some medications, but these are primarily
low-risk meds, such as vaccines and prophylactic ophthalmic ointments. However, sicker newborns requiring intensive care need more advanced
medication management. This may be challenging, especially for pharmacists less familiar with their care, since small dosing errors can lead to
significant harm in such small patients.

Pharmacists should familiarize themselves with their hospital antibiogram and commonly used antibiotic regimens for sepsis. This can help
answer prescribing questions and follow-up on important monitoring, as required. Pharmacists may also want to review hospital protocols for
meds such as palivizumab, which may contain restrictive criteria. Finally, treatment regimens for neonatal abstinence syndrome can be quite
complex and require careful review to ensure the correct dose is being dispensed. By becoming more familiar with medications commonly given
to newborns, pharmacists can be better prepared to verify orders, dispense medications, and assist prescribers with questions. Pharmacists
should also be aware of their hospital policies and procedures to prevent errors in this high-risk population.

Quiz Questions

Question #1
Which newborn may be cared for at a level II special care nursery?
a. 30 weeks’ gestation with significant respiratory compromise

b. 32 weeks’ gestation, weighing at least 1,500 grams, moderately ill

c. 35 weeks’ gestation, weighing at least 2,000 grams, medically stable

d. 37 weeks’ gestation, critically ill, requiring complex, specialized surgery

Question #2
Which route of administration for vitamin K is most likely to be part of newborn nursery order sets?
a. Intramuscular

b. Intravenous

c. Oral

d. Sublingual

Question #3
Which best describes which newborns should receive erythromycin ophthalmic ointment
prophylaxis?
a. All newborns

b. Born before 32 weeks’ gestation

c. Delivered vaginally

d. Weighing less than 1,500 grams

Question #4
What is the longest recommended interval between birth and administration of the hepatitis B
vaccine for infants born to HBsAg-positive mothers?
a. 1 month

b. 10 days

c. 7 days

d. 12 hours

Question #5
Which regimen is recommended for an infant weighing 2,500 grams born to an HBsAg-positive
mother?
a. One dose of pediatric hepatitis B vaccine (0.5 mL), given IM (with completion of the dosing
series given as an outpatient).
b. One dose of hepatitis B immune globulin 0.5 mL and one dose of pediatric hepatitis B
vaccine 0.5 mL, both given IM (with completion of the hepatitis B vaccine dosing series given
as an outpatient).
c. Two doses of hepatitis B immune globulin (0.5 mL/dose), given IM separated by 12 hours.
d. Two doses of hepatitis B immune globulin (0.5 mL/dose) and one dose of pediatric
hepatitis B vaccine 0.5 mL, both given IM (with completion of the hepatitis B vaccine dosing
series given as an outpatient).

Question #6
Which antibiotics are commonly used for empiric treatment of EARLY-onset sepsis?
a. Vancomycin plus gentamicin

b. Vancomycin plus ciprofloxacin

 c. Ampicillin plus gentamicin

d. Ampicillin plus ciprofloxacin

Question #7
Which mothers should receive prophylactic antibiotics during delivery to prevent group B
Streptococcus (GBS) infections in their newborns?
a. All mothers should receive prophylactic antibiotics during delivery.

b. Mothers delivering by cesarean without prior amniotic membrane rupture

c. Mothers delivering more than one baby at a time (e.g., twins, triplets)

d. Mothers with an unknown GBS status delivering before 37 weeks’ gestation

Question #8
Which infant should receive a dose of palivizumab per the American Academy of Pediatrics
guidelines?
a. Stable newborn born at 31 weeks' gestation who is 3 months old at the start of RSV
season
b. 14-month-old admitted with hemodynamic instability from heart disease during RSV
season
c. Newborn born at 38 weeks' gestation with cystic fibrosis who is 10 months old at the start
of RSV season
d. Newborn born at 28 weeks' gestation who is 11 months old at the start of RSV season

Question #9
An infant weighing 2.5 kg is prescribed 0.05 mg/kg of morphine. Your hospital’s standardized
morphine liquid concentration is 0.5 mg/mL. What is the volume of the morphine dose for this
infant?
a. 0.062 mL

b. 0.125 mL

c. 0.25 mL

d. 0.375 mL

Question #10
An infant with neonatal abstinence syndrome is initially prescribed morphine. How should morphine
be adjusted, if Finnegan scores are consistently 12 after starting morphine?
a. Decrease morphine dose

b. Decrease morphine frequency

c. Increase morphine dose

d. Increase morphine frequency

Submit your answers

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