FEBRUARY 2021

NOVEMBER 2024
Vol.25
Vol. 22No.
No.11
2
[Link]

ARTICLES
ARTICLES
Gastroesophageal
Disorders of CoagulationRefl ux Disease
in the Newbornin
Neonates: Facts and Figures
Thrombotic Disorders in the Newborn
Fetal Heart Rate Tracing Category II:
Hemoglobinopathies
A �road Category in Need ofin Stra�
the Neonate
fica�on
MATERNAL-FETAL CASE STUDIES
Maternal Hematologic Condi�
Alloimmunization ons and
in Pregnancy:
Fetal/NeonatalImplications
Outcomes of Pregnancy
for the Fetus
and Neonate
Obesity and Pregnancy
VISUAL DIAGNOSIS
COMPLEX
Unusual Dermatologic FETAL in
Findings CARE
an
FetalExtremely
Sacrococcygeal Teratoma and the
Low Birthweight Infant:
Development
The GeneticofDiagnosis
Hydrops

VISUAL DIAGNOSIS
Sudden Onset of a Unilateral Erythematous
Preauricular Mass in a Preterm Infant

NeoReviews® and NeoReviewsPlus™ are supported,

in part, throu�h an educa�onal �rant from A��o�
Nutri�on, a proud supporter of the American Academy
of Pediatrics.

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 NeoReviews
PERSPECTIVES Editor-in-Chief: Dara Brodsky, Boston, MA
Associate Editor, IOS Cases: Elizabeth Schulz, Bethesda, MD
e677 XIII Consenso SIBEN sobre Traslado Neonatal: Establecer Associate Editor, IOS Cases: Jayasree Nair, New York, NY
Associate Editor, CME: Santina A. Zanelli, Charlottesville, VA
protocolos estructurados para el proceso del traslado Associate Editor, NeoQuest: Rita Dadiz, Rochester, NY
neonatal podría mejorar los desenlaces Associate Editor, Perspectives: Mamta Fuloria, Bronx, NY
Associate Editor, Maternal-Fetal Medicine: Brett Young, Boston, MA
Lemus-Varela ML, Golombek SG, Sola A, Davila-Aliaga CR, Pleitez J, Associate Editor, Video Corner: Akshaya Vachharajani, Columbia, MO
Baquero-Latorre H, Celiz M, Fernández P, Lara-Flores G, Lima-Rogel MV, Mir R, Assistant Editor, CME: Theodore De Beritto, Los Angeles, CA
Associate Editor, Complex Fetal Care: •••
Montes-Bueno Mt, Neira F, Sánchez-Coyago J, Young A, y los participantes del Carl Backes, Columbus, OH •
•• •

XIII Consenso Clınico de Traslado Neonatal de la Sociedad Iberoamericana de

•
•
Neonatologıa (SIBEN)
EDITORIAL BOARD
Jane E. Brumbaugh, Rochester, MN MOC

•
•
• •
Anisha Bhatia, Canton, OH
••
•••

Colby Day, Jacksonville, FL

Jennifer Hanford, Columbia, MO
ARTICLES Alison Chu, Los Angeles, CA
Corinne L. Leach, Buffalo, NY
e694 Disorders of Coagulation in the Newborn Krithika Lingappan, Houston, TX
Sai Mukthapuram, Cincinnati, OH
Lorena Ostilla, Karyssa Knopoff, Patrick Myers, Perry Morocco Zeynep Salih, Carmel, IN
Thomas E. Wiswell, Honolulu, HI
e710 Thrombotic Disorders in the Newborn Clyde Wright, Aurora, CO
Karyssa Knopoff, Lorena Ostilla, Perry Morocco, Patrick Myers Manager, Journal Publishing: Josh Sinason
Medical Copy Editor: Beena Rao
e720 Hemoglobinopathies in the Neonate Publisher: American Academy of Pediatrics
Katrina Blankenhorn, Kaitlin Strumph President: Benjamin D. Hoffman
Chief Executive Officer/Executive Vice President:
Mark Del Monte
Chief Product and Services Officer/SVP Membership, Marketing,
and Publishing:
INDEX OF SUSPICION IN THE NURSERY Mary Lou White
Vice President, Publishing: Mark Grimes
e729 Term Neonate With Right-Sided Limb Swelling: A Potpourri Director, Journal Publishing: Joseph Puskarz
of Etiology and Complication NeoReviews™
Tehsin Patel, Abhilasha Kumari, Prashanth Ranya Raghavendra, Sruthi Nair, (ISSN 1526-9906) is owned and controlled by the American Academy of Pediatrics. It is
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Anitha Haribalakrishna, Sumeet Anant Dhulshette, Hemangini Thakkar, Statements and opinions expressed in NeoReviews™ are those of the authors and not
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MATERNAL-FETAL CASE STUDIES CME/MOC Information:

The American Academy of Pediatrics (AAP) is accredited by the Accreditation Council
for Continuing Medical Education (ACCME) to provide continuing medical education
e742 Alloimmunization in Pregnancy: Implications for the Fetus for physicians.
and Neonate The AAP designates this journal-based CME activity for a maximum of 24.0 AMA PRA
Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the
Scott N. MacGregor extent of their participation in the activity.
In order to earn CME credits and/or ABP MOC Part 2 points, you must participate in
this activity online at [Link], where you will view additional information,
complete your CME quizzes, and claim credit online.
VISUAL DIAGNOSIS NeoReviews™ and NeoReviewsPlus™ are supported, in part, through an educational grant
from Abbott Nutrition, a proud supporter of the American Academy of Pediatrics.
e747 Unusual Dermatologic Findings in an Extremely Low The American Academy of Pediatrics is committed to principles of equity, diversity, and
inclusion in its publishing program.
Birthweight Infant: The Genetic Diagnosis
[Link]/neoreviews
L. Elizabeth Ricker, Matthew Saxonhouse, Lauren Carter

[Link]/AAPJournals

COMPLEX FETAL CARE

e751 Pallister-Killian Syndrome
Ritu Chitkara, Valerie Chock, Richard Barth, Hisham Dahmoush, Carly Smith,
Dena R. Matalon, Melissa Herring, Susan Hintz

Answer Key appears on page e750.

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 PERSPECTIVES

XIII Consenso SIBEN sobre Traslado

Neonatal: Establecer protocolos
estructurados para el proceso del
traslado neonatal podr
ıa mejorar
los desenlaces
Lemus-Varela ML,*,† Golombek SG,*,‡ Sola A,*,§ Davila-Aliaga CR,*,k Pleitez J,*,# Baquero-Latorre H,*,** Celiz M,*,††
Fern
andez P,*,‡‡ Lara-Flores G,*,§§ Lima-Rogel MV,*,kk Mir R,*,## Montes Bueno MT,*,*** Neira F,*,†††
S
anchez-Coyago J,*,‡‡‡ Young A*,§§§ y los participantes del XIII Consenso Cl
ınico de Traslado Neonatal
de la Sociedad Iberoamericana de Neonatolog
ıa (SIBEN)
*SIBEN, Sociedad Iberoamericana de Neonatolog
ıa
†
Departamento de Neonatolog
ıa, Hospital de Pediatr
ıa, UMAE, CMNO, Instituto Mexicano del Seguro Social. Guadalajara, Jalisco, M
exico
‡
SUNY Downstate Health Sciences University, Brooklyn, NY, Estados Unidos
§
Director General de SIBEN, Profesor Em
erito de SIBEN
k
Neonat
ologa del Instituto Nacional Materno Perinatal, Lima Per
u
#
Neonato
logo del Instituto Nacional de Salud, El Salvador
**Profesor titular Departamento de Medicina, Universidad del Norte, Barranquilla, Colombia
††
Neonat
ologa CERHU, San Luis, Argentina
‡‡
Neonat
ologa coordinadora del Hospital Brit
anico y del Ministerio de Salud de la Naci

on, Buenos Aires, Argentina
§§
Profesor de Neonatolog
ıa Hospital Luis Castelazo Ayala, UMAE 4, Instituto Mexicano del Seguro Social, Ciudad de M
exico
kk
Departamento de Neonatolog
ıa, Hospital Central Dr. Ignacio Morones Prieto, San Luis Potos
ı, SLP, M
exico
##
Profesor Titular de Pediatr
ıa, Hospital de Cl
ınicas, Asunci

on, Paraguay
***Enfermera de Neonatolog
ıa, Hospital Universitario La Paz, Madrid, Espan ~a
†††
Profesor Universidad del Norte, Barranquilla, Colombia
‡‡‡
Neonatolog
ıa, Hospital de Especialidades Carlos Andrade Mar
ın, Quito, Ecuador
§§§
Decano de la Facultad de Ciencias de la Salud, UNITEC, Tegucigalpa, Honduras

RESUMEN

n de los partos de alto riesgo en los hospitales con el m
as alto
La centralizacio
nivel de atencio
n es fundamental para ampliar el margen de seguridad materno-
neonatal y mejorar los desenlaces. Por lo tanto, es altamente recomendable
trasladar oportunamente a las pacientes gestantes portadoras de embarazos de
alto riesgo y/o con amenazas de parto pret
ermino a centros de atencio
n terciaria,
sin embargo, no siempre es posible anticipar los riesgos antenatalmente, lo cual
resulta en la necesidad de trasladar a neonatos en estado cr
ıtico.
Lamentablemente, la movilizacio
n de los reci

en nacidos compromete au
n m
as
su estado de salud, especialmente en los pa
ıses latinoamericanos.
El presente trabajo resume los resultados del XIII Consenso Cl
ınico de SIBEN de AUTHOR DISCLOSURES Drs Lemus-Varela,
Golombek, Sola, Davila-Aliaga, Pleitez,
Traslado Neonatal, en el cual colaboraron 65 miembros de SIBEN, neonato
logos
Baquero-Latorre, Celiz, Fernandez,
y licensiados en enfermer
ıa de 14 pa
ıses de Iberoam
erica, que participaron Lara-Flores, Lima-Rogel, Mir, Montes Bueno,
activamente durante el 2022, antes, durante y despu

n presencial
es de la reunio Neira, Sanchez-Coyago, and Young have
disclosed no financial relationships relevant
que se llevo
a cabo en M
erida, Yucat
an, M
exico el 12 de noviembre del 2022.
to this article. This article does not contain a
En esta reunio
n se consensuaron las recomendaciones aqu
ı vertidas. discussion of an unapproved/investigative
use of a commercial product/device.

