MAY 2022

Mexican Edition, Volume 1, No. 5

www.neoreviews.org

ARTICLES

Updates for the Neonatal Resuscitation

Program and Resuscitation Guidelines

Appropriate Management of the

Nonvigorous Meconium-Stained
Newborn

INDEX OF SUSPICION IN THE NURSERY

Term Male Infant with Abdominal Mass

An Uncommon Cause for Respiratory

Failure in a Preterm Neonate

Preterm Infant with Respiratory

Distress, Hypotonia, and Hypoglycemia
 NeoReviews
ARTICLES Editor-in-Chief: Dara Brodsky, Boston, MA
Associate Editor: Josef Neu, Gainesville, FL
Associate Editor, CME: Henry C. Lee, Palo Alto, CA
1 Updates for the Neonatal Resuscitation Program Associate Editor, NeoQuest: Rita Dadiz, Rochester, NY
and Resuscitation Guidelines Associate Editor, Perspectives: Mamta Fuloria, Bronx, NY
Associate Editor, Visual Diagnosis: Beena Sood, Detroit, MI
Gary M. Weiner, Jeanette Zaichkin Associate Editor, Video Corner: Akshaya Vachharajani, Columbia, MO
Assistant Editor, CME: Santina A. Zanelli, Charlottesville, VA
11 Appropriate Management of the Nonvigorous Early Career Physician:
Theodore De Beritto, Los Angeles, CA
Meconium-Stained Newborn Editorial Fellow:
Arpitha Chiruvolu, Thomas E. Wiswell Colby Day, Jacksonville, FL
EDITORIAL BOARD
Carl Backes, Columbus, OH
Alison Chu, Los Angeles, CA
INDEX OF SUSPICION IN THE NURSERY Sergio Golombek, Valhalla, NY
Corinne L. Leach, Buffalo, NY
21 Term Male Infant with Abdominal Mass Krithika Lingappan, Houston, TX
Thomas E. Wiswell, Honolulu, HI
Arya Kudalmana, Bo Rum Kim, Euming Chong Clyde Wright, Aurora, CO
Brett Young, Boston, MA

24 An Uncommon Cause for Respiratory Failure in a Managing Editor: Heidi Willis

Manager, Journal Publishing: Josh Sinason
Preterm Neonate Medical Copy Editor: Beena Rao
Sanchi Malhotra, Vikram Anand, Jeffrey M. Bender, Arlene Garingo Publisher: American Academy of Pediatrics
President: Moira A. Szilagyi
Chief Executive Officer/Executive Vice President:
27 Preterm Infant with Respiratory Distress, Mark Del Monte
Chief Product and Services Officer/SVP Membership, Marketing,
Hypotonia, and Hypoglycemia and Publishing:
Venkata S. Gupta, Tiffany L. Walker, Christelle M. Ilboudo, Anjali Mary Lou White
Vice President, Publishing: Mark Grimes
P. Anders Director, Journal Publishing: Joseph Puskarz
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ARTICLE

Updates for the Neonatal

Resuscitation Program and
Resuscitation Guidelines
Gary M. Weiner, MD,* Jeanette Zaichkin, RN, MN, NNP-BC†
*Department of Pediatrics, Neonatal-Perinatal Medicine, C.S. Mott Children’s Hospital, University of Michigan, Ann Arbor, MI
†
Positive Pressure, PLLC, Shelton, WA

PRACTICE GAP
Updated treatment guidelines for neonatal resuscitation need to be
applied to clinical practice.

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

1. Explain the process of developing neonatal resuscitation guidelines and

educational materials.
2. Summarize the steps included in the Neonatal Resuscitation Program
treatment algorithm.
3. Discuss 6 practice changes included in the Neonatal Resuscitation
Program, 8th edition.
4. Describe 6 ventilation corrective steps that may improve the
effectiveness of positive pressure ventilation in the newborn.

AUTHOR DISCLOSURES Ms Zaichkin is the ABSTRACT

Associate editor of the Textbook of Neonatal
Resuscitation. Dr Weiner is the Editor in chief
Although most newborns require no assistance to successfully transition to
of the Textbook of Neonatal Resuscitation. This extrauterine life, the large number of births each year and limited ability to
commentary does not contain a discussion of predict which newborns will need assistance means that skilled clinicians must
an unapproved/investigative use of a
be prepared to respond quickly and efficiently for every birth. A successful
commercial product/device.
outcome is dependent on a rapid response from skilled staff who have
mastered the cognitive, technical, and behavioral skills of neonatal resuscitation.
ABBREVIATIONS
Since its release in 1987, over 4.5 million clinicians have been trained by the
AAP American Academy of Pediatrics American Heart Association and American Academy of Pediatrics Neonatal
AHA American Heart Association
CoSTRs Consensus on Science with
Resuscitation ProgramV R . The guidelines used to develop this program were

Treatment Recommendations updated in 2020 and the Textbook of Neonatal Resuscitation, 8th edition, was
CPAP continuous positive airway released in June 2021. The updated guidelines have not changed the basic
pressure
approach to neonatal resuscitation, which emphasizes the importance of
ETT endotracheal tube
HR heart rate anticipation, preparation, teamwork, and effective ventilation. Several practices
ILCOR International Liaison Committee have changed, including the prebirth questions, initial steps, use of electronic
on Resuscitation
cardiac monitors, the initial dose of epinephrine, the flush volume after
PPV positive pressure ventilation
RQI Resuscitation Quality intravascular epinephrine, and the duration of resuscitation with an absent heart
Improvement

Vol. 1 No. 5 MAY 2022 1

 rate. In addition, the program has enhanced components of the textbook to improve learning, added new course
delivery options, and offers 2 course levels to allow learners to study the material that is most relevant to their role
during neonatal resuscitation. This review summarizes the recent changes to the resuscitation guidelines, the
textbook, and the Neonatal Resuscitation Program course.

INTRODUCTION called Consensus on Science with Treatment Recommen-

Most neonates born at or near term will initiate breathing dations (CoSTRs). The individual CoSTRs are published
shortly after birth either spontaneously or in response to on the ILCOR website (www.ilcor.org) for public com-
stimulation and drying. Approximately 5% to 7% of term ments, and summaries of multiple statements are pub-
newborns will require positive pressure ventilation (PPV) lished periodically in the journals Circulation and
with a face mask to initiate spontaneous respiratory effort Resuscitation. (2)(6) Based on local resources, systems of
in the delivery room and a smaller number will require care, and other contextual issues, ILCOR consensus state-
advanced resuscitation skills such as tracheal intubation, ments are used by member councils to inform their
chest compressions, or emergency epinephrine adminis- national or regional guidelines. In North America, the
tration. (1)(2) A successful outcome is dependent on a CoSTRs are used by the AHA and AAP to develop neona-
rapid response from skilled clinicians who have mastered tal resuscitation guidelines. The most recent AHA Guide-
the cognitive, technical, and behavioral skills of neonatal lines for Cardiovascular Care and Emergency Cardiac Care:
resuscitation. Part 5: Neonatal Resuscitation were released on October 21,
In 1987, the American Academy of Pediatrics (AAP) 2020. (4) Finally, the AAP NRP Steering Committee cre-
and the American Heart Association (AHA) released the ates the educational materials that support the goal of hav-
first educational program specifically designed to address ing a qualified individual who can initiate resuscitation at
the resuscitation of newborns immediately after birth. every birth and a qualified team with full resuscitation
Since that time, the Neonatal Resuscitation ProgramV
R
skills immediately available for every resuscitation.
(NRP) has become the North American training standard
for health care professionals who are responsible for the THE NEONATAL RESUSCITATION ALGORITHM
care of newborns in the hospital setting. (3) The guidelines In contrast to adult cardiopulmonary resuscitation, estab-
used to develop the program were updated in 2020 and lishing effective ventilation remains the focus of neonatal
the 8th edition of the Textbook of Neonatal Resuscitation resuscitation. Although a large volume of research has
was released in June 2021. (4)(5) This review will summa- been published since the NRP 7th edition textbook was
rize the recent changes in the resuscitation guidelines, the released, the most recent ILCOR CoSTR summary and
textbook, and the NRP course. AHA guidelines have not changed the basic approach to
neonatal resuscitation, and the NRP 8th edition algorithm
GUIDELINE DEVELOPMENT (Fig 1) is largely unchanged. (5)
When the AAP and AHA released the first edition of the
NRP textbook, most guidelines were based on current • Before birth, the obstetric and newborn care clinicians
practice, rational conjecture, and expert consensus with lit- meet to identify risk factors that increase the likelihood
tle scientific evidence. Since 2000, the evidence support- of requiring resuscitation after birth, plan the appropri-
ing resuscitation practices for adults, children, and ate team to attend the birth, agree on the plan for umbil-
newborns has been evaluated by the International Liaison ical cord management, and perform a standardized
Committee on Resuscitation (ILCOR). ILCOR is a multi- equipment check.
national collaboration of experts representing resuscitation • Regardless of the appearance of the amniotic fluid, term
councils from around the world. The United States is rep- newborns who are breathing or crying and have good
resented on ILCOR by the AHA and members of the NRP muscle tone may be placed skin-to-skin with their mothers
Steering Committee who participate on the ILCOR Neona- to complete the initial steps of newborn care, thermal
tal Life Support Task Force. Using a rigorous process, the management, and ongoing assessment. Term newborns
task force evaluates the strength and certainty of evidence without respiratory effort or with poor tone and all preterm
for key resuscitation questions and releases a series of newborns are brought to a radiant warmer for the initial
consensus statements. These consensus statements are steps.

2 NeoReviews
 Antenatal counseling.
Team briefing.
Equipment check.

Birth

Term gestation? Yes

Good tone? Stay with mother for initial steps,
Breathing or crying? routine care, ongoing evaluation.

No
1 minute

Warm, dry, stimulate, position

airway, suction if needed.

Apnea or gasping? No Labored breathing or

HR < 100 bpm? persistent cyanosis?

Yes Yes

PPV. Position airway, suction if needed.

Pulse oximeter. Pulse oximeter.
Consider cardiac monitor. Oxygen if needed.
Consider CPAP.

No
HR < 100 bpm?

Yes

Ensure adequate ventilation. Post-resuscitation care.

Consider ETT or laryngeal mask. Team debriefing.
Cardiac monitor.

No Target Oxygen Saturation Table

HR < 60 bpm?

Yes 1 min 60%-65%

2 min 65%-70%
ETT or laryngeal mask.
Chest compressions. 3 min 70%-75%
Coordinate with PPV-100% oxygen.
UVC.
4 min 75%-80%

5 min 80%-85%
No
HR < 60 bpm?
10 min 85%-95%
Yes
Initial oxygen concentration for PPV
IV epinephrine every 3-5 minutes.
If HR remains < 60 bpm, ≥35 weeks’ GA 21% oxygen
• Consider hypovolemia.
• Consider pneumothorax. < 35 weeks’ GA 21%-30% oxygen

Figure 1. Neonatal Resuscitation ProgramV R 8th edition algorithm. CPAP=continuous positive airway pressure, ETT=endotracheal tube, GA=gestational

age, HR=heart rate, PPV=positive pressure ventilation, UVC=umbilical venous catheter. (Reprinted with permission from Weiner GM, Zaichkin J. Textbook
of Neonatal Resuscitation. 8th ed. Itasca, IL: American Academy of Pediatrics; 2021.)

Vol. 1 No. 5 MAY 2022 3

 • After the initial steps, if the newborn’s heart rate (HR) ○ When compressions are started, the oxygen concentra-
is less than 100 beats/min, or if the newborn is apneic tion used for PPV is increased to 100%.
or gasping, PPV should be started within the first • After 1 minute of coordinated compressions and ventila-
minute after birth. PPV is initiated with 21% oxygen in tions, if the HR remains less than 60 beats/min, epi-
term and late preterm newborns ($35 weeks’ gestation) nephrine administration, volume expansion, and
and 21% to 30% oxygen in preterm newborns of less consideration of other causes of cardiorespiratory failure
than 35 weeks’ gestation. The oxygen concentration used may be required.
for PPV is adjusted to achieve minute-specific preductal • Throughout neonatal resuscitation, it is essential to
oxygen saturation targets measured using pulse oxime- maintain attention to ventilation technique, thermal
try on the right hand or wrist. management, and effective teamwork.
• If the newborn’s HR does not rapidly improve and the
chest is not moving with PPV, a series of ventilation cor- NEONATAL RESUSCITATION CLINICAL PRACTICE
rective steps are recommended to address mask leak REVISIONS
and airway obstruction and ensure adequate ventilating Although interim research has largely confirmed previous
pressure. recommendations and added to the certainty of evidence,
○ The ventilation corrective steps are described in the
several practices have been revised in the NRP 8th edition to
NRP textbook using the mnemonic MR. SOPA (Table improve patient safety and educational efficiency (Table 2).
1). Once chest movement with PPV is achieved, venti-
lation is continued for 30 seconds, and the HR is Prebirth Questions
reassessed. To improve coordination between the obstetric and new-
○ If the newborn’s chest is still not moving after the first born care clinicians immediately after birth, the 4 prebirth
5 ventilation corrective steps, an endotracheal tube questions have been revised to include a question about
(ETT) or laryngeal mask should be inserted to opti- the umbilical cord management plan. For both term and
mize ventilation. preterm newborns, systematic reviews have confirmed the
○ Once placement is confirmed, PPV continues for safety and potential benefits of delayed umbilical cord
another 30 seconds, and the HR is reassessed. In clamping. (7)(8) In preterm newborns of less than 34 0/7
most cases, the HR will improve after these weeks’ gestation who do not require immediate resuscita-
interventions. tion, low-to-moderate certainty evidence suggests that
• If the newborn’s HR remains less than 60 beats/min deferring cord clamping for at least 30 to 60 seconds after
despite optimizing ventilation with an alternative airway, birth improves cardiovascular transition and hematologic
chest compressions are started using both thumbs. measures and may improve survival. (4) Although intact
○ Chest compressions are always coordinated with PPV umbilical cord milking may be an alternative for some
in a 3:1 ratio. preterm newborns, it is not recommended for newborns

Table 1. The Ventilation Corrective Steps (MR. SOPA)

Step Description
MR. Mask adjustment
Reposition head and neck
 Give 5 breaths, check chest movement
 If no chest movement, move to the next step
SO Suction mouth and nose
Open mouth
 Give 5 breaths, check chest movement
 If no chest movement, move to the next step
P Pressure increase in 5-10 cm increments (maximum 30-40 cm H2O)
 Give 5 breaths after each increment, check chest movement
 If no chest movement at maximum pressure, move to next step
A Alternative airway (endotracheal tube or laryngeal mask)
 Confirm insertion
 Assess heart rate after 30 seconds of PPV with chest movement

Adapted from Weiner GM, Zaichkin J. Textbook of Neonatal Resuscitation. 8th ed. Itasca, IL: American Academy of Pediatrics; 2021. (5)

4 NeoReviews
Table 2. Neonatal Resuscitation Program, 8th edition, Practice Changes
Practice Change NRP 7th Edition NRP 8th Edition
Umbilical cord management added to 1. Gestational age? 1. Gestational age?
prebirth questions 2. Amniotic fluid clear? 2. Amniotic fluid clear?
3. How many infants? 3. Additional risk factors?
4. Additional risk factors? 4. Umbilical cord management plan?
Initial steps reordered Warm, position airway, clear secretions if Warm, dry, stimulate, position airway,
needed, dry, stimulate suction if needed
Earlier use of electronic cardiac monitor When chest compressions start When an alternative airway is needed
Simplified initial dose of epinephrine IV/IO dose range 0.01–0.03 mg/kg Suggested initial dose:
ET dose range 0.05–0.1 mg/kg IV/IO = 0.02 mg/kg
ET = 0.1 mg/kg
(while establishing vascular access)
Increased flush volume for intravascular Flush IV/IO dose with 0.5–1 mL normal Flush IV/IO dose with 3 mL normal saline
epinephrine saline
Expanded timeframe for cessation of Reasonable to stop after 10 minutes of If appropriate steps have been performed,
resuscitative efforts with confirmed resuscitation; however, decision should consider cessation around 20 minutes
absence of heart rate be individualized after birth; however, decision should be
individualized based on patient and
contextual factors

ET=endotracheal, IO=intraosseous, IV=intravenous.

of less than 28 0/7 weeks’ gestation because of a poten- the newborn remains apneic and PPV is anticipated, gentle
tially increased risk of severe intraventricular hemorrhage. suction of the mouth and nose is recommended, followed by
(9) In vigorous term and late preterm newborns, low to initiation of PPV.
very low certainty evidence suggests that deferring cord Research published since release of the NRP 7th edition
clamping for at least 30 seconds improves hematologic textbook has provided additional evidence supporting the rec-
measures after birth and, although uncertain, deferring ommendation against routine immediate laryngoscopy, with
clamping for at least 60 seconds may improve early child- or without tracheal suction, for nonvigorous newborns with
hood neurodevelopmental outcomes. (4) meconium-stained amniotic fluid. The current ILCOR and
AHA recommendations are based on a meta-analysis of 4
Initial Steps small, randomized trials that showed no benefit in the pre-
Although there is no research comparing the order of the vention of meconium aspiration syndrome or improvement
initial steps, these steps have been reordered to better in survival to hospital discharge from routine laryngoscopy
reflect common practice. Some of the steps may be com- and tracheal suction. (2)(4)(5)(15)(16)(17)(18)(19) The certainty
pleted simultaneously. As described in the NRP 8th edi- of evidence in this meta-analysis was rated as low or very
tion textbook, the initial steps are warm, dry, stimulate, low largely because the study personnel could not be blinded
position the airway, and gently suction the mouth and to the intervention, and the total number of subjects enrolled
nose if needed. Immediately after birth, the initial steps of in the 4 trials (n=571) was below the calculated optimal infor-
newborn care focus on preventing hypothermia by warm- mation size. All 4 randomized trials were completed in
ing and drying the newborn. Preventing hypothermia is India. There has not yet been a randomized trial examining
particularly important for preterm newborns. (10)(11) The this question in a high-resource setting. Four cohort studies
updated scientific review has confirmed the importance of have examined the incidence of meconium aspiration syn-
using a combination of interventions, such as radiant drome before and after the NRP 7th edition practice change.
warmers, plastic wraps, hats, and thermal mattresses, to (20)(21)(22)(23) Although 1 study found an increase in over-
prevent hypothermia in newborns of less than 32 weeks’ all admissions to the NICU for respiratory distress during
gestation. (2) When using a combination of interventions, the epoch following the practice change, no study found an
the newborn’s temperature must be monitored to prevent increase in the incidence of meconium aspiration syndrome.
unintended hyperthermia. Ongoing research is evaluating
the efficacy of various types of tactile stimulation to support Electronic Cardiac Monitor
initiation of spontaneous respiratory effort. (12)(13)(14) The In the NRP 8th edition, use of a basic electronic cardiac
updated consensus supports the previous guidelines, which monitor is recommended earlier during resuscitation than
recommended using gentle tactile stimulation and ensuring in the NRP 7th edition. Earlier use of a cardiac monitor is
an open airway. If the airway is obstructed by secretions, or if advised because HR is the primary indicator of response

Vol. 1 No. 5 MAY 2022 5

 and determines which interventions will be performed. To further enhance safety, the NRP 8th edition sug-
Quickly and accurately determining the newborn’s HR is gests stocking only the dilute epinephrine solution (0.1
critically important, but clinical assessment has been mg/mL, formerly labeled 1:10,000) with neonatal emer-
shown to be unreliable. (24)(25) Research has shown that gency supplies. Other preparations of epinephrine, includ-
nearly half of the errors made during NRP simulations are ing a concentrated 1-mg/mL solution, are frequently
the result of inaccurate HR assessment. Even among stocked with adult emergency supplies and are used in the
healthy newborns, clinicians have difficulty palpating the pediatric and adult resuscitation algorithms. If the concen-
umbilical pulse and they underestimate the newborn’s HR trated solution is available, research has shown that many
on either auscultation or palpation, which could lead to clinicians will inadvertently use it, potentially resulting in
inappropriate interventions. In addition, when team mem- a 10-fold overdose. (34)(35)
bers are required to calculate and report the HR, they fre- In addition to simplifying the initial epinephrine dose,
quently make both calculation and communication errors. the recommended flush volume after intravascular epi-
(26) nephrine administration has been increased. Evidence
Several studies have shown that an electronic cardiac from animal studies suggests that a 1-mL flush may
monitor is the most rapid and accurate way to assess a deposit epinephrine in the umbilical vein or hepatic circu-
newborn’s HR during resuscitation. (27)(28)(29) It reports lation rather than allowing it to reach the heart. (36) Pend-
the HR faster than pulse oximetry and is more accurate ing additional studies to identify the ideal flush volume in
than pulse oximetry during bradycardia. In the unusual newborn human infants, the NRP 8th edition textbook
setting of pulseless electrical activity, clinicians should be recommends a 3-mL saline flush after either IV or IO epi-
aware that an electronic monitor may show an electrical nephrine administration. This single volume applies to all
HR even when there is no cardiac output. (30) Although weights and gestations.
an electronic cardiac monitor may be considered for high-
Cessation of Resuscitative Efforts
risk newborns even earlier during resuscitation, the NRP
The final practice change involves the timeframe for con-
8th edition textbook recommends that a cardiac monitor
sidering cessation of resuscitative efforts with an absent
should be used to assess the newborn’s HR once an alter-
HR. Failure to achieve an HR after 10 to 20 minutes of
native airway becomes necessary.
intensive resuscitation is associated with a high rate of
death or severe impairment among survivors. Identifying
Epinephrine Administration the time to stop resuscitative efforts must balance the risk
To improve educational efficiency and patient safety, the of adverse outcomes among survivors with the desire to
suggested initial intravenous (IV) and intraosseous (IO) not cease efforts in a newborn who would have survived
epinephrine doses have been simplified. The suggested with a good prognosis. In the NRP 7th edition, cessation
initial IV/IO dose is 0.02 mg/kg (0.2 mL/kg of 0.1 mg/ of resuscitative efforts was considered reasonable after 10
mL solution), and the suggested initial ETT dose is 0.1 minutes of an absent HR. Based on a recent systematic
mg/kg (1 mL/kg of 0.1 mg/mL solution). The full recom- review, if asystole has been confirmed after all appropriate
mended range has not changed (IV/IO 0.01–0.03 mg/kg; resuscitative steps have been performed and reversible
ETT 0.05–0.1 mg/kg), but the single suggested initial dose causes excluded, the NRP 8th edition suggests that it is
may be easier for NRP clinicians to remember during an reasonable to consider cessation of resuscitative efforts
emergency, may improve teamwork by allowing the team around 20 minutes after birth. (2)(4)(37) This allows addi-
member preparing the dose to anticipate what will be tional time to complete resuscitative steps and discuss the
requested, and may support easier preparation across a decision with the clinical team and family. Evidence
wide range of newborn weights. (4) Although there is included in the systematic review indicates that it often
emerging evidence that the lower end of the dosing range takes longer than 10 minutes to perform all appropriate
may be less effective, the simplified doses do not represent steps. (37) Moreover, contemporary studies suggest that
an endorsement of any dose within the recommended survival without significant neurodevelopmental disability
range. (31) Although administering a single dose of ETT is possible despite an absent HR for 10 minutes after
epinephrine is reasonable while vascular access is being birth. (38)(39) Because it is unlikely that any single recom-
secured, the NRP 8th edition continues to caution that mended duration of resuscitation will accurately predict
ETT epinephrine is unreliable. (32)(33) mortality or severe impairment in all settings, the decision