Vol. 25 No. 11 N O V E M B E R 2 0 2 4 e677

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 SIBEN recomienda mejorar las pol
ıticas de regionalizaci
on
referring hospital, receiving hospital and
de la salud en Latinoam
erica, que exista absoluta equidad
personnel carrying out the transfer. This would
e intentar que las unidades de nivel terciario no se concen-
lead to a correct and timely transfer with a wide
tren u
nicamente en las grandes ciudades. Es necesario
margin of security.
mejorar los procesos del traslado neonatal, protocolizar y
sistematizar cada paso a cumplir para mejorar los desenla-
ces, desde la identificaci
on temprana, siempre que sea
posible antenatalmente, mantener en forma continua los INTRODUCCIÓN
canales de comunicaci
on en forma tripartita: hospital de En la d
ecada de los setenta, se propuso en Estados Unidos
referencia, hospital receptor y equipo del personal que de Norteam
erica la regionalizaci
on de la atenci

on neonatal
ua el traslado y as
ı, trasladar oportuna y correcta-
efect
como una estrategia para mejorar los resultados, lo cual
mente con amplio margen de seguridad a un tercer nivel signific
o el traslado de neonatos cr
ıticos a centros con ni-
de atenci
on. veles de atenci
on de alta complejidad. (1) El traslado neo-
natal ideal es el que ocurre antes de nacer, es decir, el
traslado intrauterino o materno-fetal, que permite la cen-
Summary tralizaci

on de la atenci
on a los embarazos de alto riesgo
The centralization of high-risk births in hospitals en un nivel terciario en las mejores condiciones y en el
with the highest level of neonatal care is essential momento adecuado, sin embargo, no todas las patolog
ıas
to increase maternal-neonatal safety and improve neonatales pueden detectarse antenatalmente. Resulta fun-
outcomes. Therefore, it is highly recommended damental anticipar oportunamente el nivel de atenci
on
the timely transfer to tertiary care centers of high- correcto, establecer la coordinaci
on previa con los centros
risk pregnant women and/or with threats of asistenciales y con el equipo profesional encargado del
preterm birth. However, it is not always possible traslado. (2)(3)
to anticipate the risks prenatally. This results in El concepto del traslado neonatal implica el desplaza-
the need to transfer neonates in critical condition. miento del reci
en nacido (RN) desde el centro que deriva
Unfortunately, the mobilization of these (hospital de referencia, remitente o emisor) al centro que
newborns further compromises their health recibe (receptor). (2) Los distintos pasos que deben in-
status, especially in Latin American countries. cluirse son: la toma de decisi
on en el centro de referencia,
This narrative reports the results of the XII estabilizaci

on del neonato previa al traslado en dicho centro,
SIBEN Clinical Consensus on Neonatal Transport. b
usqueda de un hospital receptor adecuado, coordinaci
on y
In this Consensus, 65 members of SIBEN comunicaci
on constante, un medio de transporte correcto y
(Neonatologists and Nurses from 14 Latin personal con entrenamiento profesional para llevar a cabo el
American countries) collaborated during 2022, traslado oportuna y correctamente dentro de un amplio mar-
before, during and after the meeting that gen de seguridad. (2) Es absolutamente necesario estabilizar
took place in M
erida, Yucatan, M
exico on al neonato antes de su traslado y contar con un equipo de
November 12, 2022. In this joint meeting the profesionales de la salud expertos en el traslado neonatal,
recommendations conveyed here were agreed con amplio conocimiento de la reanimaci
on neonatal, de an-
upon. ticipaci

on a los riesgos a enfrentar y de la sistematizaci

on del
SIBEN recommends improving health proceso de traslado. Siempre se debe cuidar cada detalle con
regionalization policies in Latin America, ensuring el objetivo de brindar atenci
on continuada desde la sala de
that there is absolute equity and trying to ensure partos, la estabilizaci

on y el traslado neonatal, hasta el arribo
that tertiary level units do not concentrate only in a la UCIN del hospital receptor. Todo esto impactar
a positi-
large cities. It is necessary to improve neonatal vamente en el desenlace final. (4)
transport processes and systematically La separaci
on de los padres de su reci
en nacido enfermo
protocolize each step, to improve outcomes. This es una experiencia amenazante, estresante, con p
erdida del
includes early risk identification, whenever contexto familiar, situaci
on que nos debemos plantear para
possible prenatally, continuously maintaining mejorar la atenci
on integral del RN y sus familias. (4)
communication channels in a three-way manner: En el presente manuscrito se incluyen y resumen indi-
caciones, tipos, m
etodos y medios de traslado neonatal, as
ı

e678 NeoReviews

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 como factores de riesgo, condiciones b
asicas y fundamen- traslado materno-fetal, en contraste con el traslado neonatal, y
tales, material necesario, implementaciones que facilitan y resulta m
as evidente en embarazos de menos de 28 semanas
ampl
ıan el margen de seguridad antes y durante el tras- de edad gestacional. (14)(15)(16)(17)(18)(19)(20) Asimismo, es
lado neonatal, aspectos
eticos y las recomendaciones del importante evitar traslados innecesarios, dado el impacto social,
XIII Consenso de SIBEN. familiar y el coste sanitario que esto representa. (21)(22)(23)(24)
En concreto, el traslado materno-fetal intrauterino es el
TIPOS DE TRASLADO NEONATAL est
andar de oro, representa la mejor opci
on en t
erminos
Existen tres tipos de traslado neonatal: de seguridad, log
ıstica, asequibilidad, costos y resultados
finales para el binomio, (25) las indicaciones precisas y
1. Traslado prenatal o materno-fetal. contraindicaciones del traslado materno-fetal se muestran
2. Traslado neonatal o interhospitalario. en el cuadro 1.
3. Traslado por contrarreferencia o de retorno.
2. TRASLADO NEONATAL O INTERHOSPITALARIO
1. TRASLADO PRENATAL O MATERNO-FETAL Se refiere a trasladar a un neonato hacia otro centro de
Es esencial el traslado de la gestante ante cualquier atenci
on de mayor complejidad. En 2017, la Academia
patolog
ıa o alteraci
on que precise cuidados intensivos, Americana de Pediatr
ıa (AAP) y el Colegio Americano de
abordajes diagn
osticos o terap
euticos complejos que re- Ginecolog
ıa y Obstetricia (ACOG), publicaron la 8.a edici
on
quieren de un nivel de atenci
on mayor, tanto para el RN, de las Gu
ıas para el Cuidado Perinatal, la cual incluye un
como para la madre. (5)(6)(7)(8)(9)(10) cap
ıtulo titulado: “Transferencia interhospitalaria materna y
A mediados de los setenta, se inform
o acerca de la me- neonatal”, el cual identifica al traslado como un compo-
jor supervivencia neonatal con el traslado materno-fetal. El nente esencial de la regionalizaci
on en la atenci

on materna
traslado materno-fetal resulta m
as sencillo, seguro y me- y neonatal. (11)
nos costoso en contraste con el neonatal y puede realizarse
por v
ıa terrestre o a
erea. (11) 3. TRASLADO DE CONTRARREFERENCIA O DE
La derivaci
on oportuna de la gestante de alto riesgo, con RETORNO
amenaza de parto pret
ermino, abombamiento de membranas El traslado de contrarreferencia o de retorno favorece la
o ruptura prematura de membranas y con trasladado oportuno mejor utilizaci
on de camas en un sistema regionalizado,
a un nivel terciario de atenci
on report
o mejores desenlaces en facilita las visitas de los padres a su hijo ya que, en gen-
el binomio. A
un en RN pret
erminos de peso extremadamente eral, el hospital de referencia est
a m
as cerca de su domi-
bajo se ha informado menor incidencia de comorbilidades; cilio. Adem
as, favorece la relaci
on interpersonal con los
consecuentemente mayor sobrevida y mejor pron
ostico neuro- profesionales de ambos hospitales y disminuye el coste.
l
ogico. (12,13) La mortalidad es significativamente menor en el Resulta deseable que la madre tambi
en sea trasladada al

Cuadro 1. Indicaciones y Contraindicaciones Del Traslado Materno-Fetal

Indicaciones Contraindicaciones
 Amenaza de parto prematuro con #32 semanas de gestaci
on, ) Desprendimiento de placenta normoinserta con sangrado
con o sin ruptura de membranas transvaginal profuso
 Embarazo m
ultiple <34 semanas ) Crisis hipertensiva materna
 Restricci

on de crecimiento intrauterino grave ) Eclampsia
 Incompatibilidad sangu
ınea grave ) Necesidad de cuidados intensivos maternos
 Hidropes
ıa fetal ) Parto inminente
 Polihidramnios u oligoamnios ) P
erdida de bienestar fetal grave
 Preeclampsia grave o s
ındrome HELLP (hem
olisis, aumento de ) Procidencia de cord
on umbilical o extremidades
las enzimas hep
aticas y plaquetopenia) ) Distancia extensa al hospital receptor
 Malformaciones cong
enitas que obligan a un tratamiento ) No contar con disponibilidad de camas en el hospital receptor
inmediato ) Condiciones precarias clim
aticas o ambientales que impiden el
 Diagno
stico prenatal de enfermedad metabo
lica que necesite traslado por cualquier medio
control inmediato
 Patolog
ıa materna grave o complicaciones serias del embarazo**

**Las condiciones maternas incluyen: patolog
ıa cardiol
ogica o hemodin
amica, diabetes insulinodependiente o diabetes gestacional descom-
pensada, enfermedad autoinmune o metab
olica, hipo/hipertiroidismo, f
armaco-dependencia, o toxicoman
ıas, patolog
ıa psiqui
atrica grave y
sepsis. Por otro lado, lamentablemente no todas las patolog
ıas neonatales se detectan prenatalmente. Se estima que entre 30 y 50% de el-
las se diagnostican durante el parto o en el periodo neonatal inmediato(26).

Vol. 25 No. 11 N O V E M B E R 2 0 2 4 e679

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 hospital receptor tan pronto como sea posible, en condi- c) Traslado Mar
ıtimo-Fluvial
ciones de estabilidad. (27) Botes o yates para transportar RN graves desde islas a
Se han realizado m
ultiples avances para reducir la mor- tierra firme, en coordinaci
on estrecha con ambulancia ter-
bimortalidad neonatal, uno de ellos es la regionalizaci
on restre. (39)
de los niveles de atenci
on neonatal que incluyan la posibi- Resulta deseable que los traslados que excedan los 250 km
lidad de los tres tipos de traslados. Es fundamental identi- o que superen las tres horas por v
ıa terrestre se realicen en
ficar oportunamente a los fetos y RN que requieren avi

on y, en el caso de distancias intermedias (menores de
derivaci

on a centros de alta especialidad. (28) 250 km o 150 millas, o de dif
ıcil acceso) se deber
ıa considerar
traslado en helic

optero, siempre que se cuente con las facili-
MEDIOS DE TRASLADO NEONATAL dades de aterrizaje tanto en el centro emisor como en el re-
El traslado neonatal puede realizarse por v
ıa terrestre, v
ıa ceptor. El traslado en helic
optero a menudo equivale a un
a
erea y mar
ıtima o fluvial. tercio de tiempo del requerido en traslado terrestre, por lo
cual el helic
optero es beneficioso cuando el tiempo es cr
ıtico.
El helic
optero requiere solo un
area peque~ na y plana
a) Traslado Terrestre
Seg
un los est
andares regulados por organizaciones inter- (30 m×30 m) libre de obst
aculos para aterrizar, se evita el
nacionales, el veh
ıculo terrestre debe contar con caracter
ısticas
til en condiciones como inunda-
tr
afico terrestre, resulta muy u
espec
ıficas con relaci
on a: seguridad, espacio, ventilaci

on, con- ciones, tormentas de nieve, tornados u otros desastres natu-
trol de temperatura, capacidad de almacenaje del material nec- rales. (30) Sin embargo, se debe considerar la interferencia,
esario, sistema de gases medicinales como ox
ıgeno y aire ruido, vibraci

on y turbulencia. Adem
as, el traslado en heli-
comprimido con mezclador, incubadora espec
ıfica dise~ nada c

optero es significativamente m
as caro que el viaje por tierra.
para traslado neonatal, preferentemente equipada con ventila- (31) Se muestran ventajas y desventajas de traslado terrestre y
dor neonatal, sistemas de fijaci

on, generador de corriente y el- a
ereo en el cuadro 2. (31)
Ante la necesidad de trasladar al RN por v
ıa a
erea, y
evaci

on neum
atica. (2)
ante la expansi

on de los gases por los cambios en las pre-
siones barom
etricas, se debe prestar atenci
on a los si-
MEDIOS DE TRASLADO TERRESTRES:
guientes puntos, en especial cuando se traslade a RNPT
AMBULANCIAS
extremos.
1. Baja complejidad (traslados electivos o de bajo riesgo).
2. Alta complejidad (traslados de urgencia de RN cr
ıticos *
Toda “ventana” artificial (tubo de t
orax, paracentesis,
o de alto riesgo). tubo orotraqueal, etc.) debe estar permeable.
* La v
ıa a
erea antes de iniciar el transporte y durante el
b) Traslado A
ereo mismo debe estar despejada y en lo posible, libre de
Pueden ser aeronaves de ala fija, como los aviones, o de secreciones.
ala giratoria, como los helic
opteros. Representan la mejor * Evaluar frecuentemente la presencia de aire extrapulmonar
elecci
on en el caso de traslados a grandes distancias. Se (neumot
orax) y tener a disposici

on el equipo para drenarlo
debe tener en cuenta determinados aspectos como: en caso de ser necesario.
* Volar a la menor altitud. (32)
 Efecto de la altitud en el paciente.
 La reducci
on de la presi
on barom
etrica y expansi

on del on del veh
ıculo para el traslado
En concreto la elecci

aire (especialmente en algunas afecciones, como patolog
ıas neonatal ser
a determinada por tres grupos de variables,
respiratorias y abdominales). (11) tal como se muestra en el cuadro 3.
 Exceso de ruido a elevados decibeles y/o vibraciones,
potencialmente da~ ninos para el RN.
 Conocer las condiciones meteorol
ogicas: las bajas tem- EQUIPO HUMANO PARA EL TRASLADO
peraturas ambientales representan alto riesgo para el RN, NEONATAL
especialmente para el RN pret
ermino. El equipo de traslado neonatal debe estar integrado por
 Asegurar la disponibilidad de helipuerto o aeropuerto, personal calificado con formaci
on en neonatolog
ıa y es-
lo m
as cercano posible al hospital receptor, donde debe pec
ıficamente formaci
on en traslados de RN cr
ıticos, con
esperar el transporte terrestre (ambulancia equipada). (29) las siguientes caracter
ısticas:

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 Cuadro 2. Ventajas y Desventajas de Los Medios de Traslado Terrestres y A
ereos
Medio de transporte Ventajas Desventajas
Terrestre  Mayor espacio de trabajo ) Vibraciones, aceleraciones y
 Capacidad de detener el veh
ıculo para desaceleraciones repentinas
realizar ciertos procedimientos ) Limitaciones por tr
afico lento
 Disponibilidad y menor costo ) Consumo de bater
ıas
Helic

optero  Rapidez entre hospital emisor y hospital ) Elevados decibeles
receptor (helipuertos) ) Espacio reducido


 Areas inaccesibles ) Alto costo
) Limitaciones de peso
) Sin presurizacio
n

n
Avio  Cobertura y rapidez de grandes ) Descompensacio
n hemodin
amica
distancias asociada a la altitud
 Menores restricciones clim
aticas y mayor ) La presi

on barom
etrica y la presi

on
seguridad inspiratoria de la FiO2 disminuyen
 Cabina presurizada conforme incrementa la altitud con

n
 Menor ruido y vibracio presurizacio
n insuficiente
) Si hay descompresio
n puede ser

fica
catastro
) Necesidad de ambulancia terrestre en
cada extremo
) Costo elevado

* Contar con la experiencia suficiente para proporcionar consumibles y material en general, debidamente or-
el cuidado neonatal adecuado, tanto en el hospital de ganizado y etiquetado. (33)
referencia como durante el traslado.
* Amplio conocimiento para reanimaci
on cardiopulmonar, FASES DEL TRASLADO NEONATAL
preparaci
on y administraci
on de medicamentos y destreza * Administraci
on del traslado. A medida que se desarrolla
para la realizaci

on de procedimientos. y protocoliza un programa organizado de traslado neo-
* Capacidad de anticipar y tratar los posibles problemas o natal, disminuye la morbimortalidad neonatal y ma-
emergencias que se presenten. terna. Para el
exito de este programa, su organigrama
*
Establecer comunicaci
on efectiva entre el equipo, con el tiene que incluir un director m
edico de calidad y un di-
hospital de referencia, el hospital receptor, la familia y, rector de programa para llevar a cabo toda la proto-
si existe, con el centro coordinador del transporte. colizaci

on del equipo humano, el medio de traslado, y el
*
Conocer y completar en forma constante una hoja equipamiento y materiales necesarios. Los coordinadores
de verificaci
on, lista de requisitos o lista de chequeo realizan la vinculaci

on entre el hospital de referencia y el
del equipamiento necesario para traslado, f
armacos, receptor. (34)

Cuadro 3. Variables Determinantes Para Elegir el Medio de Traslado Neonatal

GRUPO 1 GRUPO 2 GRUPO 3
Variables determinadas por gravedad/ Variables determinadas por el sistema
complejidad cl
ınica: de salud: Variables que afectan al veh
ıculo:
Diagn
ostico cl
ınico y su gravedad: por Disponibilidad de los distintos veh
ıculos Velocidad, distancia a recorrer, densidad
ejemplo: prematurez extrema, asfixia existentes para traslado/disponibilidad de del tr
afico y estimaci
on de la duraci
on
perinatal severa, SDR, quir
urgico personal entrenado. del viaje.
complejo, quir
urgico estable con Posibilidad de afrontar distintos costos Ejemplos:
necesidad de ayuno prolongado, o (bajo, medio, alto). <1 h / <50 km / trafico normal
reci
en nacido estable para completar <1 h / <80 km / tr
afico denso
tratamiento en menor nivel de <2 h / 80–240 km / tr
afico variable
complejidad. >2 h / >240 km / tr
afico variable
Habit
aculo sanitario: dimensiones del Geograf
ıa/modificaciones del terreno:
habit
aculo sanitario para asistir al reci
en llanura, meseta, montan ~a, colina, cuenca
nacido en el traslado: limitado, acu
atica, edificios a gran altura
espacioso. Disponibilidad de pistas de aterrizaje,
Habilidad del personal que remite al personal capacitado, veh
ıculos de
paciente para asistir y estabilizar hasta trasbordo y servicio para despejar el
que llegue la ambulancia de traslado. tr
ansito: aeropuerto, helipuerto
Clima/condicio
n meteorolo
gica: buen
clima, ventisca / sensibilidad a la
intemperie

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 * Fase de referencia o fase inicial del proceso. (Conocida • Determinar el medio de traslado correcto.
en algunos pa
ıses como “la regulaci
on del paciente”). • Completar check list.
En la llamada inicial se informan las condiciones ac- • Confirmar estabilidad del neonato previo al traslado.
tuales del RN y los diagn
osticos que motivan el traslado. (34)
Si la respuesta del hospital receptor es afirmativa, se pro-
cede a la siguiente fase. COMUNICACIÓN (COMMUNICATION)
* Fase pretraslado o fase de planificaci
on, nivel de atenci

on Es uno de los elementos clave en el proceso del traslado
apropiado, medio de traslado correcto e involucraci
on del neonatal. Incluye la comunicaci
on estrecha y eficaz en
equipo humano del traslado. todo momento entre el personal de salud (equipo de tras-
* Fase del viaje hacia el hospital que deriva al RN. lado entre s
ı y con el hospital de referencia y con el equipo
Comunicaci
on frecuente entre el equipo y el centro que recibir
a al RN). La comunicaci
on continua, los canales
remitente. de comunicaci
on y la coordinaci
on, de acuerdo a la alianza
* Fase dentro del hospital que deriva al RN. Evaluaci
on mundial para la seguridad del paciente, es una de las pri-
lo m
as detallada posible, sin demoras innecesarias. oridades para realizar un traslado neonatal de alta calidad.
Comunicaci
on respetuosa con el personal local. Brindar Establecer canales de comunicaci
on es un pilar fundamen-
tratamientos requeridos para asegurar en la mayor medida tal en el proceso del traslado neonatal. El proceso de
posible un traslado lo menos riesgoso posible. comunicaci
on debe ser bidireccional entre los profesio-
* Fase del traslado propiamente dicha. nales de la salud involucrados en el proceso, ya que esto
* El proceso completo y todas las fases son fundamentales favorece la anticipaci
on de acciones necesarias en benefi-
para llevar a cabo un triage apropiado para el RN. El cio del neonato y la madre.
triage es un concepto que incluye la clasificaci
on o prior- Al llegar al hospital de referencia es muy importante di-
izaci
on de la atenci
on oportuna. (34) alogar con el equipo de salud local con sumo respeto pro-
fesional y recibir la informaci
on actualizada con lujo de
ORGANIZACIÓN DEL MODELO DE TRASLADO detalles. El centro que deriva debe entregar por escrito la
El proceso puede organizarse de acuerdo a “ACCEPT”, historia cl
ınica con informaci
on detallada perinatal, ante-
nemotecnia que en ingl
es significa: Assessment, Control, cedentes de importancia, evoluci
on, condiciones actuales,
Communication, Evaluation, Preparation and Packaging, and y los resultados laboratoriales y de im
agenes que se hayan
Transportation. (34) realizado. (34)
De igual importancia es la comunicaci
on en detalle y
VALORACIÓN (ASSESSMENT) sin tecnicismos con los padres o tutores. Esto incluye la
El equipo de salud del hospital de referencia determina la solicitud del consentimiento informado. La informaci
on
urgencia del traslado. Qui
en lleva a cabo el traslado var
ıa de la madre y el padre cuando se realiza el traslado materno-
seg
un los centros, unidades, hospitales y regiones. En al- fetal o del RN debe ser precisa, organizada y completa. Este
gunos, existe un sistema de traslado neonatal indepen- proceso de comunicaci
on tambi
en debe ser bidireccional. Los
diente de los hospitales (centros de referencia). En otros canales de comunicaci
on se dividen en verbales y escritos, la
es el hospital que recibe al RN el encargado de realizar el estructura de los mismos se presenta en el cuadro 4. (35)
traslado y en otros puede ser el hospital que deriva al RN.
El l
ıder del equipo de traslado efect

ua el triage. (34) EVALUACIÓN (EVALUATION)
El traslado exitoso necesita una evaluaci

on meticulosa del
CONTROL (CONTROL) RN tanto por el m
edico y el equipo del centro de referen-
La evaluaci
on inicial detallada generalmente controla la cia, el l
ıder del equipo m
edico y el personal de traslado, y
situaci
on. finalmente el m
edico y enfermer
ıa que lo reciben. Por su-
puesto, esto permite tomar decisiones y acciones oportunas
• >Qui
en ser
a el l
ıder del equipo cuya funci
on es coordi- en consecuencia. (34) Es fundamental y absolutamente nec-
nar antes, durante y despu
es del traslado? esario que todo RN sea apropiadamente estabilizado antes
• Distribuci
on de funciones y tareas que deben realizarse del traslado. El hospital que recibe debe tener preparado
(atenci
on cl
ınica, equipamiento, medicamentos y recur- equipo humano de salud y m
odulo completo de recepci

on.
sos en general). (34)

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n
Cuadro 4. Estructura de Los Canales de Comunicacio
Presentacio
n Situacio
n Cl
ınica Documentacio
n Informacio
n
䊏 Equipo asistencial. Nombres 䊏 Antecedentes y alergias 䊏 Documentos de remisio
n, 䊏 Familiares si son los
de las personas que se 䊏 El estado fisiol
ogico del RN, historia cl
ınica acompa~ nantes: identificaci

on
comunican incluido el conjunto completo 䊏 Informes y pruebas completa y parentesco,
䊏 Nombre completo del RN y de signos vitales actuales complementarias n
umero de tel
efono, direcci
on
n
umero de registro civil 䊏 Enfermedad actual y 䊏 Consentimientos informados 䊏 Sensibilidad del tiempo
䊏 Edad gestacional exploracio
n f
ısica (ejemplo: emergencia,
䊏 Fecha y hora de nacimiento 䊏 Pruebas complementarias urgencia, no emergencia,
䊏 Medidas antropom
etricas 䊏 Tratamiento electiva)
䊏 Sexo 䊏 Intervenciones y resultados de 䊏 Tiempo aproximado de
䊏 Identificaci

on de los padres - las intervenciones realizadas llegada
nombre completo de su antes de la llegada del equipo 䊏 Disposici
on inmediata de
madre y documento de de transporte y despu
es de la quir

ofano
identidad llegada del equipo de 䊏 Informacio
n adicional, la cual
transporte debe intercambiarse durante
el contacto

PREPARACIÓN Y EQUIPAMIENTO (PREPARATION ➢ Tubos de ox
ıgeno y de aire comprimido port
atiles, de