6 NeoReviews
to discontinue resuscitative efforts should be individual- lessons 5 through 11, including intubation, chest compres-
ized based on patient and contextual factors, including sions, emergency medication administration, resuscitation of
gestational age, presence of congenital anomalies, the tim- preterm infants and those with abdominal wall and neural
ing of the perinatal event leading to birth depression, the tube defects, management of a pneumothorax or pleural effu-
family’s preferences and values, and the availability of sion, postresuscitation care, and end-of-life care. If learners
postresuscitation intensive care resources. (4) will only initiate unanticipated resuscitation with PPV and will
not participate in advanced resuscitation because a fully
TEXTBOOK ENHANCEMENTS trained team is immediately available to take over, they may
In addition to clinical practice changes, the Textbook of Neo- be assigned the NRP essentials course. If clinicians may par-
natal Resuscitation, 8th edition, includes several enhance- ticipate in resuscitations that require skills beyond PPV, they
ments to improve learning. Many lessons include Quick need to complete the NRP advanced course. Although 2 lev-
Response codes that can be scanned with a mobile device els are offered, hospitals may require all clinicians who par-
and lead the learner directly to short videos demonstrating ticipate in resuscitations to complete the NRP advanced
key skills. Additional material has been added to the Special course.
Considerations lesson describing the resuscitation and stabi- The NRP 8th edition also introduces the option to use
Resuscitation Quality Improvement (RQIV) for NRP. Sev-
R
lization of newborns with a myelomeningocele or an abdom-
inal wall defect. The NRP 8th edition textbook has new eral educational best practices are incorporated into this
supplemental lessons that include information about improv- option for delivering the NRP essentials course, including
ing team performance by considering human factors, ergo- mastery learning and distributed practice. (41) This is an
nomics, and resuscitation outside the delivery room. Because alternative to the traditional instructor-led course in hospi-
learning how to do something well does not always translate tals that subscribe to the RQI program. RQI for NRP is a
into clinical practice, the textbook has an enhanced focus on self-directed, high-frequency, low-intensity, simulation-
quality improvement. An additional supplemental lesson based program incorporating mastery learning with delib-
includes information about establishing and sustaining a erate practice and automated feedback for lessons 1
resuscitation quality improvement program. In addition, sug- through 4. It uses brief quarterly online simulations and
gested process and outcome measures that can be used to hands-on PPV practice using a manikin with a sensor at a
support your hospital-based quality improvement program mobile kiosk and is a method that has already been used
have been added to many lessons. by other AHA-sponsored resuscitation courses. In hospi-
tals that use RQI for NRP, everyone maintains their essen-
NRP COURSE OPTIONS tials provider status by completing quarterly cognitive and
Changes have also been implemented to the structure of skills activities at the mobile kiosk, but advanced providers
the curriculum and the methods of delivering the course. must also complete an instructor-led advanced provider
The NRP curriculum has always been based on adult edu- course every 2 years to maintain their advanced provider
cation principles including self-efficacy, experiential learn- status.
ing, reflection, problem solving, internal motivation, and
the importance of transformative experiences, but the PRINCIPLES THAT HAVE NOT CHANGED
design has evolved over time. (3)(40) To further support Many key principles have not changed in the NRP 8th edi-
contextual learning and allow clinicians to excel in the tion. The program continues to emphasize the importance
course material most relevant to their role during neonatal of anticipation, preparation, and team briefings. The
resuscitation, the NRP 8th edition course offers 2 levels of emphasis on achieving effective ventilation continues.
learning: NRP essentials and NRP advanced. Each organi- Most newborns who require resuscitation will recover
zation will decide who should be NRP essential clinicians with effective ventilation of their lungs and will not
and who should be NRP advanced clinicians. The NRP require either chest compressions or epinephrine. (4)
essentials learner is responsible only for material in lessons 1 However, mask ventilation can be a difficult skill to
through 4. That includes the foundations of neonatal resusci- achieve and maintain. Both obstruction and mask leak are
tation, anticipating and preparing for resuscitation, the initial common, occurring in nearly half of assisted breaths deliv-
steps, PPV with a face mask and laryngeal mask, and CPAP ered to preterm newborns. (42) As a result, it is important
administration. The NRP advanced learner is responsible for to learn how to implement the MR. SOPA ventilation cor-
the NRP essentials components as well as the material in rective steps. The NRP 8th edition textbook continues to

Vol. 1 No. 5 MAY 2022 7

 Figure 2. Two-hand hold on face mask. (Reprinted with permission from Figure 4. Insertion of a laryngeal mask. (Reprinted with permission from
Weiner GM, Zaichkin J. Textbook of Neonatal Resuscitation. 8th ed. Itasca, IL: Weiner GM, Zaichkin J. Textbook of Neonatal Resuscitation. 8th ed. Itasca, IL:
American Academy of Pediatrics; 2021.) American Academy of Pediatrics; 2021.)

emphasize using the correct size mask, correctly position- an alternative airway. Overall, first attempt success with
ing the airway, and learning the 2-hand hold. In manikin tracheal intubation is low. (46) The NRP 8th edition text-
studies, the 2-hand hold (Fig 2) significantly reduces mask book suggests considering the use of a video-laryngoscope
leak. (43) The addition of a colorimetric carbon dioxide especially when working with trainees. Use of a video-
detector, or capnometer, between the mask and PPV laryngoscope allows the supervisor to provide more effec-
device (Fig 3) can improve mask ventilation. (44) If the tive coaching by seeing what the operator is seeing.
lungs are ventilated and gas is exchanged, a colorimetric Among trainees intubating newborns, studies have shown
detector will change from purple to yellow. As teams pro- that use of a video-laryngoscope improves first attempt
ceed through the MR. SOPA steps, if the detector changes success. (47)(48) Finally, the NRP 8th edition continues to
color after performing a step, the newborn’s HR will likely include the laryngeal mask on the standard list of equip-
improve within 30 seconds. (45) If the team member posi- ment and supplies for every delivery room. It is a simple
tioning the airway becomes distracted and changes posi- device that requires no instruments for insertion (Fig 4)
tion, the detector will change back to purple and can help and has a very high first attempt successful insertion rate
identify the positioning error before the infant becomes with limited training. (49) Insertion of a laryngeal mask
bradycardic. On the other hand, if the detector does not may save a newborn’s life if intubation is unsuccessful or
change color, it is another indication to proceed to the not feasible.
next ventilation corrective step.
Even with corrective steps, mask ventilation is not
always successful, and teams must be prepared to insert Summary
Although most newborns require no assistance to
successfully transition to extrauterine life, the large
number of births each year and limited ability to pre-
dict which newborns will need assistance means that
skilled clinicians must be prepared to respond quickly
and efficiently for every birth. Since its release in
1987, the NRP has trained over 4.5 million health
professionals in the cognitive, technical, and behav-
ioral skills required to save newborn lives. The NRP
8th edition builds on an established history of innova-
tion and collaboration while adding new elements of
instructional design to better meet the needs of differ-
ent health professionals. As new research answers
Figure 3. Use of a colorimetric carbon dioxide detector with face-mask gaps in our neonatal resuscitation knowledge base
ventilation.

8 NeoReviews
 7. Gomersall J, Berber S, Middleton P, et al; International Liaison
and new technologies emerge, the program will con- Committee on Resuscitation Neonatal Life Support Task Force.
tinue to evolve. Umbilical cord management at term and late preterm birth: a meta-
analysis. Pediatrics. 2021;147(3):e2020015404
8. Seidler AL, Gyte GML, Rabe H, et al; International Liaison
Committee on Resuscitation Neonatal Life Support Task Force.
American Board of Pediatrics Umbilical cord management for newborns <34 weeks’ gestation: a
meta-analysis. Pediatrics. 2021;147(3):e20200576
Neonatal-Perinatal Content 9. Katheria A, Reister F, Essers J, et al. Association of umbilical cord
Specifications milking vs delayed umbilical cord clamping with death or severe
intraventricular hemorrhage among preterm infants. JAMA.
• Know the proper approach to airway management in
2019;322(19):1877–1886
the delivery room.
10. Laptook AR, Salhab W, Bhaskar B; Neonatal Research Network.
• Know the indications for assisted ventilation, Admission temperature of low birth weight infants: predictors and
including continuous positive airway pressure, associated morbidities. Pediatrics. 2007;119(3):e643–e649
11. de Almeida MF, Guinsburg R, Sancho GA, et al; Brazilian Network
immediately after birth and how to assess its
on Neonatal Research. Hypothermia and early neonatal mortality in
effectiveness. preterm infants. J Pediatr. 2014;164(2):271–5.e1
• Understand how to use self-inflating and flow- 12. Baik-Schneditz N, Urlesberger B, Schwaberger B, et al. Tactile
stimulation during neonatal transition and its effect on vital
inflating bags or T-piece resuscitators to provide
parameters in neonates during neonatal transition. Acta Paediatr.
assisted ventilation immediately after birth. 2018;107(6):952–957
• Know indications for and proper administration of 13. Dekker J, Martherus T, Cramer SJE, van Zanten HA, Hooper SB, Te
supplemental oxygen immediately after birth. Pas AB. Tactile stimulation to stimulate spontaneous breathing
during stabilization of preterm infants at birth: a retrospective
• Know the indications for, techniques, and potential analysis. Front Pediatr. 2017;5:61
complications of chest compression immediately 14. Cavallin F, Lochoro P, Ictho J, et al. Back rubs or foot flicks for
after birth. neonatal stimulation at birth in a low-resource setting: a randomized
controlled trial. Resuscitation. 2021;167:137–143
• Know the indications, contraindications, and methods 15. Trevisanuto D, Strand ML, Kawakami MD, et al; International
of administration of drugs used for neonatal Liaison Committee on Resuscitation Neonatal Life Support Task
resuscitation. Force. Tracheal suctioning of meconium at birth for non-vigorous
infants: a systematic review and meta-analysis. Resuscitation.
2020;149:117–126
16. Singh SN, Saxena S, Bhriguvanshi A, Kumar M, Chandrakanta S.
Effect of endotracheal suctioning just after birth in non-vigorous
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10 NeoReviews
ARTICLE

Appropriate Management of the

Nonvigorous Meconium-Stained
Newborn
Arpitha Chiruvolu, MD,* Thomas E. Wiswell, MD†
*Division of Neonatology, Baylor University Medical Center, and Pediatrix Medical Group of Dallas, Dallas, TX
†
Division of Neonatology, Kaiser Permanente Moanalua Medical Center, Honolulu, HI

PRACTICE GAPS

The 2015 and 2020 American Heart Association guidelines and Neonatal
Resuscitation Program 7th and 8th edition textbooks suggest not performing
routine intubation and tracheal suctioning of nonvigorous meconium-stained
newborns. However, this was given as a weak recommendation with low-
certainty evidence. The definitive answer to appropriate management for
nonvigorous meconium-stained newborns is not known.

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

1. Explain the pathophysiology of meconium-stained amniotic fluid and

AUTHOR DISCLOSURE Dr Chiruvolu has meconium aspiration syndrome.
disclosed no financial relationships
relevant to this article. Dr Wiswell serves 2. Identify the history and rationale behind the practice of selective intubation
as a paid consultant for Neotech and suctioning of nonvigorous meconium-stained newborns.
Products, LLC. This commentary does not
contain a discussion of an unapproved/ 3. Describe the investigations comparing tracheal suctioning and routine
investigative use of a commercial resuscitation immediately after birth in nonvigorous meconium-stained
product/device.
newborns.