AND PACKAGING) aluminio, de 1 o 1,5 m3 y 3 m3 de capacidad, a fin de
La preparaci
on para el traslado comienza tan pronto como garantizar el suministro durante el triple del tiempo
se toma la decisi
on de transferir al neonato e incluye tres m
aximo previsto para el traslado, seg
un la regi

on de
componentes esenciales: la atenci
on cl
ınica, la ubicaci
on y cobertura. Deben tener soportes a media altura y al
verificaci
on de equipos y la asignaci
on de roles del equipo. piso. Se debe conocer la cantidad de ox
ıgeno probable
La atenci
on cl
ınica se puede optimizar mediante comprobaci
on a utilizar y el volumen de carga de cada cilindro, el tipo
de las v
ıas respiratorias, circulaci

on, medicamentos, ambiente de tubo con su
ındice, su presi
on de servicio (psi/bar),
(incubadora o colch
on t
ermico, necesidad de enfriamiento, por las escalas de los man
ometros, si estos son de alta o
encefalopat
ıa hip
oxico-isqu
emica [EHI]). El equipo humano baja presi
on. (37)
que realiza el traslado debe estar capacitado en el uso correcto ➢ N
umero m
ınimo de tanques o cilindros a portar en
de infraestructura, equipos y f
armacos, adem
as de ser compe- cada traslado: 2 de ox
ıgeno y 2 de aire comprimido. (37)
tente para realizar cualquier procedimiento necesario en ruta al
hospital receptor. (34) Para calcular la cantidad de ox
ıgeno disponible en el
tanque o cilindro en minutos, se recomienda utilizar la si-
TRASLADO (TRANSPORTATION) guiente f
ormula: [Constante del tanque X PSI – PSI resid-
ual/flujo en L por minuto 5 duraci
on en minutos de
Como se menciona antes, es fundamental que todo RN
sea apropiadamente estabilizado antes del traslado. A con- ox
ıgeno]. D
onde: la constante del tanque que encontramos
tinuaci
on, describimos los elementos imprescindibles para grabada en la parte superior del tanque, expresada en
el traslado de un RN enfermo. letras may
usculas: D, E, M, que tendr
an su correspondiente
constante, para D: 0,16, E: 0,28, M: 1,56, la multiplicamos
Equipo Necesario Para Realizar el Traslado Neonatal on de ox
ıgeno com-
por el resultado de la resta de PSI (presi

Todo el equipamiento debe estar inventariado y contro- primido en el tanque, el cual se lee en el man
ometro y lleno
lado, asegurando siempre su funcionamiento correcto. corresponde a 2000) – presi
on del nivel residual de ox
ıgeno
Ser
a ligero y port
atil, f
acil de limpiar y de mantener. Todo m
ınimo y seguro que corresponde a 200 years se divide en-
el material el
ectrico debe estar alimentado por bater
ıas tre los litros por minuto indicados para el paciente. Ejemplo:
que permitan suficiente autonom
ıa (el doble o el triple del Tenemos un tanque marcado con E, que corresponde a la
tiempo calculado de transporte) y estar protegido contra constante 0,28× (2000-200) dividido entre 1,5 L por minuto
interferencias electromagn
eticas. (36) que recibe el RN 5 336 minutos que corresponden a
Suministro de gases (ox
ıgeno, aire medicinal y
oxido 5,6 horas.
n
ıtrico inhalado port
atiles) con conexi
on r
apida. Otra forma de calcular la cantidad de ox
ıgeno necesaria
es tomando en cuenta el volumen minuto del paciente. Si
➢ El tablero debe contar con: regulador de ox
ıgeno, regu- consume por inspiraci
on 300 ml y tiene una frecuencia res-
lador de aire comprimido, aspirador por sistema Ven- piratoria de 20 por minuto, dar
ıa un consumo de 6000 ml
turi y mezclador con fluj
ometro. (6 litros por minuto). Esto se debe calcular en una hora

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 multiplicando por 60 years luego por las horas estimadas de La estandarizaci

on de las presentaciones (f

ormula farm-

ltimo, triplicarlo.
traslado y, por u ac
eutica y concentraci

on) facilita la transferencia del pa-
ciente. Una lista sugerida es:
➢ Mezclador de ox
ıgeno (blender) que ofrezca FiO2 desde
0,21 a 1,0, de 3 years de 10 litros por minuto. FLUIDOS INTRAVENOSOS
➢ Sistema de aspiraci
on, regulable. ➢ Dextrosa 10%
➢ Calentador humidificador colocar temperatura entre ➢ Dextrosa 5%
36,5 C y 37 C. ➢ Soluci
on salina al 0,9%


➢ Oxido n
ıtrico port
atil (400/800 ppm) (38) Cuando se participa como sitio receptor, una medida
que salva vidas es nunca asumir que el centro que refiere
EL COMPARTIMENTO O MÓDULO PARA EL dispone de todo el equipo y f
armacos necesarios. Por
NEONATO DEBERÁ CONTAR CON LA SIGUIENTE tanto, debe confirmarse mediante comunicaci
on efectiva,
DOTACIÓN MÍNIMA EN EQUIPOS protocolizada y sistematizada, qu
e medicamentos ha recibido,
qu
e recibe y evaluar qu
e debe recibir. (41) En el cuadro 5, se
➢ Incubadora port
atil o de traslado.
presentan los f
armacos sugeridos para el traslado.
➢ Equipo completo de manejo de v
ıas a
ereas neonatales,
En concreto, es muy importante trasladar al neonato
suficientes tubos endotraqueales y c
anulas lar
ıngeas.
cr
ıtico en condiciones de asepsia, estabilidad t
ermica, res-
➢ C
amara o escafandra (hood) neonatal.
piratoria, metab
olica, hidroelectrol
ıtica, hemodin
amica y
➢ Equipo de venodisecci
on neonatal.
neurol
ogica, igual que si estuviese en la UCIN, con lo cual
➢ Man
ometro en el aspirador port
atil y sondas de aspiraci

on
se reducen significativamente los riesgos. (42)
➢ Ox
ımetros de pulso.
➢ Respirador o ventilador neonatal.
PUNTOS CLAVE PARA EL TRASLADO NEONATAL
➢ Colch
on de gel con o sin almohadilla de espuma, modifi-
POR APARATOS Y SISTEMAS
car la bandeja de la incubadora, insertando una sujeci
on
de espuma entre la bandeja y el riel para reducir el movi- a) V
ıa A
erea y Respiratoria
miento de la bandeja, lo cual resulta en disminuci
on El cuidado de la v
ıa a
erea durante el traslado neonatal re-
de la vibraci

on y menor riesgo de movilizaci

on por quiere especial cuidado. La evaluaci
on cl
ınica y radiol

ogica
aceleraci

on-desaceleraci
on. (39) y la experiencia que se tenga en el manejo del soporte res-
piratorio son vitales para la realizaci

on de un traslado exi-
toso y seguro. (43)
MEDICAMENTOS NECESARIOS PARA EL No todos los RN deben intubarse antes del traslado,
TRASLADO NEONATAL pese a que la raz
on principal del traslado fuese respirato-
El objetivo de todo traslado neonatal es mantener al paciente ria, como es el caso de los RN pret
ermino (RNPt) con
en las mismas condiciones de asepsia, estabilidad t
ermica, s
ındrome de dificultad respiratoria (SDR). En el pasado,
respiratoria, metab
olica, hidroelectrol
ıtica, hemodin
amica antes de realizar el traslado de RNPt con SDR, en la gran
y neurol
ogica que tendr
ıa en una unidad neonatal donde fuese mayor
ıa de los casos se realizaba intubaci
on endotraqueal
atendido por la patolog
ıa que origina su movilizaci

on. (40) previo al traslado. (44)(45) Sin embargo, actualmente la
Las medicaciones (incluidos los l
ıquidos) y las dosis meta es favorecer el soporte ventilatorio de protecci
on pul-
necesarias para un proceso de traslado de un RN son simi- monar, administraci
on de esteroides prenatales, siempre
lares a las que se utilizan en los servicios de neonatolog
ıa que sea posible iniciar CPAP desde sala de partos, admin-
y var
ıan seg

un el nivel de soporte vital que necesite el RN istraci

on oportuna de surfactante y disponibilidad de
que ser
a trasladado. (40) modos de ventilaci
on menos invasiva sin tubo endotraqueal

n de F
armacos o Medicamentos Para el Traslado

Cuadro 5. Seleccio
Gluconato de calcio Dobutamina Adenosina Dexametasona Lidoca
ına
Sulfato de magnesio Dopamina Amiodarona Hidrocortisona Insulina
Cloruro de sodio Norepinefrina Fentanilo Ampicilina Vecuronio
Cloruro de potasio Epinefrina Morfina Gentamicina Prostaglandinas
Bicarbonato de sodio Milrinona Fenobarbital Cefotaxima Furosemida
Vitamina K Atropina Lorazepam Paracetamol Bumetanida

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 que puedan mantenerse durante el traslado. No obstante, de- Durante el traslado se debe asegurar la fijaci
on del tubo
finitivamente es indicaci
on de intubaci
on electiva previa- de ONi para evitar ca
ıdas o desplazamientos, mantener la
mente a iniciar el traslado siempre que exista el riesgo misma dosis todo el traslado. Si la SPO2 est
a por encima
de progreso de la dificultad respiratoria, inminencia de de lo correcto, bajar la FiO2, evitar la discontinuaci

on acci-
fatiga diafragm
atica, apneas y gasometr
ıa ominosa. (46) dental del flujo de ONi, la hipotermia y la sobreestimulaci
on
La meta de la SpO2 para el RN en estado cr
ıtico durante sensorial y lum
ınica, conocer y aplicar los protocolos de se-
el traslado es id
entica a la deseada en la UCIN y se deben guridad durante el traslado e incluso los referidos al recam-
seguir las recomendaciones de SpO2(47). La lectura de la bio ambiental para evitar la acumulaci
on de
oxido n
ıtrico
SpO2 durante el traslado puede ser interferida por el ex- residual. Actualmente existen equipos digitalizados que nos
ceso de movimiento o vibraciones. Preferiblemente uti- permiten controlar la concentraci

on del ONi. (56)
lizar satur
ometros con tecnolog
ıa con extracci
on de se~ nal
(SET) que funcionan bien aun con movimiento. (48) b) Cardiovascular
Es menester confirmar que todas las conexiones vincu- La estabilidad hemodin
amica durante el traslado neonatal
ladas a la administraci
on de gases (aire u ox
ıgeno) est
en es fundamental. Los tres primeros d
ıas de edad postnatal
correctas desde las fuentes de los gases hasta los dispositi- representan un per
ıodo de cambios en la din
amica del sis-
vos colocados al RN. Se deben revisar todos los sitios de tema cardiovascular que forman parte importante de la
entrada de tubuladuras en la incubadora y fijarlos de adaptaci
on a la vida aer
obica. Al nacer, con el pinzamiento
modo que sea posible acceder al RN sin inconvenientes. del cord
on y el inicio de la respiraci
on se desencadena una
Los par
ametros del ventilador de traslado deben ser fijados cascada de fen
omenos complejos para la transici
on de la
antes de conectar al RN, y siempre gui
andose por la vida fetal a la neonatal. La primera respiraci
on y el au-
evoluci
on cl
ınica y gasom
etrica. (44) mento del contenido arterial de ox
ıgeno se acompa~ nan de
El uso de ventilaci
on de alta frecuencia (VAF) permaneci
o aumento en la resistencia vascular sist
emica (RVS) y dis-
excluido para el traslado neonatal, hasta que los ventiladores de minuci
on de la resistencia vascular pulmonar (RVP), que
traslado estuvieron disponibles. (49) Algunas incubadoras conduce al incremento del flujo sangu
ıneo pulmonar. Algu-
de traslado neonatal est
an equipadas con ventiladores capa- nos neonatos particularmente pret
ermino podr
ıan enfrentar
ces de dar soporte en modo convencional y de alta frecuen- incapacidad del miocardio inmaduro para adaptarse al au-
cia. (50) Recientemente se public
o un trabajo de 12 a~ nos mento repentino de la RVS. (57)
que muestra el incremento de los traslados llevados a cabo La presi
on arterial (PA) ha sido tradicionalmente un de-
bajo la modalidad de VAF. Los resultados demuestran que terminante de la estabilidad hemodin
amica que marca la
el traslado de neonatos con VAF es posible y seguro a pesar pauta para considerar compromiso cardiovascular y debe
de los desaf
ıos que esto significa. (51) Otros estudios reali- estar incluida en la evaluaci
on cl
ınica de rutina para val-
zados concluyen resultados similares, aunque con menor orar el estado hemodin
amico del RN. (57)
n
umero de RN. (52). La utilizaci
on de esta modalidad Cuando se considera que el estado cardiovascular es
tambi
en parece segura y efectiva en RN con hernia dia- inestable, ser
a recomendable intentar colocar un cat
eter
fragm
atica cong
enita. (53) arterial para el monitoreo de la PA invasiva antes del tras-
En RN con hipertensi
on pulmonar, candidatos a ad- lado. No se deben tomar decisiones basadas exclusiva-
ministraci
on de
oxido n
ıtrico inhalado (ONi), es impor- mente en el monitoreo de la PA no invasiva en RN
tante realizar ecocardiograma para confirmar diagn
ostico y gravemente enfermos. Estas mediciones son menos exac-
descartar cardiopat
ıa cong
enita, especialmente si un alto tas y t
ecnicamente dif
ıciles de obtener durante el traslado.
porcentaje del flujo sist
emico se efect
ua a trav
es del duc- Por otro lado, evaluar necesidad de soporte farmacol
ogico
tus por el cortocircuito de derecha a izquierda ya que la vasoactivo e iniciar antes del traslado, siempre a trav
es de
disminuci
on de la presi
on pulmonar por el ONi dismi- abordaje venoso central. En el cuadro 6 se presentan los
nuye el flujo sist
emico y disminuir
ıa el gasto cardiaco. principales factores de riesgo de descompensaci
on hemo-
Es conveniente colocar sensores de SpO2 pre y posductales din
amica y los signos que la apoyan. (57)
y tomar radiograf
ıa de t
orax para asegurar adecuados En RN con cardiopat
ıa cong
enita, claramente estable-
vol
umenes pulmonares. Los alv
eolos colapsados dismi- cida o sospechada, dependiente del ductus arterioso, debe
nuyen la efectividad del ONi. Mantener los par
ametros del iniciarse prostaglandinas (PgE1) en infusi
on continua an-
respirador que aseguren un buen volumen pulmonar y op- tes del traslado. Esto podr
ıa favorecer apneas, con lo cual
timizar la situaci
on hemodin
amica. (54)(55) se recomienda evaluar la pertinencia de asegurar la v
ıa

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 Cuadro 6. Factores de Riesgo de Descompensacio
n deben ser trasladados a centros de nivel III de atenci
on
Hemodin
amica y Signos de Perfusio

n Inadecuada multidisciplinaria con protocolo de enfriamiento ter-

n hemodina
Factores de riesgo de descompensacio
mica ap
eutico estandarizado. El periodo de ventana de la HT es
durante la fase de reperfusi
on de la EHI, es decir en las
 Demora en la transici
on desde la vida intrauterina a la
extrauterina seis primeras horas posnatales, lo cual representa una ur-
 Miocardio inmaduro gencia terap
eutica, ya que la m
axima eficacia de la HT se
 Falta de esteroides prenatales
 Conducto arterioso persistente obtiene cuanto m
as temprano se inicie. (63)(64) Esto ha
 Corioamnionitis demostrado incremento de la supervivencia y reducci
on
 Depresi
on perinatal/asfixia
 Inmadurez del eje hipot
alamo-hip
ofisis-suprarrenal del da~ no neurocognitivo.
 Insuficiencia suprarrenal relativa El traslado neonatal de un RN con EHI debe cumplir el
 Sepsis
 Enterocolitis necrosante
mismo protocolo de traslado que se aplica a cualquier RN
 Hipovolemia cr
ıtico, con algunas singularidades que se detallan a con-
Signos de perfusio
n inadecuada tinuaci
on. (65)(66)(67)(68)(69)
 Taquicardia

Indice de perfusi
on <0,7
 Pulsos d
ebiles ➢ Equipo de salud capacitado y entrenado con conocimien-
 Piel moteada
 Oliguria
tos espec
ıficos en HT, RCP avanzado y estabilizaci
on de
 Acidosis metabo
lica RN de alto riesgo, asegurar v
ıa a
erea y canalizar vasos
 Letargia umbilicales antes de iniciar HT para evitar dificultades
 Relleno capilar (no es sensible ni espec
ıfico)
t
ecnicas atribuidas a vasoconstricci
on.
➢ Evitar hipertermia.
a
erea previamente al traslado. Es fundamental en estos ➢ Enfriamiento pasivo, que empieza en el mismo lugar
RN no usar FiO2 elevada ya que favorece el cierre del duc- de nacimiento.
tus, lo que podr
ıa agravar considerablemente la condici

on ➢ La hipotermia pasiva se logra apagando la cuna radi-
cl
ınica. (58) ante y las fuentes ex
ogenas de calor para conseguir el
rango de 33-35 C y evitar oscilaciones. Si despu
es de
c) Neurol

ogico un per
ıodo de tiempo no se lograra, habr
ıa otra posi-
No todos los neonatos requerir
an el uso de sedantes du- bilidad que SIBEN no puede recomendar en funci
on
rante el traslado. Sin embargo podr
ıan presentar dolor o de la evidencia disponible. Incluye ventiladores de
molestia asociados principalmente a movimientos y a las aspa o bolsas de gel fr
ıo/hielo (“Hot-Cold Gel Pack”).
vibraciones de los medios de transporte y el ruido que ex- Estas bolsas nunca deben entrar en contacto con el
ceden los est
andares aceptables. Esto es de mayor riesgo RN. Deben situarse a unos 10 cm del per
ımetro del
en traslados en helic
optero. Es recomendable tomar medi- RN para evitar quemaduras por fr
ıo y alejarlas cuando
das no farmacol
ogicas como “orejeras”, nidos de con- la temperatura sea inferior a 35 C.
tenci
on, leche materna, sacarosa al 24% y succi
on no ➢ Durante el traslado neonatal se debe tomar y registrar
nutritiva, (61)(62) uso de colchones de gel, arneses, cober- la temperatura central (rectal) cada 15 minutos y man-
tores de incubadoras, y otros. Por tanto, las iniciativas en tenerla entre 33 years 34 C. Para lograrlo se debe fijar
los cuidados del neurodesarrollo dentro de la UCIN desti- el servocontrol de la incubadora de transporte en 35 C.
nadas a reducir los est
ımulos ambientales nocivos son am- Si no es suficiente se debe apagar la incubadora y man-
pliamente aceptadas y deben llevarse a cabo durante el tener las escotillas abiertas.
traslado neonatal. A veces es necesario iniciar sedaci
on an- ➢ Si la temperatura rectal es <33 C, se debe encender la
tes del traslado ya que los niveles de ruido excesivo tienen incubadora.
efectos adversos en los sistemas endocrino, cardiovascular ➢ La hipotermia profunda (<32 C axilar/central) es el
y auditivo. Los efectos del ruido en los RNPt incluyen principal riesgo durante el traslado por la tendencia
cambios en la frecuencia card
ıaca, la frecuencia respirato- al sobreenfriamiento que acontece en las primeras
ria, la saturaci
on de ox
ıgeno y la presi

on arterial, as
ı como horas de vida, sobre todo en los RN con EHI severa.
efectos negativos a largo plazo en el sistema nervioso cen- ➢ Lo ideal es trasladar al RN con EHI moderada-severa
tral. (59,60) en HT con sistemas de enfriamiento servocontrolado,
Frecuentemente los RN con encefalopat
ıa hip
oxico- con dispositivos de enfriamiento activo de peque~ no
isqu
emica (EHI) moderada a severa, $35 semanas de edad tama~ no, con respaldo de bater
ıa, portables y econ

omicos
gestacional candidatos a hipotermia terap
eutica (HT), dise~nados justamente para el traslado neonatal.

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 ➢ En caso de hipotensi
on arterial, se recomienda iniciar de venopunci
on, solicitar estudios de laboratorio pre-
dobutamina o dopamina ya que el evento hip
oxico- viamente al traslado. Si las plaquetas son <50.000,
isqu
emico perinatal puede ocasionar disfunci
on mioc
ard- transfundir concentrado plaquetario. Tiempo parcial
ica. De acuerdo a la respuesta evaluar la pertinencia de de tromboplastina activada (kPTT o TTPa) >65-80
epinefrina. Evitar hipotensi
on y todo lo que ocasione dis- segundos, en muestras correctas en las primeras ho-
minuci
on del flujo sangu
ıneo cerebral (FSC), como la hi- ras de edad postnatal, tiempo de protrombina (TP o
pocapnia y la inadecuada posici
on de la cabeza y el Quick) >15 segundos o <40%, INR (international nor-
cuello. Cambiar de posici
on cada 4 horas, movilizando malized ratio) >3, o fibrin
ogeno <100 mg/dl: admin-
en bloque y manteniendo la nariz alineada con el resto istrar vitamina K (1 mg IV) y 10-15 ml/kg de plasma
del cuerpo, no girar solamente la cabeza para evitar oscil- fresco congelado, es importante evitar sobrecargar la
aciones del FSC. volemia agudamente.
➢ Mantener normoglucemia, un flujo de glucosa entre 4 a ➢ Evitar el estr
es (llanto, molestia), se recomienda fenta-
6 mg/kg/minuto que asegure una glucemia >45 mg/dl nilo a 1 mcg/k/dosis administrar en bolo lento, o mor-
y <150 mg/dl. fina 0.1 mg/kg/dosis.
➢ En caso de presentar convulsiones durante el traslado,
se recomienda administrar fenobarbital. Como se- d) Metab

olico
gunda elecci
on puede ser levetiracetam. Ante un Los RN en general son susceptibles al estr
es por fr
ıo. Los
“status epilepticus”, iniciar midazolam o lorazepam RNPt extremos y RN con malformaciones cong
enitas ex-
como tercera alternativa. No usar
acido valproico ya puestas son m
as sensibles a la p
erdida de calor en los mo-
que favorece la hiperamonemia y es hepatot
oxico. El mentos posteriores al parto, donde esta p
erdida de calor
tiopental tampoco ya que tiene efectos adversos graves. suele exceder a la producci
on del mismo. La hipotermia
El uso de fenobarbital profil
actico no se recomienda, (temperatura central/axilar menor a 36,5 0C) se asocia con
pero si hay convulsiones de contexto cl
ınico o si se mayor mortalidad neonatal, sepsis de inicio tard
ıo, SDR y
sospechan, es conveniente iniciar fenobarbital a las hemorragia intraventricular. As
ı mismo, puede perjudicar
dosis neonatales recomendadas y observar durante el la transici
on a la vida extrauterina, empeorar la acidosis y
traslado y los primeros d
ıas en la UCIN. Se debe real- la utilizaci

on de glucosa y afectar la funci
on inmune y la
izar evaluaci
on electroencefalogr
afica lo antes posible, pref- coagulaci
on sangu
ınea. (70)
erentemente de amplitud integrada (aEEG) o convencional. Es necesario el adecuado calentamiento de los gases in-
➢ Previo al traslado colocar sonda vesical para medir la di- spirados, as
ı como su humidificaci
on, al igual que el de
uresis y realizar balances estrictos. Evitar la hiponatremia las incubadoras de traslado y considerar la cambiante tem-
secundaria a SIADH (s
ındrome de secreci
on inadecuada peratura del ambiente. Se debe mantener el ambiente
de hormona antidiur
etica) o insuficiencia renal con t
ermico neutro, lo cual puede representar un verdadero
exceso h
ıdrico. Corregir hipocalcemia e hipomagne- desaf
ıo durante el traslado. Por otro lado, la hipertermia
semia ya que pueden agravar o potenciar las crisis puede ocasionar cambios f
ısicos que han sido asociados
convulsivas en EHI. Se debe tener especial cuidado con muerte s
ubita. (71)
con los aportes de potasio, ya que la hipotermia pro- El mantenimiento de un nivel de glucemia por encima
duce cambios en el potasio intracelular. Evitar medi- de 50 mg/dl en las primeras 48 horas de vida y por en-
caci
on nefrot
oxica. cima de 60 mg/dl despu
es asegura un aporte adecuado a
➢ Individualizar el tratamiento hidroelectrol
ıtico y hemo- nivel de todos los
organos, fundamentalmente del cerebro.
din
amico a las circunstancias cl
ınicas y hemodin
ami- Los RN con condiciones inestables generalmente deben
cas de cada RN con EHI y evitar el exceso de l
ıquido o mantenerse en ayuno, proveyendo l
ıquidos parenterales
sobrecargas agudas de volumen. con aporte adecuado de glucosa a una tasa inicial de 4 a
➢ La HT desplaza la curva de disociaci
on de la Hb a la 6 mg/Kg/min. (72)
izquierda y reduce la entrega de ox
ıgeno a los tejidos Los factores que afectan los niveles de glucemia en el
y el metabolismo anaerobio no se ve incrementado. Si per
ıodo neonatal son m
ultiples y cambian a medida que
est
a elevado el
acido l
actico es por gravedad de la as- avanza la edad postnatal. El nacimiento prematuro, la asfixia
fixia y no por la HT. perinatal, los antecedentes maternos de diabetes, infecciones
➢ En caso de signos de trastorno de la coagulaci
on tales perinatales, SDR, uso de cierto tipo de medicamentos y la tem-
como sangrado g
astrico, hematuria, sangrado en sitios peratura corporal pueden alterar la homeostasis metab
olica del