ABBREVIATIONS
4. Interpret the current data on management for nonvigorous meconium-
stained newborns.
AHA American Heart Association
ET endotracheal tube
HIE hypoxic-ischemic
encephalopathy ABSTRACT
ILCOR International Liaison Committee
Before 2015, major changes in Neonatal Resuscitation Program (NRP)
on Resuscitation
iNO inhaled nitric oxide recommendations not supporting previously endorsed antepartum, intrapartum
MAS meconium aspiration syndrome and postpartum interventions to prevent meconium aspiration syndrome were
MSAF meconium-stained amniotic
based on adequately powered multicenter randomized controlled trials. The
fluid
NLS Neonatal Life Support 2015 and 2020 American Heart Association guidelines and 7th and 8th edition
NRP Neonatal Resuscitation Program of NRP suggest not performing routine intubation and tracheal suctioning of
OR odds ratio nonvigorous meconium-stained newborns. However, this was given as a weak
PPHN persistent pulmonary
hypertension of the newborn
recommendation with low-certainty evidence. The purpose of this review is to
PPV positive pressure ventilation summarize the evidence and explore the question of appropriate delivery room
RCT randomized controlled trial management for nonvigorous meconium-stained newborns.
RR risk ratio
VON Vermont Oxford Network

Vol. 1 No. 5 MAY 2022

 INTRODUCTION constituents, blood, and mucus, as well as cellular debris
Meconium-stained amniotic fluid (MSAF) is a common such as desquamated skin, amniotic fluid, vernix caseosa,
perinatal concern, occurring in 8% to 10% of all term and lanugo. (5) Two major mechanisms cause in utero
deliveries, and is primarily associated with advanced gesta- passage of meconium (Fig 1). As the fetal intestine physi-
tional age and fetal distress. (1) Meconium aspiration syn- ologically matures during the third trimester and beyond
drome (MAS), a serious complication of MSAF, occurs in (particularly at $41 weeks’ gestation), increasing amount
at least 2% to 3% of these deliveries. MAS is rare before of the gastrointestinal hormone motilin is secreted. This
39 weeks’ gestation and the risk markedly increases after peptide promotes peristalsis, stimulating the movement
41 weeks’ gestation. The incidence of MAS has been of meconium. Fetal stress is the second major mecha-
reportedly decreasing in developed countries during the nism causing meconium passage and MSAF. During epi-
past several decades, whereas in developing countries it sodes of fetal hypoxia, increased parasympathetic activity
remains a substantial problem. (2)(3)(4) may lead to increased peristalsis and relaxation of anal
sphincter, leading to meconium release. (6) Other stres-
PATHOPHYSIOLOGY OF MSAF sors, such as intrauterine inflammation, may also stimu-
Meconium is a dense, sterile, odorless, black-green mat- late the passage of meconium. This meconium may be
ter first observed in the fetal intestine during the third aspirated into the lungs in utero when there is fetal gasp-
month of gestation. Although much of the meconium is ing associated with hypoxia or another stressor. Intra-
composed of water, this complex substance also contains alveolar meconium found in autopsy specimens of still-
gastrointestinal and pancreatic secretions, bile born infants provides evidence for antepartum aspiration.

Figure 1. The pathophysiology of meconium-stained amniotic fluid and the meconium aspiration syndrome (adapted from Fuloria M, Wiswell TE. Resus-
citation of the meconium-stained infant and prevention of meconium aspiration syndrome. J Perinatol. 1999;19(3):234–241).

12 NeoReviews
In addition, meconium aspiration may occur with the ini- EPIDEMIOLOGY AND PREVENTION OF MAS
tial breaths of a newborn. If the latter occurs, meconium On the basis of various observational and cohort studies,
present in the trachea may migrate into the more distal the approach to MSAF during the mid-1970s was for the
airways. (7)(8) obstetrician to immediately suction the oronasopharynx of
the newborn as soon as the head was out (at the perineum
PATHOPHYSIOLOGY OF MAS or cesarean section incision) before the delivery, followed
The pathophysiology of MAS is complex with multiple by direct laryngoscopy and suctioning of the trachea
mechanisms involved (Fig 1). When aspirated into the through the endotracheal tube (ET) by the neonatal clini-
lungs, an intense inflammatory response occurs. This cian. (12)(13)(14) This process was adopted at most institu-
may stimulate the release of various mediators and vaso- tions and the practice continued for decades. An ensuing
active substances, leading to chemical pneumonitis. significant decline in the incidence of MAS as well as
These substances may cause pulmonary vasoconstriction death due to MAS was documented by Wiswell et al in a
or direct injury to the lung parenchyma. Surfactant can series of 21,472 meconium-stained infants who were born
be inactivated by meconium fatty acids, leading to atelec- over a 15-year period from 1973 to 1987 (Fig 2). (15) The
tasis and ventilation-perfusion mismatch. Physical authors attributed the decrease primarily to the routine
blockage of large airways can cause local and diffuse atel- intrapartum oronasopharyngeal and postpartum intratra-
ectasis. In addition, meconium aspiration can cause cheal suctioning. A subsequent decline in the incidence of
MAS was documented by Yoder et al during the period
obstruction of airways, leading to air leaks in the form
1990 to 1998 which was ascribed to the reduction in deliv-
of pneumothorax, pneumomediastinum, or pulmonary
eries at more than 41 weeks’ gestation, a practice adopted
interstitial emphysema. Pulmonary vasoconstriction and
by obstetricians in the late 1980s. (16) In the early 1990s,
vascular remodeling due to intrauterine hypoxia may lead
Bent and colleagues assessed multiple techniques of
to persistent pulmonary hypertension of the newborn
removing meconium from the trachea and found the Neo-
(PPHN) which is an important cause of morbidity and
tech Meconium AspiratorV R (Neotech, Valencia, CA) to
mortality. (9)(10) The mechanisms causing MAS may
retrieve the largest quantities effectively. (17) Shortly after-
result in acidosis, hypoxemia, and hypercapnia, which
wards, the Neonatal Resuscitation Program (NRP) recom-
can further contribute to PPHN.
mended use of such a device when suctioning meconium
More than 2 decades ago, Cleary and Wiswell defined
from the airways of newborns.
MAS as respiratory distress in an infant born through
A selective approach to tracheal intubation was used in
MSAF whose symptoms cannot be otherwise explained.
a quasi-randomized study of 572 vigorous (1-minute Apgar
(11) MAS includes a heterogenous group of respiratory dis-
score of 9 or 10) meconium-stained newborns delivered
orders reflecting inflammation, air trapping, both alveolar
vaginally. (18) The results indicated no difference in the
and interstitial disease, and PPHN. The radiographic find-
incidence of MAS between the groups with and without
ings are diverse and most commonly present with diffuse, tracheal suctioning. Daga and colleagues assessed intratra-
asymmetric patchy or streaky infiltrates alternating with cheal suctioning in a small randomized controlled trial
areas of atelectasis and hyperinflation. The respiratory (RCT) of 49 “unasphyxiated” infants born through thick-
manifestations of the disorder include retractions, tachyp- consistency MSAF. (19) They similarly found intratracheal
nea, cyanosis, oxygen desaturation, apnea, and air leaks. suctioning to be of no benefit. The uncertainty regarding
MAS can be further divided into 1) mild MAS needing tracheal suctioning of vigorous infants born through
less than 40% oxygen for less than 48 hours; 2) moderate MSAF was settled with an adequately powered multicenter
MAS requiring more than 40% oxygen for more than 48 RCT of 2,094 infants. (20) The investigators reported that
hours; and 3) severe MAS needing assisted ventilation for tracheal suctioning did not decrease the risk of MAS in
more than 48 hours, often associated with increased pul- the vigorous infants born through MSAF compared to no
monary pressures. (11) Severe MAS occurs in one-third of suctioning (3.2% vs 2.7%). Based on this evidence, the
the infants with MAS, with approximately 15% to 20% 2000 American Heart Association (AHA) guidelines and
having concomitant PPHN. Currently in developed coun- the 4th edition of the NRP textbook cautioned against tra-
tries, overall mortality from MAS is approximately 2.5%, cheal suctioning of vigorous newborns, but continued to
with the highest rates up to 8% in those with severe MAS. recommend routine tracheal suctioning for nonvigorous
(1) Mortality is typically higher in developing nations. meconium-stained newborns. (21) Subsequently, in a

Vol. 1 No. 5 MAY 2022 13

 multicenter RCT of 2,514 infants, Vain et al showed no et al in the 1970s. (14) These investigations resulted in the
benefit in preventing MAS or mortality using intrapartum publications that led to the widespread performance of
oronasopharyngeal suctioning compared to no suctioning. intratracheal suctioning of meconium-stained newborns.
(22) Similarly, the widespread practice of amnioinfusion The widely used definition of a nonvigorous infant is
to prevent MAS was shown to be of no value in another one who, within seconds of birth, demonstrates depressed
large RCT that enrolled 1,998 women with thick-consis- breathing, poor tone, and/or heart rate lower than 100
tency MSAF. (23) Based on these large trials, the latter 2 beats/min. (20) Recent data indicate a wide range of
practices (intrapartum oronasopharyngeal suctioning and infants born through MSAF who are considered to be
amnioinfusion) were no longer recommended. (24) In nonvigorous, ranging from 10% in a developed country to
summary, before the year 2015, the major changes in rec- almost 40% in a developing country. (28)(29)(30)(31)(32)
ommendations to no longer support previously endorsed Approximately 50% to 80% of these nonvigorous infants
antepartum, intrapartum, and postpartum interventions to will have demonstrated in utero distress, typically abnor-
prevent MAS were based on high-quality, adequately pow- mal fetal heart rate tracings. The occurrence of MAS has
ered multicenter RCTs. (20)(22)(23) been recognized as higher among nonvigorous depressed
infants compared to vigorous infants born through MSAF.
MANAGEMENT OF NONVIGOROUS MECONIUM- Starting in the mid-1970s and continuing for 4 decades,
STAINED NEWBORNS nonvigorous meconium-stained newborns routinely under-
The history of delivery room management for meconium- went intratracheal suction with direct laryngoscopy soon
stained infants is fascinating. (25) In 1948, Clifford was after birth. This was the recommendation of the NRP from
the first to suggest that meconium-stained newborns its inception in the year 1987 until year 2015.
might benefit from intubation and suctioning. (26) Twelve The 2015 AHA guidelines for neonatal resuscitation
years later, in a resuscitation textbook, James also recom- stated that the evidence to continue routine intratracheal
mended this procedure. (27) During the 1960s, individu- suction for nonvigorous newborns born through MSAF
als who had worked with Dr James brought the technique was insufficient. (33) The organization stated that greater
to the West coast of the United States and influenced the “value” was placed on avoidance of harm from either delay
performance of the studies that led to the aforementioned in starting ventilation or from potential injury through the
works of Gregory et al, (12) Ting et al, (13) and Carson procedure itself. Despite the fact that neither of these

Figure 2. A graphic depiction of the significant decline in the incidence of the meconium aspiration syndrome after widespread implementation of ini-
tial oronasopharyngeal suctioning of the infant’s head before delivery of the chest, followed by immediate intubation and tracheal suctioning (adapted
from Wiswell TE, Tuggle JM, Turner BS. Meconium aspiration syndrome: have we made a difference? Pediatrics. 1990;85(5):715–721).

14 NeoReviews
adverse outcomes have been reported from routine perfor- Moreover, the data the authors used in the sample size
mance of the procedure through the years, the new recom- calculations are not contained in the reference cited. (25)
mendation was published in the 7th edition of the NRP A single-center trial from Lucknow, India, by Singh
textbook. Moreover, the 2015 AHA guidelines stated that a et al (31) included late preterm and term gestation infants,
definitive RCT was needed to assess risks and benefits of of which 76 were randomized to the ET suction group
this procedure. Of note, the 3 meconium-related procedure and 79 to the no suction group. The intubation attempts
recommendations that were previously eliminated during were performed only by pediatric trainees. These investi-
the preceding 15 years (intratracheal suctioning of vigorous gators reported using meconium aspirators connected to
infants, oronasopharyngeal suctioning, and amnioinfusion) ETs to suction the trachea of intubated newborns. The
were abolished after large, conclusive RCTs were performed. incidence of MAS was 41% in the ET suction group versus
(20)(22)(23) Four small RCTs on intratracheal suctioning of 57% in the no suction group, with an odds ratio of 0.53
the nonvigorous meconium-stained infants were performed (95% CI, 0.28–1.01; P=.05), showing a near statistically
in a developing country (India). (29)(30)(31)(32) We will next significant benefit for preventing MAS with ET suctioning.
discuss characteristics of these investigations, as well as sev- There was no statistically significant difference in mortal-
eral observational cohort studies. ity between the groups (5% vs 9%, respectively). However,
the intratracheally suctioned infants had a significantly
The Randomized Controlled Trials shorter length of hospital stay, as well as a trend toward a
In a single-center trial from Pondicherry, India, by Chettri lower rate of moderate to severe hypoxic-ischemic enceph-
et al, (29) 122 term gestation, nonvigorous meconium- alopathy (HIE). Their sample size analysis was appropriate.
stained newborns were randomized to either ET suction (61 A single-center trial from Varanasi, India, by Kumar
infants) or no suction (61 infants). The intubation attempts et al (32) included late preterm and term gestation infants.
were only performed by pediatric trainees and no meconium The investigators randomized 66 infants to ET suction
aspirator device was used (the ET was directly attached to and 66 to no suction. Intubation attempts were performed
the wall suction). There were no significant differences in only by pediatric trainees and no meconium aspirator
the need or the extent of resuscitation between the 2 groups. devices were used. There were no significant differences
Most infants (90%) in each group received positive pressure between the suctioned versus nonsuctioned group in the
ventilation (PPV). Approximately half (51%) of the infants in incidence of MAS (32% vs 23%) or in mortality (14% vs
the ET suction group were actually intubated, whereas 44% 8%). This investigation was also underpowered, as the
in the no suction group had to be intubated in the delivery authors used the same reference as the Chettri et al group
room. There were no differences in the incidence of MAS to calculate their sample size.
(ET suction vs no suction, 33% vs 31%, respectively), perina- Some differences in the methodology and the patient
tal asphyxia (31% vs 28%), or mortality (11% vs 13%). This characteristics were noted among the 4 RCTs. However,
study was underpowered to find the difference in outcomes they do not explain the differences in results noted in the
other than MAS, because the authors used a sample size cal- Singh et al trial compared to the other 3 investigations.
culation based on data from a study performed 40 years pre- The former trial was the only 1 to use a meconium aspira-
viously that included both vigorous and nonvigorous tor while suctioning the trachea. Late preterm infants
meconium-stained newborns. (13) were included in only 2 trials (Singh et al and Kumar
In a single-center pilot trial from New Delhi, India, of et al). Oropharyngeal suctioning was performed before ET
term gestation nonvigorous meconium-stained infants, suctioning in the Nangia et al and Kumar et al trials,
Nangia et al (30) randomized 87 infants to the ET suction potentially stimulating the neonates and initiating breath-
group and 88 to the no suction group. The intubation ing efforts leading to aspiration before ET suctioning.
attempts were performed only by pediatric trainees. The Overall, data on the success or complications of intubation
authors stated that suction techniques were in accordance were insufficient. The incidence of MAS and mortality in
with the 2010 NRP guidelines, but did not use a meco- these trials were greater than expected for higher medi-
nium aspirator device (ET was directly attached to the wall cally resourced countries, questioning the generalizability.
suction). No statistically significant differences were found Risks of imprecision, bias, and type II error were high in
in either the incidence of MAS (ET suction vs no suction, these trials. These studies did conclude the feasibility of
32% vs 26%) or mortality (10% vs 5%). The investigators randomization and the justification for an adequately pow-
enrolled only 47% of their calculated sample size. ered multicenter RCT.