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 RN. Se recomienda la medici
on de glucemia mediante ti-
ras reactivas durante el traslado especialmente en RN de
riesgo. (73)
Una vez que se instaura el tratamiento para la hipogli-
cemia neonatal se debe medir la glucemia cada 30 minu-
tos hasta que sea mayor de 50 mg/dl en dos pruebas
consecutivas. Pueden presentarse niveles de glucemia ele-
vados previamente por estr
es metab
olico, pero posteriormente
se agotar
an las reservas y podr
ıa presentar hipoglucemia. (74)

MODELO CONCEPTUAL DEL TRASLADO

NEONATAL
La regionalizaci
on del cuidado intensivo neonatal ha dis-
minuido la mortalidad. Sin embargo, en ocasiones no es
posible realizar el traslado prenatal o intrauterino y el tras-
lado neonatal se convierte en la mejor opci
on en la cadena
asistencial del RN cr
ıtico. Si bien la celeridad del traslado
es importante, lo esencial es la calidad de este, que de- Figura. Modelo conceptual del traslado neonatal.
pende de los m
ultiples factores presentados en el presente
Consenso Cl
ınico. ACoRN: Acute Care of at Risk Newborn, por sus siglas en in-
Es fundamental que exista un sistema o modelo con- gl
es, es un programa que fue desarrollado en Canad
a para
ceptual, que inicie con la correcta identificaci
on del RN identificar y manejar a los RN de alto riesgo mediante el
cr
ıtico que necesita traslado apropiado y oportuno, y que proceso de evaluaci
on-decisi
on-acci
on. (77) TRIPS: Trans-
se realicen todas las medidas descritas previamente. Es port Risk Index of Physiologic Stability, por sus siglas en in-
necesario que los neonat
ologos del hospital de referencia gl
es, es un puntaje o score de gravedad, dise~ nado para
est
en capacitados para la pronta estabilizaci
on adecuada y evaluar el riesgo en t
erminos de morbilidad y mortalidad
expedita del neonato previo a su traslado, adem
as hay que de RN enfermos que ser
an trasladados a otro hospital y
contar con un equipo de personal altamente capacitado y as
ı actuar en consecuencia. (78) Todos los participantes
que pueda brindar reanimaci
on y estabilizaci
on neonatal del proceso deben dominar el programa y las gu
ıas de re-
antes y durante el traslado. Lamentablemente, la for- animaci
on neonatal; NRP: Neonatal Resuscitation Program,
maci
on del personal sanitario de transporte, en general, es por sus siglas en ingl
es, y llevar a cabo las actualizaciones
inadecuada en Latinoam
erica. Todos los miembros del del programa. (79)
equipo humano de traslado deben recibir entrenamiento
continuo que permita mantener y actualizar sus capacita-
ciones. As
ı mismo, deben ser evaluados peri
odicamente. RECOMENDACIONES FINALES DEL XIII
Dicho equipo humano debe estar integrado por enferme- CONSENSO DE SIBEN SOBRE TRASLADO
ras neonatales, terapistas respiratorios, neonat
ologos y/o NEONATAL
residentes del mayor grado de neonatolog
ıa. Cada integra- El presente manuscrito del XIII Consenso de SIBEN, que
nte del equipo debe tener muy clara su funci
on. (75) representa una extensa edici

on del trabajo original (80) re-
Con base en la evidencia disponible y la racionalizaci
on comienda las siguientes pr
acticas basadas en la mejor evi-
l

ogica, se dise~n
o el siguiente modelo conceptual que permita dencia cient
ıfica disponible y que podr
ıan adaptarse a las
realizar traslados neonatales en forma protocolizada (figura). circunstancias y posibilidades de cada pa
ıs, regi

on, unidad
Existen estrategias y programas de estabilizaci
on neonatal de cuidados intensivos neonatales y, en general, a los hos-
previos al traslado, estructurados y dise~nados para simplificar pitales que trasladan neonatos.
el proceso de estabilizaci
on antes, durante y al arribo del tras-
lado. Una de las m
as utilizadas: es el programa S.T.A.B.L.E.:
Sugar, Temperature, Artificial breathing, Blood pressure, Labo- GENERALIDADES
ratory work, Emotional support, por sus siglas en ingl
es. Pro- ➢ Identificar oportunamente la necesidad del traslado,
vee una gu
ıa integral para el proceso. (76) Otros incluyen: preferentemente materno-fetal siempre que sea posible.

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 ➢ Una vez decidido el traslado, activar inmediatamente ➢ Siempre implementar medidas no farmacol
ogicas para
canales de comunicaci
on que continuar
an hasta finali- aliviar el estr
es y las molestias, incomodidad o mal-
zar el traslado. estar del paciente. No es necesaria la sedaci
on durante
➢ Redactar la historia cl
ınica del neonato que ser
a trasla- el traslado, salvo en casos especiales, como por ejem-
dado e incluir evoluci
on, condici
on actual, resultados plo algunos RN con hipertensi
on pulmonar.
laboratoriales y de im
agenes tomadas en el hospital de ➢ Analgesia apropiada y oportuna siempre que sea necesaria.
referencia. ➢ Monitorizaci
on completa y adecuada.
➢ Comunicar de inmediato a los padres en cuanto se ➢ Si el traslado ser
a largo y el RN amerita, es aconsejable
tome la decisi
on del traslado explicando detenida- disponer de control de la TA invasiva y la posibilidad
mente y en detalle el motivo, las condiciones ac- de un analizador port
atil de gases sangu
ıneos o mon-
tuales del RN y los riesgos y beneficios, con palabras on de CO2 espirado.
itorizaci

sencillas y sin tecnicismos, precisando la ubicaci
on ➢ En caso de traslado a
ereo, vigilar el efecto de la altitud
del hospital receptor. sobre la expansi
on del aire y la oxigenaci
on.
➢ Solicitar a los padres que firmen la autorizaci
on del ➢ Trasladar al RN en el momento apropiado, con «margen
consentimiento informado de traslado que debe in- de actuaci
on», es decir, antes de que requiera una asis-
cluir dos testigos. tencia que puede no estar disponible durante el traslado.
➢ Siempre que sea necesario se debe brindar a los pa- ➢ Siempre que sea necesario, asegurar antes del traslado
dres tiempo a solas para hablar e informar a sus fa- acceso venoso central.
miliares sobre el traslado cuando as
ı lo decidan. ➢ Preparar de antemano las diluciones de f
armacos pre-
➢ Permitir a los padres ingresar a la sala en donde se en- visiblemente necesarios durante el traslado, tomar en
cuentra su hijo(a) previo al traslado e involucrarlos cuenta que el n
umero de bombas de infusi
on es limitado.
como parte fundamental del proceso de traslado. ➢ Cantidad m
ınima de f
armaco/infusi
on: el doble de la
➢ El equipo m
edico encargado del traslado debe presen- estimada para la duraci
on del traslado.
tarse con los padres antes del traslado y darles con- ➢ Diluir los f
armacos, de forma que la relaci
on ritmo de
fianza y seguridad de que est
an capacitados, as
ı como infusi
on/dosis sea f
acil de deducir o interpretar.
responder sus dudas e inquietudes. ➢ Rotular apropiadamente los f
armacos.
➢ En caso que el padre o madre pueda ir en la ambulan- ➢ Posicionar al RN sobre una superficie acolchada y uti-
cia, se le debe explicar su rol, y lo que puede pasar du- lizar sujeciones que lo aseguren correctamente para
rante el traslado y en qu
e forma actuar
a el equipo si se evitar movilizaciones, aceleraci
on-desaceleraci
on.
presenta alguna eventualidad. ➢ Intentar posiciones similares a las fetales (flexionados
hacia la l
ınea media), ya que disminuyen el estr
es.
ACERCA DEL NEONATO QUE SERÁ TRASLADADO ➢ Asegurar un adecuado aislamiento t
ermico y ac
ustico
➢ Valorar y anticiparse a la intubaci
on endotraqueal, de del RN.
acuerdo a la evoluci
on o progresi
on de la patolog
ıa ➢ Elevar la camilla hidr
aulica dentro del veh
ıculo.
respiratoria y la vulnerabilidad del RN. Tener en ➢ El conductor del equipo de traslado terrestre debe evi-
cuenta el tiempo estimado del traslado. tar aceleraciones s
ubitas y frenados bruscos.
➢ Asegurar la correcta fijaci
on del tubo endotraqueal ➢ Cargar y descargar la incubadora desde del veh
ıculo
para evitar desplazamientos, desconexiones o extuba- con suavidad.
ciones accidentales durante el traslado. En RN que se trasladan con hipotermia terap
eutica, es
➢ Realizar radiograf
ıa toracoabdominal o USG pulmonar, muy importante monitorizar la temperatura de forma con-
as
ı como gasometr
ıa una vez ajustada la ventilaci
on. tinua (sensor perif
erico y central).
Confirmar la permeabilidad del tubo endotraqueal antes
de salir. ARRIBO AL HOSPITAL RECEPTOR
➢ Es fundamental estabilizar al neonato cr
ıtico antes del ➢ Al arribar al hospital receptor, el equipo profesional del
traslado. traslado debe presentar detalladamente al RN y proveer
➢ Verificar equipo m
edico de traslado completo y listo y toda la informaci
on solicitada por el equipo receptor y en-
mediante check list, confirmar equipamiento, material tregar en f
ısico la historia cl
ınica completa, la evoluci

on
como tubos endotraqueales, c
anulas lar
ıngeas, tubos de por escrito, los procedimientos realizados y los resultados
toracotom
ıa, etc., as
ı como f
armacos para el traslado. de laboratorio y de im
agenes en el hospital de origen.

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 ➢ Inmediatamente despu
es, informar a los padres de las Chinea Jimenez Bibiana, Corpe~ no Olivas Tania, Dachesvsky
condiciones del RN a su llegada, aclarar todas sus du- Judith, D
ıaz Castro Alexander, Diez Ana, Escala Melida,
das e inquietudes y asegurarles que su hijo(a) recibir
a Fari~na Diana, Favareto Ver
onica, Febles Jaquez Steffani,
la atenci
on requerida. Genes Larissa, Giusti Graciela, Golombek Sergio, Grosso
➢ Posteriormente el personal que recibe al paciente in- Zandra, Josefkowicz Mariela, Lacarrubba Jos
e, Lovera Alexander,
formar
a a los padres de las condiciones y plan a se- Mart
ınez Romero Luis Ernesto, Massache Cecilia, Mendoza
guir, preferentemente al pie de la cuna del RN o por ~ ez Elina, Menzio Monica, Monta~
Ib
an no Marcela, Morcillo
llamada telef
onica directa. Nicol
as, Mu~noz Cristian, Muz~ ner Ximena Karina, Navarro
Francisco, Oliva Jose Luis, Pereira Anabell, Rivera Rueda
CONCLUSIONES Mar
ıa Antonieta, Rodr
ıguez Cari~ no Hermelinda, Rojas Van
En definitiva, el traslado antenatal o materno-fetal es la mejor Hetten Wine In
es, Ruano Marroqu
ın Elia Isabel, Segovia
opci
on en t
erminos de seguridad, abordaje terap
eutico opor- Cristina, Sosa Ignacio, Saskya Vallejo, Vallejos Mar
ıa Liseth,
tuno, calidad de atenci
on y, por supuesto, para obtener los Venegas Mar
ıa Elena, Velandia Lorena.
mejores desenlaces materno-neonatales. Sin embargo, no
siempre se diagnostican los riesgos o problemas antenatal-
mente, sino que se detectan al nacer o poco despu
es del naci-
miento, con lo cual el traslado neonatal constituye una parte
fundamental en la estructura de los servicios asistenciales
American Board of Pediatrics
neonatales. Es necesario contar con protocolos establecidos Neonatal-Perinatal Content
de traslado neonatal, organizados, sistematizados, con amplio Specification
conocimiento, compromiso y actualizaciones peri
odicas, que • Know the issues in the organization of perinatal care
permitan garantizar un nivel de atenci
on muy similar al que (e.g., regionalization, transport, practice guidelines,
el RN recibir
a en el hospital receptor. benchmarking data, quality improvement).
Existen grandes diferencias en el proceso de traslado neo- • Know the various types and mechanisms of action of
natal en cada pa
ıs y regi
on de Latinoam
erica. Lamentable- devices to maintain a neutral thermal environment.

mente, en la mayor
ıa de los pa
ıses latinoamericanos no • Know the causes, metabolic consequences, and treat-
ment of infants with hypothermia.
existe un sistema unificado y espec
ıfico para traslado neona-
• Know the causes, metabolic consequences, and treat-
tal, con personal calificado y formado o entrenado para tal ment of infants with hyperthermia.
fin, ni con el equipamiento requerido. Es necesario centrarse • Know the mechanisms of heat gain and loss.
en mejorar la equidad en las prestaciones de servicios de • Know the definition and physiological implications of
salud y enfocarnos en buscar la excelencia en el proceso del a neutral thermal environment.
traslado neonatal en aras de mejorar los desenlaces maternos
y neonatales. A la vez, hay que hacer todo lo posible para di-
agnosticar tempranamente embarazos de alto riesgo y deri-
varlos oportunamente a centros de tercer nivel de atenci
on. References
En SIBEN nos esforzamos por tratar de reducir la amplia bre-
1. Kunz SN, Dukhovny D, Profit J, Mao W, Miedema D, Zupancic
cha que existe entre lo que se conoce y lo que se lleva a cabo
JAF. Predicting Successful Neonatal Retro-Transfer to a Lower Level
en la pr
actica cotidiana y es nuestro mejor deseo que la pre- of Care. J Pediatr. 2019;205:272–276.e1
sente narrativa ayude a favorecer el proceso del oportuno y 2. Moreno Hernando J, Thi
o Lluch M, Salguero Garc
ıa E, et al.
apropiado traslado neonatal. Recomendaciones sobre transporte neonatal. An Pediatr.
2013;79(2):117. e1–117.e7

ACKNOWLEDGMENTS 3. Trevisanuto D, Cavallin F, Loddo C, et al. Servizio Trasporto

Emergenza Neonatale STEN Group. Trends in neonatal emergency
Participantes del XIII Consenso Cl
ınico de Traslado Neo- transport in the last two decades. Eur J Pediatr. 2021;180(2):635–641
natal de la Sociedad Iberoamericana de Neonatolog
ıa 4. Aagaard H, Hall EOC, Ludvigsen MS, Uhrenfeldt L, Fegran L.
(SIBEN): Acosta Polo Amparo del Socorro, Alfier Gabriela, Parent's experiences of neonatal transfer. A meta-study of qualitative


Almada Sonia, Alvarez Gallardo Laura, Andr
es Silvia, Barrios research 2000-2017. Nurs Inq. 2018;25(3):e12231 PMID: 29446189.
5. Kaneko M, Yamashita R, Kai K, Yamada N, Sameshima H, Ikenoue
Luis, Bautista Rossana, Bola~ nos Vizcarra Fernando Enrique,
T. Perinatal morbidity and mortality for extremely low-birthweight
Brezigar Ariel, Br
ıtez Sebasti
an, Caballero Doris Lupe, Cardetti infants: A population-based study of regionalized maternal and
Marcelo, Carisa Nieves, Casas Ofelia, Cespedes Elizabeth, neonatal transport. J Obstet Gynaecol Res. 2015;41(7):1056–1066

e690 NeoReviews

Downloaded from /neoreviews/issue/25/11

by Almoosa Hospital user
 6. Singh J, Dalal P, Gathwala G, Rohilla R. Transport characteristics Rep

ublica Dominicana. 2018. [Internet] Disponible en: [Link].
and predictors of mortality among neonates referred to a tertiary [Link]
care centre in North India: a prospective observational study. BMJ 22. Musson RE, Harrison CR. The burden and outcome of in utero
Open. 2021;11(7):e044625
transfers. Acta Paediatr. 2015;105(5):490–493
7. Jord
an-Lucas R, Boix H, S
anchez-Garc
ıa L, Cernada M, de las
23. Bellani P. Estabilizaci

on del reci
en nacido antes del traslado. En Sola
Cuevas I, Couce ML, en representaci
on de las Comisiones de
A, Golombek S. Cuidando al reci
en nacido a la manera de SIBEN;
Est
andares y Transporte Neonatal, Sociedad Espa~ nola de
1 ed. Argentina; EDISIBEN. 2020; p.913–922
Neonatolog
ıa. Recommendations on the skills profile and standards
of the neonatal transport system in Spain. An Pediatr (Engl Ed). 24. Colaco SM, Karande T, Bobhate PR, Jiyani R, Rao SG, Kulkarni S.
2021;94(6):420el–420eII Neonates with critical congenital heart defects: Impact of fetal
8. Blanco D, Garc
ıa-Alix A, Valverde E, Tenorio V, Vento M, Caba~ nas diagnosis on immediate and short-term outcomes. Ann Pediatr
F. Neuroprotecci
on con hipotermia en el reci
en nacido con Cardiol. 2017;10(2):126–130
encefalopat
ıa hip
oxico-isqu
emica. Gu
ıa de est
andares para su 25. Sachs BP, Marks JS, McCarthy BJ, Burton A, Rochat RW, Terry J.
on cl
ınica. An Pediatr. 2011;75(5):341.e1–341–e20
aplicaci
Neonatal transport in Georgia: Implications for maternal transport
9. American Academy of Pediatrics. Section on transport medicine. In: in high-risk pregnancies. South Med J. 1983;76(11):1397–1400
Insoft RM, Schwartz HP, (eds). Guidelines for air and ground 26. Celiz M, Montes-Bueno MT, Cardetti M. Secci
on 3 – Traslado
transport of neonatal and pediatric patients. 4rd ed. Elk Grove Village, neonatal. En: Montes-Bueno MT, Cardetti M, Sola A. T
ecnicas y
IL: American Academy of Pediatrics; 2016;488 procedimientos en neonatolog
ıa a la manera de SIBEN. 1ra ed. Ed.
10. Karlsen KA, Trautman M, Price-Douglas W, Smith S. National EdiSIBEN. Quito. 2019. 49–68
Survey of Neonatal Transport Teams in the United States. Pediatrics.
27. Munthali K, Harrison C. The continuing impact of capacity on a
2011;128(4):685–691
region’s in utero transfer requests. Acta Paediatr. 2020;109(6):
11. Perry SE. Fifty years of progress in neonatal and maternal transport 1148–1153
for specialty care. J Obstet Gynecol Neonatal Nurs. 2021;50(6):
28. Del Moral T, Bancalari E. Evoluci

on de la actitud frente al reci
en
774–788
nacido prematuro. Bol Pediatr. 2010;50:39–42 (supl1):
12. Chien LY, Whyte R, Thiessen P, Matthew D, Aziz K, Lee SK, The
29. Goswami I, Redpath S, Langlois RG, Green JR, Lee KS, Whyte
Canadian Neonatal Network. Improved outcome of preterm infants
HEA. Whole-body vibration in neonatal transport: a review of
when delivered in tertiary care centers. Obstet Gynecol.
current knowledge and future research challenges. Early Hum Dev.
2001;98(2):247–252
2020;146:105051
13. Rijken M, Stoelhorst G, Martens S, et al. Mortality and Neurologic,
30. Cetin I, Schlembach D, Bonnard N, et al. European Standards of
Mental, and Psychomotor Development at 2 Years in Infants Born
Less Than 27 Weeks’ Gestation: The Leiden Follow-Up Project on Care for Newborn Health: Maternal transfer for specialist care. 2018.
Prematurity. Pediatrics. 2003;112(2):351–358 Disponible en: [Link]
standards-english/birth-transfer/maternal-transfer-for-specialist-care/
14. Niermeyer S, Domek G. Neonatal transport in developing country
settings: A systematic review. Montevideo: Pan American Health 31. Bailey V, Szyld E, Cagle K, et al. Modern Neonatal Transport: Sound
Organization; 2016. Disponible en: [Link] and Vibration Levels and Their Impact on Physiological Stability.
handle/123456789/31317. Accessed on 1 March 2022 Am J Perinatol. 2019;36(4):352–359
15. Helenius K, Longford N, Lehtonen L, Modi N, Gale C. Neonatal 32. Kleinman ME. Neonatal Transport, En: Cloherty and Stark
s. ed.
Data Analysis Unit and the United Kingdom Neonatal Collaborative. Manual of Neonatology Care 8th Edition. India. Wolters Kluwer
Association of early postnatal transfer and birth outside a tertiary Health, 2021: 224–235
hospital with mortality and severe brain injury in extremely preterm 33. Bose A. Transfer of the Sick Neonate: What Is Needed? J Trop
infants: observational cohort study with propensity score matching. Pediatr. 2017;63(3):165–166
BMJ. 2019;367:l5678
34. Woodward GA. Transport Medicine. en Comprehensive Pediatric
16. Shah KP, de Regnier RAO, Grobman WA, Bennett AC. Neonatal Hospital Medicine. 2007; 68–72. Disponible en:
Mortality After Interhospital Transfer of Pregnant Women for
35. Alejandre C, G
omez J. Transferencia del paciente en el transporte
Imminent Very Preterm Birth in Illinois. JAMA Pediatr.
pedi
atrico y neonatal. Protoc Diagn Ter Pediatr. 2021;1:695–703
2020;174(4):358–365
36. Brennan G, Colontuono J, Carlos C. Neonatal Respiratory Support
17. Esqu
e MT, Salvia MD, Thi
o M. El traslado intra
utero, un dato
olvidado en la historia neonatal. Pediatr catal
an. 2004;64(2):61–67 on Transport. Neoreviews. 2019;20(4):e202–e212

18. Knox GE, Schnitker KA. In-utero transport. Clin Obstet Gynecol. 37. Comit
e Nacional de Emergencias y Cuidados Cr
ıticos. Consenso
1984;27(1):11–16 nos cr
ıticamente enfermos. Arch Argent
sobre el traslado de ni~
Pediatr. 2019;117:S1–S23 Supl 1:
19. Kronick JB, Frewen TC, Kissoon N, et al. Pediatric and neonatal
critical care transport: A comparison of therapeutic interventions. 38. Gien J, Nuxoll C, Kinsella JP. Inhaled nitric oxide in emergency
Pediatr Emerg Care. 1996;12(1):23–26 medical transport of the newborn. Neoreviews. 2020;21(3):e157–e164

20. Mart
ınez-Ver

onica R, L
opez-Gallo L, Rodr
ıguez-Medina D, et al. 39. Mill
an-Garc
ıa del Real N, S
anchez-Garc
ıa L, Ballestero-Diez Y, et al.
Transporte neonatal seguro en la poblaci
on abierta del estado de Importancia del transporte pedi
atrico y neonatal especializado.
Jalisco: impacto del programa S.T.A.B.L.E. en la morbilidad y Situaci

on actual en Espa~ na: Hacia un futuro m
as equitativo y
mortalidad. Bol Med Hosp Infant Mex. 2011;68(1):34–39 universal. An Pediatr. 2021;95(6):485.e1–485.e10
21. Ministerio de Salud P
ublica. Gu
ıa de Pr
actica Cl
ınica Para la 40. De Sisto CL, Oza-Frank R, Goodman D, Conrey E, Sellhaas C.
Atenci
on del Reci
en Nacido Prematuro. Organizaci
on Panamericana Maternal transport: an opportunity to improve the system of risk-
de la Salud/Organizaci
on Mundial de la Salud. Primera edici
on: appropriate care. J Perinatol. 2021;41(9):2141–2146