Vol. 1 No. 5 MAY 2022 15

 A recent systematic review included these 4 RCTs and authors reported a minimal decrease in the diagnosis of
showed no differences in the risks of MAS, with a risk MAS among NICU admissions from 1.8% to 1.5%, a
ratio (RR) of 1.00 (95% CI, 0.80–1.25) or all-cause neona- decline that means little without knowing whether the
tal mortality with an RR of 1.24 (95% CI, 0.76–2.02) with rates of MSAF were similar between the groups. The
or without ET suctioning. No differences were reported in investigators reported a decline in ET suctioning from
the risk of HIE of any severity (RR, 1.05; 95% CI, 57% to 29% in infants admitted with the diagnosis of
0.68–1.63; 1 study, 175 neonates) or moderate to severe MAS. Although surfactant use increased in infants with
HIE (RR, 0.68; 95% CI, 0.43–1.09; 1 study, 152 neonates) MAS, there were no differences in death, pneumotho-
among nonvigorous neonates born through MSAF. They rax, and moderate to severe encephalopathy. In the sub-
concluded uncertainty about the effect of ET suction on group of infants with 1-minute Apgar score of 3 or less,
the incidence of MAS and suggested that research from the proportion of infants admitted to the NICU with a
well-conducted large trials is needed. (34) diagnosis of MAS decreased from 6.8% to 4.6%, as did
the rate of endotracheal suctioning from 82% to 52%.
The Observational Cohort Studies However, among these infants with a low 1-minute
Chiruvolu et al performed a multicenter pre- and postin- Apgar score and MAS, the use of surfactant and inhaled
tervention cohort study comparing 130 nonvigorous new- nitric oxide (iNO) increased in 2017 compared to the
borns born before the implementation of the NRP 7th years 2013 to 2015. An increase in the incidence of mod-
edition textbook guidelines that no longer endorsed rou- erate to severe HIE was also noted. If the infants with
tine ET suctioning (retrospective group) with a group of MAS and a 1-minute Apgar score of 3 or less are pre-
101 newborns born after implementation (prospective sumed to represent the nonvigorous population, the change
group). (28) ET suctioning was performed 70% of the in recommendations concerning ET suctioning could be
time before the guideline change versus 2% after the associated with more severe respiratory morbidity. Increased
change. The proportion of late preterm, post-term incidence of moderate to severe HIE may suggest more
infants, and infants with fetal distress was significantly severe perinatal hypoxia. Overall, the possibility of an associ-
higher in the prospective group. The comparisons were ation between less frequent tracheal suctioning and severity
adjusted for the latter factors. The investigators found a of MAS and the increased incidence of moderate to severe
significantly higher proportion of newborns admitted to HIE is concerning.
the NICU for respiratory issues in the prospective group Using the California Perinatal Quality Care Collabora-
(no tracheal suctioning) compared to the retrospective tive database, Kalra et al showed a significant decline in
(routine tracheal suctioning) group (40% vs 22%; OR, MAS incidence as a percentage of total births and NICU
2.2; 95% CI, 1.2–3.9). Moreover, a significantly higher admissions from 2013 to 2017. (36) This investigation
proportion of the nonsuctioned group infants needed consisted of querying a database, rather than going
oxygen therapy (37% vs 19%; OR, 2.5; 95% CI, 1.2–4.5); through individual medical records. Although the overall
mechanical ventilation (19% vs 9%; OR, 2.6; 95% CI, incidence of MAS among NICU admissions decreased,
1.1–5.8); and surfactant therapy (10% vs 2%; OR, 5.8; no change was noted in the proportion of infants with
95% CI, 1.5–21.8). There was also a trend toward more MAS with respiratory symptoms. The incidence of deliv-
infants developing MAS in the nonsuctioned group (5% ery room intubation of infants who were diagnosed with
vs 11%; OR 2.3; 95% CI, 0.83–6.2; P=.14). MAS decreased significantly in the 2017 cohort compared
Edwards et al studied 222,438 infants born at 35 to the 2013 to 2015 cohort (35% vs 44%). There were no
weeks of gestation or later and admitted to NICUs at 311 differences in the need for ventilation, iNO, or extracor-
Vermont Oxford Network (VON) Centers from 2013 to poreal membrane oxygenation among the cohorts. The
2015 in the United States in comparison to 78,712 use of noninvasive ventilation increased significantly in
infants born in 2017 after the NRP 7th edition textbook 2017 compared to previous years. No differences were
guideline change. (35) Unfortunately, the investigators noted in other outcomes such as mortality or HIE. Simi-
were unable to identify during both epochs 1) the fre- lar to the VON study, the crucial data of number of
quency of meconium-staining; 2) the proportion of infants born through MSAF, the proportion of nonvigo-
meconium-stained infants who were deemed to be non- rous meconium-stained newborns, and the infants who
vigorous; and 3) the management and outcomes specific underwent ET suctioning in the delivery room are
to nonvigorous meconium-stained infants. Overall, the missing.

16 NeoReviews
 In contrast, Kalra and colleagues subsequently pub- What is the evidence for the possibility of harm? Sev-
lished results of a second investigation at their center eral publications have reported a very low incidence
addressing outcomes from a cohort of infants born during of airway complications among intubated/suctioned vig-
the routine suction era (n=2,306) with those delivered dur- orous infants. Linder et al reported that 2 infants who
ing the no suction period (n=2,019). (37) The authors pro- underwent ET suctioning developed stridor and persistent
vided data on the total number of meconium-stained airway problems. (18) Wiswell et al documented that 3.8%
infants, the proportion that was nonvigorous, and the num- of vigorous infants intubated in the delivery room had tran-
ber during each epoch that were intubated and suctioned. sient minor airway complications. (20) Active vigorous
The authors found that significantly more nonvigorous infants may struggle during the intubation procedure and
meconium-stained infants were born during the no suction there is likely greater potential for bradycardia, apnea, and
era who developed MAS compared to those born during injury of the vocal cords. Such complications may not occur
the routine suction period (53% vs 15%, P=.0008). (37) often in depressed infants. Chettri et al reported 1 episode
of vocal cord injury in the newborn who underwent ET suc-
CURRENT STATUS OF THE MANAGEMENT OF tioning in the delivery room. (29) Chiruvolu et al reported
NONVIGOROUS MECONIUM-STAINED no such complications in their large observational study.
NEWBORNS (28)(40) There were no differences in Apgar scores between
the ET suction and the no ET suction groups in any of the
Trevisanuto et al (38) performed a systematic review and
4 RCTs, suggesting minimal to no effect of delays in resus-
meta-analysis which included the previously mentioned
citation in 1 group compared to another. (29)(30)(31)(32) A
4 RCTs as well as the Chiruvolu et al cohort study. (28)
recent investigation using a mannequin showed that per-
The primary outcome of this study was survival at dis-
forming immediate laryngoscopy with intubation and suc-
charge, not the incidence of MAS. The authors con-
tioning was associated with a 12- to 13-second longer period
cluded that no significant differences were observed
until initiation of PPV compared to immediate PPV without
between the tracheal suctioning group and the expectant
intubation and suctioning, a difference the authors believed
management group in terms of mortality, HIE, and
not to be clinically relevant. (41)
MAS. (38) They also stated that they could not exclude
Most intubations in academic centers are performed
either benefit or harm with tracheal suctioning. The
by pediatric trainees. The success rate is considerably
authors acknowledged that the certainty of their analy-
lower in pediatric residents, in the range of 20% to 25%,
ses was very low for most outcomes due to inconsis-
compared to that of more experienced clinicians such as
tency and imprecision. The investigators stated that a attending neonatologists, neonatology fellows, hospital-
future large, high-quality RCT to settle the issue would ists, and nurse practitioners. (42)(43)(44)(45) One sin-
be challenging to perform. Based on this systematic gle-center study demonstrated a strikingly low success
review, the 2020 AHA guidelines and the NRP 8th edi- rate of 6% among trainees for intubation performed to
tion textbook suggested not performing routine intuba- suction the meconium in nonvigorous newborns. (42)
tion and tracheal suctioning of the nonvigorous With such low success rates, it is not surprising that 3
meconium-stained newborns. (39) Nevertheless, this of the 4 small RCTs assessing the technique did not
was given as a weak recommendation with low-certainty find the procedure to be of value when intubating and
evidence. The Neonatal Life Support (NLS) task force suctioning nonvigorous meconium-stained newborns.
recognized that, although several studies published after One should have a great deal of skepticism with the
2015 provide additional evidence to support the recom- results of trials in which trainees are the ones primarily
mendation, the certainty of the findings remains low or performing intubation. Historically, much of the intuba-
very low because it is difficult to perform unbiased stud- tion skills gained by trainees have been in the delivery
ies. In addition, even when the data are combined from room while intubating meconium-stained newborns.
all studies, optimal information size is not attained, However, over the past 25 years, pediatric residents are
leading to insufficient power for certainty. The NLS task spending considerably less of their training experience
force and the NRP steering committee considered that in the NICU, contributing to the decline in their acquisi-
the procedure of laryngoscopy and tracheal suctioning tion of multiple technical skills, including intubation and
are invasive and potentially harmful, particularly if the suctioning. Moreover, during the 2 decades since the
initiation of ventilation is delayed. intubation of vigorous meconium-stained infants was no

Vol. 1 No. 5 MAY 2022 17

 longer recommended, the chances for trainees to gain trials on therapies for meconium-stained infants, partic-
experience with the procedure have markedly decreased. ularly MAS.
These opportunities are even fewer since the 2015 AHA
guidelines stated that routine intubation of nonvigorous
infants was no longer recommended. Downes et al con-
Summary
cluded that trainees are unlikely to become sufficiently Is the question of appropriate management of nonvigo-
proficient in the intubation procedure during their pediat- rous meconium-stained newborns answered? No! The
ric residency training. (43) These authors also suggested changes that have been made to the guidelines for
that other models for intubation training should be devel- management are considered to be “weak” and of “low
oped to address this issue. Unfortunately, success in the certainty.” In addition, no central repository has been
simulation environment may not translate into improved established for clinicians to report the outcomes of
clinical performance. (46) these infants since the recommendations were changed.
Are there selective meconium-stained newborns who Therefore, we currently have no idea whether infants
may benefit from ET suctioning? Recent studies indicated have benefited or been harmed from the changes. It is
that in approximately 50% of nonvigorous newborns under- an important issue, as globally at least 1 to 3 million
going ET suctioning, meconium is recovered. (28)(47) A nonvigorous meconium-stained infants are born annu-
potential advantage of intratracheal suctioning immediately ally. The question of appropriate management for non-
after birth would be to prevent the distal migration of such vigorous meconium-stained newborns will not be
meconium with breathing and ventilation and hence miti- answered until a high-quality, well-powered RCT is per-
gate adverse effects of the substance (Fig 1). However, non- formed. Based on data from the Singh et al and Chiru-
vigorous infants may experience in utero gasping followed volu et al investigations, we estimate that at least 750
by deep aspiration of the material long before delivery and infants would have to be randomized in such a trial.
negate any potentially positive effects of intratracheal suc- Randomization would have to take place before birth or
tioning. The question of whether this therapy could be ben- a cluster randomization approach may help with the
eficial can only be answered definitively by a sufficiently feasibility of conducting such a trial. (38) With the
powered, well-performed RCT. inherent difficulties of obtaining consent with laboring
Weiner and Zaichkin have described the process in pregnant women or in situations where MSAF may not
which evidence from clinical trials is assessed and con- be noted until delivery is imminent, an approach that
sidered in order for changes to be made in the guide- could be considered is a waiver of informed consent
lines such as the NRP. (48) The quality of evidence is protocol as seen in 2 of the previous delivery room tri-
first reviewed by the International Liaison Committee als. (20)(22) The rationale for this approach was
on Resuscitation (ILCOR). ILCOR will subsequently described in these publications. Such a waiver would
release a series of statements known as the “Consensus have to satisfy the requirements of the Combined Fede-
on Science with Treatment Recommendations.” The lat- ral Regulations developed by the Department of Health
ter are used by the AHA and the American Academy of and Human Services for the protection of research sub-
Pediatrics to develop the resuscitation guidelines pub- jects. An overview was also recently discussed by the
lished in the NRP. The ILCOR Neonatal Task Force and Society of Critical Care Medicine for use in emergency
Neonatal Resuscitation Content Expert Group recently treatment trials. (50) We do not believe that inexperienced
published what are considered to be the 25 most impor- trainees should be performing the intubation and suction
tant outcomes related to neonatal resuscitation. (49) procedure. In all participating centers, a meconium aspi-
These will be used to develop treatment recommenda- rator device should be used to suction the ET tube. We
tions. Unfortunately, this list did not include the follow- hope that if a significant difference in the incidence of
ing as important outcomes: MAS, PPHN, use of iNO, MAS was to be found, ILCOR and the NRP Steering
HIE, and the duration of mechanical ventilation. None Committee would consider this to be an important out-
of these outcomes would be considered by ILCOR as come, potentially worthy of making changes to the resus-
critical for making decisions about guideline changes citation guidelines. Without a large, well-conducted RCT,
for the management of infants born through MSAF. We we will never know the optimal management approach
believe that these outcomes are important in future for a nonvigorous, meconium-stained newborn.

18 NeoReviews
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20 NeoReviews
INDEX OF SUSPICION IN THE NURSERY

Term Male Infant with Abdominal Mass

Arya Kudalmana, MD,* Bo Rum Kim, MD,* Euming Chong, MD†
*Department of Pediatrics, Driscoll Children’s Hospital, Corpus Christi, TX
†
Department of Neonatology, Driscoll Children’s Hospital, Corpus Christi, TX

PRESENTATION
A male neonate is born at 38 weeks, 5 days of gestation to a 34-year-old gravida
4, para 4 mother via urgent cesarean delivery due to a nonreassuring heart rate.
The maternal history is significant for hypothyroidism. The infant was found on
prenatal ultrasonography to have an abdominal mass. The neonate is crying on
presentation with no significant distress; he has a birthweight of 2,560 g and
his Apgar scores are 9 and 9 at 1 and 5 minutes, respectively.
On examination, the neonate is found to have a 5-cm nontender, hard abdom-
inal mass over the right upper quadrant extending to the midline. The remain-
der of the examination findings are unremarkable. He is admitted to the NICU
for further management. In the NICU, he remains clinically stable with vital
signs within the normal range for age. Abdominal ultrasonography shows a
complex heterogeneous mass in the upper abdomen near the midline.

DISCUSSION
Diagnosis
The differential diagnosis for abdominal mass includes neuroblastoma, tera-
toma, meconium pseudocyst, and fetus in fetu (FIF). Computed tomography
(CT) of the abdomen and pelvis reveals a well-demarcated retroperitoneal mass
in the upper abdomen measuring 5.12 × 4.14 × 5.66 cm. Bony structures were
noted within the mass (Fig 1). Laboratory studies including complete blood cell
count, complete metabolic panel, and direct bilirubin were unremarkable.
Serum a-fetoprotein level is normal at 79,888.0 ng/mL (79,888.0 mg/L; range,
5–105,000 ng/mL; [5–105,000 mg/L]), and serum human chorionic gonadotro-
pin and lactate dehydrogenase are mildly elevated at 4 mIU/mL (range, 0–2
mIU/mL) and 846 U/L (14.1 mkat/L; range, 178–629 U/L [2.9–10.6 mkat/L],
respectively. Surgery and hematology/oncology services are consulted for further
assessment and management.
On day 3, exploratory laparotomy was conducted, which showed a 60-g retro-
peritoneal mass with the common duct draped anteriorly and the hepatic artery
AUTHOR DISCLOSURES Drs Kudalmana,
Kim, and Chong have disclosed no along the upper edge of the mass. On the macroscopic pathologic evaluation,
financial relationships relevant to this the mass measures 6.5 × 5.3 × 3.0 cm and is composed of an external skinlike
article. This commentary does not layer with central myxoid tissue and long bones. Microscopically, the outer
contain a discussion of an unapproved/
investigative use of a commercial portion of the mass is reported to be keratinizing squamous epithelium with
product/device. skin adnexa. Deep to the epidermis is loose fibromyxoid tissue. The tubular

Vol. 1 No. 5 MAY 2022 21

 Figure 1. Computed tomography of abdomen and pelvis showing complex retroperitoneal mass.

structures are well-formed small and large bowels with On day 11, the neonate was discharged from the hospi-
central meconiumlike material with probable enteric tal with postoperative complications including cholestasis
neurons. A focus of respiratory mucosa is noted. Radi- and hepatic fibrosis. He is being closely followed by gas-
ography and CT of the specimen show soft tissue and a troenterology and oncology.
bone-containing mass (Fig 2). The bony structures sug-
gest the presence of an oval-shaped skull-like structure. The Condition
Partially fused vertebral bodies are seen in contact with In the late 18th century, Johann Friedrich Meckel was the
this structure. Bony structures that resemble lower first to describe the term “fetus in fetu” as a malformed or
extremities are seen, one of them related to a flat bone parasitic monozygotic diamniotic twin that is found inside
that likely represents part of the pelvis. The pathology
the body of its host. (1)(2)(3) Initially, FIF was thought to
showed that the outer lining of the mass was composed
be a form of mature teratoma, but FIF is now distin-
of epidermis, which gave a clue to our diagnosis because
guished by its composition of highly differentiated tissue
teratomas usually exhibit internal epidermis (Fig 3). The
about a vertebral skeleton. Teratomas are composed of
pathology and imaging studies revealed a diagnosis of
pleuripotential cells representing all 3 germ layers, with
FIF.
poor organization with independent growth potential and
increased risk of malignancy compared to FIF. (1)(2)(3)(4)(5)
Even though the pathogenesis causing this anomaly is not
fully known, it is widely thought that this phenomenon

Figure 2. 3D rendering of surgically removed mass showing the bony

components. Figure 3. External epidermal surface of the mass.

22 NeoReviews
results during the 2nd and 3rd week of development when 1
twin absorbs the other twin during ventral folding of the tri- American Board of Pediatrics
laminar embryonic sac. It is speculated that in the develop- Neonatal-Perinatal Content
ing blastocyst, the unequal division of the totipotent inner
Specification
cell mass results in the smaller mass being enveloped by
• Know the etiology, clinical and laboratory features, and
the maturing embryo. (2)(5) Other theories include the for- management of abdominal masses in the neonate.
mation of an inclusion body after 1 blastocyst implants on
another and FIF occurring as a result of twin-twin transfu-
sion syndrome (4).
The incidence is reported as 1 in 500,000 births, with Acknowledgments
most cases presenting during infancy as an asymptomatic We thank Dr Mohammad Emran, pediatric surgeon, Dr
abdominal mass. (1)(2)(3)(4)(5) The growth of an FIF is Van Savell, pathologist, Dr Elena Romero, radiologist, and
reported to parallel the twin host until vascular limitations the NICU team at Driscoll Children’s Hospital, for assis-
occur, which are secondary to dominance of the host or a tance with diagnosis and patient management.
defect in the parasitic twin, resulting in developmental stagna-
tion (1). FIF is most commonly discovered in a complete References
fluid-filled sac suspended by a single intra-abdominal pedicle. 1. Gangopadhyay AN, Srivastava A, Srivastava P, Gupta DK, Sharma SP,
(2) Most FIF cases reported are benign, with complete surgi- Kumar V. Twin fetus in fetu in a child: a case report and review of
cal excision being the main management. Postoperative sur- the literature. J Med Case Rep 2010;4:96

veillance using tumor markers is recommended for 2 years. 2. Prescher LM, Butler WJ, Vachon TA, Henry MC, Latendresse T,
Ignacio RC. Fetus in fetu: review of the literature over the past 15
(1)(2)(3)(4)(5)
years. J Pediatr Surg Case Rep 2015;3:554–562
3. Harigovind D, Babu Sp H, Nair SV, Sangram N. Fetus in fetu: a rare
Lessons for the Clinician developmental anomaly. Radiol Case Rep 2018;14:333–336
• Fetus in fetu is a rare condition resulting from atypical 4. Landmann A, Calisto J, Reyes-M ugica M, Thomas D, Malek M.
embryogenesis. Fetus-in-fetu presenting as a cryptorchid testis and abdominal mass: a
• Due to the unknown pathogenesis and possible associated report of a case and review of the literature. J Pediatr Surg Case Rep
2016;13: 38–40
long-term sequela, it should be included in the differential
5. Sitharama SA, Jindal B, Vuriti MK, Naredi BK, Krishnamurthy S,
for an abdominal mass in the pediatric population.
Subramania DB. Fetus in fetu: case report and brief review of
• Surgical therapy is the treatment of choice with contin- literature on embryologic origin, clinical presentation, imaging and
ued postoperative monitoring recommended. differential diagnosis. Pol J Radiol 2017;82:46–49.

Vol. 1 No. 5 MAY 2022 23

 INDEX OF SUSPICION IN THE NURSERY

An Uncommon Cause for Respiratory

Failure in a Preterm Neonate
Sanchi Malhotra, MD,* Vikram Anand, MD, PhD,* Jeffrey M. Bender, MD,* Arlene Garingo, MD†
*Division of Infectious Diseases, Children’s Hospital Los Angeles, Los Angeles, CA
†
Division of Neonatology, Children’s Hospital Los Angeles, Los Angeles, CA

CASE PRESENTATION
A preterm female neonate is born at a community hospital in Los Angeles, CA,
at a gestational age of 27 weeks and 6 days via spontaneous vaginal delivery to a
30-year-old, gravida 3, para 1, aborta 1 woman. The mother had received regular
prenatal care, and results of infectious disease screening (HIV, syphilis, hepatitis
B, gonorrhea, chlamydia) were negative, rubella status was immune, and group
B Streptococcus testing was not yet performed. The mother had presented to the
hospital with preterm premature rupture of membranes. Before delivery, she
had received 1 dose of ampicillin, 1 dose of betamethasone, and magnesium for
neuroprotection for the fetus. The infant is delivered within 2 hours of admis-
sion to the hospital.
At delivery, the infant has Apgar scores of 1, 3, and 7 at 1, 5, and 10 minutes
after birth, respectively. She presents with a minimal cry and low heart rate
requiring positive pressure ventilation (PPV) via mask. As there is no improve-
ment in the heart rate with PPV, the infant is intubated and transferred to the
NICU. Admission examination demonstrates a 1,300-g (95th percentile) girl
with nondysmorphic facies. Air exchange is poor, with coarse rhonchi heard
bilaterally in the lungs. Cardiac and abdominal examination findings are not
remarkable. She exhibits spontaneous movements and the tone is appropriate
for age. Her skin is pink, with mild acrocyanosis, no jaundice, no rashes, and
the capillary refill time is less than 3 seconds. She is given exogenous surfactant
and has oxygen saturations in the high 80% range with 100% fraction of
inspired oxygen on conventional ventilator settings. Umbilical lines are placed,
and initial arterial blood gas demonstrates a pH of 7.29, PCO2 of 41 mm Hg
(5.4 kPa), PO2 of 42 mm Hg (5.6 kPa), and base deficit of 6.6. She is subse-
quently placed on high-frequency oscillatory ventilation due to difficulties with
oxygenation.
Admission chest radiography shows diffuse ground-glass reticular densities.
AUTHOR DISCLOSURE Drs Malhotra,
No focal consolidation, pleural effusions, or pneumothorax are seen. Pulmonary Anand, Bender, and Garingo have
vascular markings are within normal limits. Lungs are expanded to 8 ribs with disclosed no financial relationships
an endotracheal tube placed in good position (Fig). Initial laboratory tests reveal relevant to this article. This commentary
does not contain a discussion of an
that the infant has a white blood cell count of 5,700/mL (5.7 × 109/L) with 7% unapproved/investigative use of a
segmented neutrophils and 1% bands with an absolute neutrophil count (ANC) commercial product/device.

24 NeoReviews
 findings were concerning for a leukocytosis, with a white
blood cell count of 20,000/mL (20 × 109/L).

DISCUSSION
Differential Diagnosis
The differential diagnosis for this presentation includes
sepsis, respiratory distress syndrome, and pneumonia.

Diagnosis and Patient Course

The infant’s respiratory culture grew Salmonella enterica
subspecies enterica serovar Typhi (S Typhi). Blood and
cerebrospinal fluid cultures remained negative. This neo-
natal infection was reported to the Los Angeles County
Department of Public Health (DPH). The mother then
underwent stool testing which was also found to be posi-
tive for S Typhi. The infant continued to receive antibiotic
monotherapy with ampicillin for 10 days after susceptibili-
Figure. Initial chest radiograph obtained on the day of birth, on admission
to the NICU. ties demonstrated a fully susceptible isolate. She under-
went extubation to noninvasive ventilation by day 8 after
of 456/mL. C-reactive protein is elevated at 5.3 mg/dL (53 birth and was weaned to room air by day 40 after birth.
mg/L; reference range 0–0.3 mg/dL [0–3 mg/L]). Hemo- She had no other significant complications during the hos-
globin, platelet count, and complete metabolic panel are pitalization and was discharged on day 59.
within normal limits. A blood culture is drawn from the In coordination with colleagues at the DPH, continued
infant and empiric treatment is started with ampicillin testing of the infant with urine and stool cultures was rec-
100 mg/kg per dose every 12 hours and gentamicin 5 mg/ ommended until 3 negative results were obtained on each.
kg per dose every 48 hours. Cefepime 30 mg/kg per dose DPH also recommended avoidance of breastfeeding until
every 12 hours is added for extended gram-negative cover- the mother had 3 negative stool cultures for S Typhi. The
age after initial laboratory results show low ANC. Given mother was discouraged from visiting the NICU while she
the respiratory failure and minimal improvement after was still shedding bacteria in her stool. She remained pos-
surfactant, a tracheal aspirate is obtained for culture. Lum- itive on repeat stool cultures by the time of discharge. The
bar puncture is also performed and cerebrospinal fluid infant was therefore discharged from the hospital with
studies are reassuring. Gentamicin is discontinued after transitional formula until outpatient follow-up confirmed
48 hours of negative blood culture, and empiric treatment that the mother had 3 negative cultures. Unfortunately,
with ampicillin and cefepime is continued for presumed the infant continued to be fed formula because the mother
sepsis. no longer had adequate supply of breast milk by the time
Of note, the mother had 2 emergency department visits her stools were cleared of bacteria. The family was fol-
before the delivery. One month earlier, she had symptoms lowed closely by DPH as an outpatient.
of high fever, cough, and congestion as well as nonbloody,
watery diarrhea. She was diagnosed with a viral illness and Condition, Treatment, and Management
discharged from the hospital. The diarrhea continued for To our knowledge, this is the first case of S Typhi pneu-
another week and after resolution, she had subjective fevers monia in a neonate in the United States. Cases of S Typhi
for 2 weeks. She was then seen again 2 weeks before this bacteremia and sepsis have been described in the neonatal
delivery, for subjective fever, cough, and congestion and period in typhoid-endemic countries, but this has decreased
sent home with supportive care. The mother had traveled significantly in the postantibiotic era with treatment of
to Guatemala with her husband and other child for 1 week typhoid in pregnancy. (1)(2)(3)(4)(5) S Typhi was known to
during the pregnancy, returning about 6 weeks before this increase maternal morbidity and cause spontaneous abor-
delivery. Her husband and child had remained well after tion, preterm labor, or fetal infection in 60% to 80% of
their return from Guatemala. Although the mother was afe- cases in the preantibiotic era (4)(5); however, in the postan-
brile at the time of her presentation in labor, her laboratory tibiotic era, Sulaiman and Sarwari describe no impact on

Vol. 1 No. 5 MAY 2022 25

 pregnancy outcome from typhoid infection if appropriately Lessons for the Clinician
treated. (6) In our patient, the maternal infection was • In a pregnant woman with a history of travel, fever, and
unknown during pregnancy and could have precipitated the diarrhea, consider evaluating for infectious etiology, as
preterm labor and early rupture of membranes. Vertical may prevent neonatal infection.
and horizontal transmission have both been described for S • Salmonella enterica subspecies enterica serovar Typhi (S
Typhi. (4)(5)(7)(8) Our patient with pneumonia immediately Typhi) can be found in blood, stool, and respiratory
in the perinatal period and positive maternal stool cultures cultures.
most likely had vertical transmission of infection. Case • S Typhi, typically responsible for typhoid fever, can
reports of typhoid infection during pregnancy describe cho- cause neonatal sepsis that may be clinically indistin-
rioamnionitis, positive amniotic fluid, and positive culture guishable from other sepsis syndromes.
for S Typhi in fetal lung tissue, supporting the likelihood of • S Typhi can continue to be shed by patients after treat-
vertical transmission. (7)(8) ment, so infection prevention measures must be fol-
Although uncommon in the United States, pediatricians, lowed by the unit and the department of public health
neonatologists, and obstetricians should remain aware of S should be contacted.
Typhi infections in the maternal/fetal period especially in
cases of travel. Neonatal sepsis with S Typhi is clinically Acknowledgments
indistinguishable from other causes of neonatal sepsis, with We thank the infant’s family for their consent to write
this report.
presentations that include lethargy, irritability, jaundice,
respiratory distress/failure, and hemodynamic instability.
(1)(2) The neonate usually does not present with the classic References
signs of typhoid fever seen in older children—fever, diar- 1. Reed RP, Klugman KP. Neonatal typhoid fever. Pediatr Infect Dis J.
rhea, and rose spots. (3)(5) Our preterm infant received 1994;13(9):774–777
appropriate antibiotic coverage for S Typhi pneumonia from 2. Sharma D, Khan J, Agarwal S. Salmonella typhi as cause of neonatal
sepsis: case report and literature review. J Matern Fetal Neonatal
the onset, initially with broad-spectrum antibiotics and sup-
Med. 2021;34(5):732–735
portive care. Once culture susceptibilities are obtained, tar-
3. Chin KC, Simmonds EJ, Tarlow MJ. Neonatal typhoid fever. Arch
geted antibiotic therapy is the definitive treatment. Dis Child. 1986;61(12):1228–1230
In addition to management of the patient, care must be 4. Obaro SK, Iroh Tam PY, Mintz ED. The unrecognized burden of
taken to avoid risk of spread across the NICU. Stool culture typhoid fever. Expert Rev Vaccines. 2017;16(3):249–260
of both the mother and infant should also be monitored. 5. Mohanty S, Gaind R, Sehgal R, Chellani H, Deb M. Neonatal sepsis
The patient should be isolated if possible and health care due to Salmonella Typhi and paratyphi A. J Infect Dev Ctries.
2009;3(8):633–638.
professionals must take great care to wash hands between
6. Sulaiman K, Sarwari AR. Culture-confirmed typhoid fever and
patients. Although S Typhi transmission/excretion through pregnancy. Int J Infect Dis. 2007;11(4):337–341
breast milk has not been proven, transmission of nonty- 7. Vigliani MB, Bakardjiev AI. First trimester typhoid fever with
phoidal Salmonella through breast milk has been described. vertical transmission of salmonella typhi, an intracellular organism.
(9) However, presence of maternal antibodies to Salmonella Case Rep Med. 2013;2013:973297

in breast milk in the developing world has also been 8. Gluck B, Ramin KD, Ramin SM. Salmonella typhi and pregnancy: a
case report. Infect Dis Obstet Gynecol. 1994;2(4):186–189
described and could be protective. (10) After treatment,
9. Qutaishat SS, Stemper ME, Spencer SK, et al. Transmission of
patients with S Typhi can have a relapse and a small per- Salmonella enterica serotype typhimurium DT104 to infants through
centage of patients can become asymptomatic chronic car- mother’s breast milk. Pediatrics. 2003;111(6 pt 1):1442–1446
riers requiring repeat or prolonged antibiotic courses to 10. Turin CG, Ochoa TJ. The role of maternal breast milk in preventing
ensure eradication. (11) The repeat negative cultures in our infantile diarrhea in the developing world. Curr Trop Med Rep.
2014;1(2):97–105
infant and mother were necessary to prove eradication. An
11. Crump JA, Sj€ olund-Karlsson M, Gordon MA, Parry CM.
inactivated typhoid vaccine, which is about 50% to 80%
Epidemiology, clinical presentation, laboratory diagnosis,
effective in preventing infection, is available for persons antimicrobial resistance, and antimicrobial management of invasive
aged 2 years or older, and often recommended to travelers Salmonella infections. Clin Microbiol Rev. 2015;28(4):901–937
to endemic countries. However, there is not enough safety 12. Jackson BR, Iqbal S, Mahon B; Centers for Disease Control and
Prevention (CDC). Updated recommendations for the use of
information to consistently recommend vaccine administra-
typhoid vaccine–Advisory Committee on Immunization Practices,
tion during pregnancy; therefore, administration is typically United States, 2015. MMWR Morb Mortal Wkly Rep. 2015;64(11):
avoided unless the benefits outweigh the risks. (12) 305–308

26 NeoReviews
INDEX OF SUSPICION IN THE NURSERY

Preterm Infant with Respiratory

Distress, Hypotonia, and Hypoglycemia
Venkata S. Gupta,* Tiffany L. Walker, MSN, NNP-BC,† Christelle M. Ilboudo,‡ Anjali P. Anders†
*Departments of Child Health and Medicine, University of Missouri–Columbia, Columbia, MO
†
Division of Neonatology, Department of Child Health, University of Missouri–Columbia, Columbia, MO
‡
Division of Infectious Diseases, Department of Child Health, University of Missouri–Columbia, MO

CLINICAL PRESENTATION
A 2,760-g boy born at 34 weeks, 5 days of gestation is admitted to the NICU
after birth because of prematurity and respiratory distress requiring continuous
positive airway pressure (CPAP). The infant is born to a 26-year-old gravida 4,
para 1-3-0-3 Amish woman via cesarean section due to nonreassuring fetal heart
tones and biophysical profile of 4/10. The pregnancy has been complicated by
complete placenta previa and history of preterm deliveries. His mother did not
use medications during pregnancy. Maternal prenatal infectious screening evalu-
ation for syphilis and HIV were negative. She was rubella nonimmune. The
mother received 1 dose of cefazolin before delivery for a positive result on group
B Streptococcus (GBS) vaginal screening. The delivery is complicated by meco-
nium-stained amniotic fluid and presence of nuchal cord. The infant requires
positive pressure ventilation and CPAP during initial resuscitation. His Apgar
scores are 5 and 7 at 1 and 5 minutes after birth, respectively. Arterial cord pH is
7.31 with base excess of 0.4. The infant requires CPAP after initial resuscitation
and is admitted to the NICU for further evaluation and management.
On admission, the infant’s height, weight, and head circumference are above
the 80th percentile. His vital signs are a temperature of 99.1 F (37.3 C), heart rate
of 154 beats/min, respiratory rate of 37 breaths/min, blood pressure of 54/36 mm
Hg (mean 40 mm Hg), and oxygen saturation of 96% on noninvasive respiratory
support with supplemental oxygen of 40%. The infant is pale in color with hypo-
tonia, shows decreased response to stimuli, and has mild subcostal retractions
with clear lung sounds. The remainder of the physical examination reveals no
focal abnormalities. The infant has hypoglycemia with point-of-care blood glucose
of 38 mg/dL (2.1 mmol/L) on admission requiring continuous intravenous dex-
trose fluid, with improvement seen after the initiation of intravenous fluids. Due
to hypoglycemia along with respiratory distress, hypotonia, and decreased
AUTHOR DISCLOSURE Drs Gupta,
response to stimuli, blood culture specimens are obtained. The infant is started
Ilboudo, and Anders and Ms Walker have
disclosed no financial relationships on empiric antibiotic therapy with ampicillin and gentamicin.
relevant to this article. This commentary
does not contain a discussion of an
LABORATORY STUDIES
unapproved/investigative use of a
commercial product/device. Initial laboratory tests performed on admission are shown in the Table.

Vol. 1 No. 5 MAY 2022 27

 Table. Initial Laboratory Findings o Enteroviruses
o Parechoviruses
Test Patient Result
• Fungal organisms
Complete blood cell
count o Candida
White blood cell count 9,200/lL (9.20 × 109/L) Other disorders should be considered in the differen-
Hemoglobin 17.0 g/dL (170 g/L) tial diagnosis for respiratory distress, hypotonia, and
Hematocrit 50.6%
Platelets 279 × 103/lL (279 × 109/L) hypoglycemia, though less likely given the combination
Immature to total 0.12 of symptoms. These include respiratory distress syn-
neutrophil ratio
Arterial blood gases
drome, neonatal encephalopathy, neuromuscular disor-
pH 7.48 (normal: 7.27–7.42) ders, intracranial lesions, genetic or metabolic disorders,
PCO2 26.9 mm Hg (3.5 kPa) or teratogen exposure.
PO2 102 mm Hg (13.5 kPa)
Bicarbonate 19.6 mg/dL (19.6 mmol/L)
Base deficit 3.4 mEq/L ACTUAL DIAGNOSIS
Biomarkers
C-reactive protein 5.92 mg/dL (normal: 0.0–0.5 mg/dL) Listeria monocytogenes sepsis.

PATIENT COURSE
RADIOGRAPHIC STUDIES Based on the infant’s presentation, he was started on
Chest radiography on admission (Fig 1) reveals bilateral empiric antibiotics. His blood culture specimen began to
reticulonodular pulmonary opacities consistent with sur- grow gram-positive rods (Fig 2A and 2B) at 30 hours, and
factant deficiency, and less likely, pneumonia. he subsequently underwent a lumbar puncture. The pre-
liminary results of lumbar puncture included a red blood
cell count of 18/μL (0.018 × 109/L) white blood cell (WBC)
DIFFERENTIAL DIAGNOSIS count of 3/μL (0.003 × 109/L), protein of 91 mg/dL (0.091
• Gram-positive organisms g/dL), and glucose of 48 mg/dL (2.6 mmol/L). Blood cul-
o Group B Streptococcus ture was determined to be positive for L monocytogenes.
o Enterococcus Cerebrospinal fluid culture and polymerase chain reaction
o Staphylococcus aureus panel for meningitis were negative. After further discus-
o Coagulase-negative Staphylococcus sion, the infant’s mother explained that she had diarrhea
o Listeria monocytogenes beginning 1 month before delivery, and low-grade fevers
• Gram-negative organisms (100.0 F [37.8 C]), headache, and nausea beginning 3
o Escherichia coli weeks before delivery. Approximately 1 week before deliv-
o Bacteroides ery, she had come to the emergency department with com-
o Klebsiella plaints of low-grade fevers and headache. Results of severe
o Enterobacter acute respiratory syndrome coronavirus 2 (SARS-CoV2)
o Serratia testing performed due to the ongoing pandemic were neg-
o Hemophilus ative and urinalysis was not concerning for a urinary tract
• Viral organisms infection. She remained symptomatic during the postpar-
o Herpes simplex virus tum period. Before the infant’s diagnosis, no blood culture
specimens were obtained from his mother. The infant’s
mother had a diet consisting of deli meats, farm fresh
eggs, apples, watermelon, lettuce, radishes, and spinach
from a local garden.
The infant’s clinical condition improved rapidly after
the initiation of antibiotics, and he was able to transition
to enteral feeds on the second day after birth and wean to
room air from CPAP on the 4th day after birth. He com-
pleted a 14-day course of ampicillin and gentamicin. He
Figure 1. Chest radiograph obtained at the time of admission illustrating
was subsequently discharged from the NICU on day 16
bilateral reticulonodular pulmonary opacities. after birth.

28 NeoReviews
Figure 2. A and B. Blood culture specimen illustrating gram-positive rods.

DISCUSSION related EOS may have provided a collateral benefit, by

Early-onset sepsis (EOS) is defined as culture-proven infec- reducing cases of neonatal listeriosis from 4.78 per
tion occurring in a newborn less than 7 days of age or in 10,000 admissions to 1.31 per 10,000 after universal
very-low-birthweight (VLBW) infants less than 72 hours of acceptance of GBS prophylaxis. (5) Despite this lower inci-
age. (1) The incidence of EOS is strongly influenced by the dence, a high index of suspicion must be maintained in
newborn’s gestational age at birth, with the highest inci- newborns delivered to mothers with risk factors.
dence seen in VLBW infants. (1) The diagnosis of EOS L monocytogenes is an intracellular gram-positive motile
rod, which is an asymptomatic colonizer of the gastroin-
is a challenge, because early signs and symptoms are
testinal tract in up to 10% of individuals, but in pregnant
nonspecific and subtle. (2) Traditionally, complete blood
women, neonates, the elderly, and immunocompromised
cell count with differential has been used to identify
individuals it can lead to invasive disease. The annual inci-
increased/decreased WBC count, increased immature-to-
dence rate of invasive listeriosis was 13 times higher in
total neutrophil ratio, and/or thrombocytopenia to help
pregnant women compared to the general population
diagnose sepsis in the right clinical context. Multiple stud-
between 2008 and 2016. (6) Consumption of contami-
ies have evaluated biomarkers for early detection of neona-
nated food can lead to severe illness and sepsis. Various
tal sepsis, however, none were comparable to the gold
foods have been associated with L monocytogenes contami-
standard of culture-proven infection. Although pediatric
nation and human infections, including unpasteurized
blood culture bottles have helped in detecting bacteremia
milk or foods containing unpasteurized milk, unwashed
at very low concentrations in very low blood volumes, the
raw produce including fruits and vegetables, deli meats,
ability to detect microorganisms in blood cultures remains
hot dogs, soft cheeses, precooked fish, and refrigerated
a challenge given the limitations of blood draws in the
spreads. (7)(8)(9)
neonatal population. (3) Diagnosis of listeriosis during pregnancy is often delayed
The leading bacterial cause of EOS continues to be due to nonspecific symptoms such as mild febrile illness,
GBS; however, with the introduction of intrapartum anti- flulike symptoms, myalgias, and headache, and occasionally
biotic prophylaxis (IAP), the incidence of EOS due to GBS preceded by nonspecific gastrointestinal symptoms such as
has reduced significantly. The use of IAP has led to vomiting/diarrhea and sore throat. Fortunately, maternal
increasing incidence of EOS caused by Escherichia coli. (1) mortality associated with listeriosis is rare, but the fetal
The majority of organisms that cause EOS are normal col- implications of vertical transmission through the placenta
onizers of maternal gastrointestinal or genitourinary tract can be significant and depend on the gestational age at
leading to ascending infection or infection during delivery, transmission. Infection during the first trimester has been
except for L monocytogenes which spreads hematogenously associated with a 65% risk of miscarriage, whereas infection
across the placenta. (1)(4) in the second and third trimester has a lower risk (26%)
L monocytogenes has long been understood as an impor- of fetal death. (7)(8)
tant causative agent of infant meningitis and deserves to Like GBS, both early- and late-onset listeriosis has been
be considered in the decision to provide empiric antibiotic reported among neonates with significant morbidity and
coverage. Interestingly, over the last 2 decades, the inci- mortality. Listeriosis in neonates can cause meningitis,
dence of EOS secondary to L monocytogenes infection has permanent neurologic deficits, sepsis, or death. Most often
declined. Widespread use of antibiotics to prevent GBS- early-onset listeriosis presents as pneumonia, respiratory

Vol. 1 No. 5 MAY 2022 29

 distress, fever, neurologic symptoms, skin rash, and jaun- References
dice. (7) Diagnosis can be made by visualization of the
1. Mukhopadhyay S, Puopolo KM. Neonatal early-onset sepsis:
organisms with their characteristic tumbling motility on wet epidemiology and risk assessment. Neoreviews. 2015;16:e221–e230
mount microscopy or on Gram stain. Because L monocyto- 2. Deleon C, Shattuck K, Jain SK. Biomarkers of neonatal sepsis.
genes is an intracellular organism, it can be missed on Gram Neoreviews. 2015;16:e297–e309
stain. Treatment is aimed at improving neonatal outcomes. 3. Dien Bard J, McElvania TeKippe E. Diagnosis of bloodstream
No randomized controlled trials have assessed the type or infections in children. J Clin Microbiol 2016;54:1418–1424
duration of an antibiotic for listeriosis, so the antibiotics of 4. Shane AL, Sanchez PJ, Stoll BJ. Neonatal sepsis. Lancet
2017;390:1770–1780
choice continue to be ampicillin, penicillin, or amoxicillin.
5. Lee B, Newland JG, Jhaveri R. Reductions in neonatal listeriosis:
No bacterial resistance has been detected to penicillin to
“Collateral benefit” of Group B streptococcal prophylaxis? J Infect
date, however, L monocytogenes is noted to be resistant to 2016;72:317–323
cephalosporins, clindamycin, and chloramphenicol. Syner- 6. Pohl AM, Pouillot R, Bazaco MC, et al. Differences among incidence
gistic activity with gentamicin has been noted. (8)(9) rates of invasive listeriosis in the U.S. FoodNet population by age, sex,
race/ethnicity, and pregnancy status, 2008-2016. Foodborne Pathog
Dis 2019;16:290–297
Lessons for the Clinician
7. Craig AM, Dotters-Katz S, Kuller JA, Thompson JL. Listeriosis in
• Infants with clinical sepsis may have subtle signs, there- pregnancy: a review. Obstet Gynecol Surv 2019;74:362–368
fore, a high index of suspicion is needed to begin early 8. Lamont RF, Sobel J, Mazaki-Tovi S, et al. Listeriosis in human
treatment for sepsis. pregnancy: a systematic review. J Perinat Med 2011;39:227–236
• It is important to obtain a thorough history, including 9. McKinney JS. Listeria infections in neonates. Neoreviews.
dietary history, from the mother for risk factors that 2016;17:e515–e520

may lead to neonatal sepsis due to congenital infections

or perinatally acquired infections.
• When treating a neonate for listeriosis, it is important to
maintain communication with obstetric colleagues as
this diagnosis may affect maternal management if the
mother continues to be symptomatic.

American Board of Pediatrics

Neonatal-Perinatal Content
Specifications
• Know the epidemiology, pathogenesis, prevention, clin-
ical manifestations, and diagnostic features of perinatal
Listeria monocytogenes infection.
• Know the treatment and complications of perinatal
Listeria monocytogenes infection.

30 NeoReviews