Vol. 25 No. 11 N O V E M B E R 2 0 2 4 e691

Downloaded from /neoreviews/issue/25/11

by Almoosa Hospital user
 41. Kronforst KD. Interhospital Transport of the Neonatal Patient. Clin 60. Harrison C, McKechnie L. How comfortable is neonatal transport?:
Pediatr Emerg Med. 2016;17(2):140–146 Disponible en: Neonatal transport. Acta Paediatr. 2012;101(2):143–147
42. Lee SK, Aziz K, Dunn M, et al. Canadian Neonatal Network. 61. Kumar P, Denson SE, Mancuso TJ, Committee on Fetus and
Transport Risk Index of Physiologic Stability, Version II (TRIPS-II): Newborn, Section on Anesthesiology and Pain Medicine.
A Simple and Practical Neonatal Illness Severity Score. Am J Premedication for Nonemergency Endotracheal Intubation in the
Perinatol. 2012;30(5):395–400 Neonate. Pediatrics. 2010;125(3):608–615
43. Whyte HEA, Jefferies AL, Lacaze T, et al. Canadian Paediatric 62. Lemus-Varela MdL, Sola A, Golombek S, et al. Consenso Cl
ınico de
Society, Fetus and Newborn Committee. The interfacility transport Dolor y Estr
es Neonatal, de la Sociedad Iberoamericana de
of critically ill newborns. Paediatr Child Health. 2015;20(5):265–275 Neonatolog
ıa (SIBEN). Consenso sobre el abordaje diagn
ostico y
44. Gente M, Aufieri R, Agostino R, et al. Neonatal transport study terap
eutico del dolor y el estr
es en el reci
en nacido. Rev Panam
group of the Italian Society of Neonatology (SIN). Nationwide survey Salud Publica. 2014;36(5):348–354
of neonatal transportation practices in Italy. Ital J Pediatr. 2019;45(1):51 63. Weiss MD, Tang A, Young L, et al. Transporting neonates with
45. Lampe G, Hillman N, Webb E. Management of Neonatal Respiratory hypoxic-ischemic encephalopathy utilizing active hypothermia.
Distress in Transport. Pediatrics. 2019;144(2_MeetingAbstract): J Neonatal Perinatal Med. 2014;7(3):173–178
881–881 Disponible en 64. Arn
aez J, Vega C, Garc
ıa-Alix A, et al. Programa multic
entrico
46. Cheema B, Welzel T, Rossouw B. Noninvasive ventilation during para la atenci

on integral del reci
en nacido con agresi

on
pediatric and neonatal critical care transport: a systematic review. hip

oxico-isqu
emica perinatal (ARAHIP). An Pediatr. 2015;82(3):
Pediatr Crit Care Med. 2019;20(1):9–18 172–182
47. Sola A, Rogido MR, Deulofeut R. Oxygen as a neonatal health 65. Leon RL, Krause KE, Sides RS, Koch MB, Trautman MS, Mietzsch
hazard: call for d
etente in clinical practice. Acta Paediatr. U. Therapeutic Hypothermia in Transport Permits Earlier Treatment
2007;96(6):801–812 Regardless of Transfer Distance. Am J Perinatol. 2022;39(6):633–639
48. Baquero H, Alviz R, Castillo A, Neira F, Sola A. Avoiding [Link] VP, Hedli L, Meurs KV, Gould J, Peiyi K, Lee H. Neonatal
hyperoxemia during neonatal resuscitation: Time to response of transport in California: findings from a qualitative Investigation.
different SpO2 monitors. Acta Paediatr. 2011;100(4):515–518 J Perinatol. 2019;40(3):394–403
49. Diehl BC. Neonatal Transport: Current Trends and Practices. Crit 67. O’Reilly KM, Tooley J, Winterbottom S. Therapeutic hypothermia
Care Nurs Clin North Am. 2018;30(4):597–606 during neonatal transport. Acta Paediatr. 2011;100(8):1084–1086;
discussion e49
50. Coe K, Jamie S, Baskerville RM. Managing common neonatal
respiratory conditions during transport. Adv Neonatal Care. 2014; 68. Golombek SA, Cap
ıtulo V. Secci
on 3. Encefalopat
ıa hip
oxico-isqu
emica
14 Suppl 5:S3–10 en el reci
en nacido a t
ermino: Cuidando al reci
en nacido a la manera
SIBEN. 1era Edici
on - Santa Cruz de la Sierra: SIBEN 2017; Tomo I,
51. Piloquet J, Genuini M, Kessous K, et al. A twelve-year neonatal and
p
ags.: 555–564
pediatric high-frequency oscillation ventilation transport experience.
Pediatr Pulmonol. 2021;56(5):1230-–1236 [Link] JL, Chock VY, Harer MW, Selewski DT, Askenazi DJ,
Newborn Brain Society Guidelines and Publications Committee.
52. Jones P, Dauger S, Leger P-L, et al. Mortality in children with
Fluid management, electrolytes imbalance and renal management in
respiratory failure transported using high frequency oscillatory
neonates with neonatal encephalopathy treated with hypothermia.
ventilation. Intensive Care Med. 2015;41(7):1363–1364
Semin Fetal Neonatal Med. 2021;26(4):101261 PMID: 34140246.
53. Zhang Q, Macartney J, Sampaio L, O’Brien K. High Frequency Jet
70. Glenn T, Price R, Culbertson L, Yalcinkaya G. Improving
Ventilation during Initial Management, Stabilization, and Transport
thermoregulation in transported preterm infants: a quality
of Newborn Infants with Congenital Diaphragmatic Hernia: A Case
improvement initiative. J Perinatol. 2021;41(2):339–345
Series. Crit Care Res Pract. 2013;2013:937871
71. Quiroga A, Chattas G, Gil-Casta~ neda A, et al. Gu
ıa de pr

actica
54. Martinho S, Adao R, Leite-Moreira AF, Bras-Silva C. Persistent
cl
ınica de termorregulaci
on en el reci
en nacido. EDISIBEN.2010.
pulmonary hypertension of the newborn. Pathophysiological
mechanism and novel therapeutic approaches. Front Pediatr. ISBN: 978-598-17.1.
2020;8:342 72. Rozance P. Management and outcome of neonatal hypoglycemia.
55. Lowe C, Trautwein J. Inhaled nitric oxide therapy during the UpToDate. 2022. Disponible en: [Link]
transport of neonates with persistent pulmonary hypertension or contents/management-and-outcome-of-neonatal-hypoglycemia/print.
severe hypoxic respiratory failure. Eur J Pediatr. 2007;166(10): 73. Alsaleem M, Saadeh L, Kamat D. Neonatal Hypoglycemia:
1025–1031 A Review. Clin Pediatr (Phila). 2019;58(13):1381–1386
56. Gianni S, Carroll RW, Kacmarek RM, Berra L. Inhaled nitric oxide 74. Haninger NC, Farley CL. Screening for hypoglycemia in healthy
delivery systems for mechanically ventilated and nonintubated term neonates: Effects on breastfeeding. J Midwifery Womens Health.
patients: A Review. Respir Care. 2021;66(6):1021–1028 2001;46(5):292–301
57. Xu XJ, Li LN, Wu WY. Importance of stabilization of the neonatal 75. Karagol B, Zencõroglu A, Ipek M, Kundak A, Okumus N.
transport network in critically ill neonates. J Int Med Res. Impact of Land-Based Neonatal Transport on Outcomes in
2019;47(8):3737–3744 Transient Tachypnea of the Newborn. Am J Perinatol.
58. Meckler GD, Lowe C. To Intubate or Not to Intubate? Transporting 2011;28(4):331–336
Infants on Prostaglandin E1. Pediatrics. 2009;123(1):e25–e30 76. Mears M, Chalmers S. Neonatal pre-transport stabilisation caring for
59. Gomes ELFD, Santos CMD, Santos ADCS, et al. Autonomic infants the STABLE way. Infant. 2005;1(1):34–37
responses of premature newborns to body position and 77. Aziz K, Ma X, Lockyer J, et al. An evaluation of Acute Care of at-Risk
environmental noise in the neonatal intensive care unit. Rev Bras Ter Newborns (ACoRN) a Canadian education program, in Chinese
Intensiva. 2019;31(3):296–302 neonatal nurseries. Pediatr Child Health. 2020;25(6):351–357

e692 NeoReviews

Downloaded from /neoreviews/issue/25/11

by Almoosa Hospital user
 78. Da Silva GE, de Souza NL, de Oliveira COP, et al. Risk assessment of 80. Golombek SG, D
avila-Aliaga C, Pleitez Navarrete J. Lemus-Varela L
morbidity and mortality in the neonatal transport. int arch med. 2017;10(24) Sola A y Miembros del XIII Consenso: XIII Consenso Cl
ınico
79. Weiner GM, Zaichkin J. Updates for the Neonatal Resuscitation SIBEN 2023 Traslado Neonatal (13th SIBEN Clinical Consensus:
Program and Resuscitation Guidelines. Neoreviews. 2022;23(4): Neonatal Transport). Ediciones SIBEN 2023. Argentina. ISBN
e238–e249 978-1-7923-9847-6

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 ARTICLE

Disorders of Coagulation in the

Newborn
Lorena Ostilla, MD,* Karyssa Knopoff, MD,† Patrick Myers, MD,* Perry Morocco, MD†
*Section of Neonatology, Department of Pediatrics, Northwestern University, Chicago, IL
†
Section of Pediatric Hematology, Oncology and Stem Cell Transplant, Department of Pediatrics, University of Chicago, Chicago, IL

EDUCATION GAPS

Coagulopathy is common in neonates and can arise from myriad causes.

As both congenital and acquired causes can contribute to a coagulopathic
state, it is important for clinicians to be able to distinguish between the 2,
begin an initial diagnostic evaluation, and initiate treatment promptly.
AUTHOR DISCLOSURES Dr Myers serves
on the executive committee for the
Council of Pediatric Sub-Specialists and
has served as chair of the Organization of OBJECTIVES After completing this article, readers should be able to:
Neonatal Training Program Directors.
Drs Ostilla, Knopoff, and Morocco have
disclosed no financial relationships 1. Initiate an appropriate initial evaluation for a neonate suspected to have
relevant to this article. This article does a congenital or acquired coagulopathy.
not contain a discussion of an
unapproved/investigative use of a 2. Identify when a neonate has a disorder of primary hemostasis, secondary
commercial product/device. hemostasis, or a disorder of the fibrinolytic system based on symptoms and
laboratory testing.
ABBREVIATIONS
3. Recognize which common coagulation abnormalities correspond to
a2-AP alpha-2 antiplasmin
patterns of laboratory tests.
aPTT activated partial thromboplastin
time
CMV cytomegalovirus
DIC disseminated intravascular ABSTRACT
coagulation
FVIII factor VIII
The coagulation system in newborns varies from that of children and
FIX factor IX adults, with many circulating hemostatic factors being lower in the
FXIII factor XIII newborn. Infants are also susceptible to diseases and conditions in the
HIV human immunodeficiency virus
pregnant person affecting their coagulation system, which can make it
HLH hemophagocytic
lymphohistiocytosis difficult to rapidly identify the cause behind coagulopathy in a neonate.
HPA human platelet alloantigen Coagulation disorders can result in high levels of infant morbidity and
HSV herpes simplex virus
mortality, which makes early diagnosis and prompt treatment critical. This
ICH intracranial hemorrhage
ITP immune thrombocytopenia review outlines the clinical characteristics, diagnosis and management,
KHE kaposiform epidemiology, and etiologies of both common and uncommon congenital
hemangioendothelioma and acquired forms of neonatal coagulopathy.
KMP Kasabach-Merritt phenomenon
NAIT neonatal alloimmune
thrombocytopenia
PT prothrombin time
The many different proteins and cells that take part in the intricate coagula-
SGA small for gestational age
TA tufted angioma tion system all work toward the goal of homeostasis or hemostasis. A visual rep-
TAR thrombocytopenia absent radii resentation of the coagulation cascade, including the different pathways and
VKDB vitamin K deficiency bleeding associated laboratory tests, is shown in the Figure. Coagulopathies can broadly
disorder
vWD von Willebrand disease be thought of as disorders of primary hemostasis, disorders of secondary hemo-
vWF von Willebrand factor stasis, or disorders of the fibrinolytic system, with different laboratory values

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 associated with each disorder (Table 1). Primary hemosta- platelets, and certain bacteria, beginning the cascade.
sis involves platelet aggregation and the development of (4)(7)(8) This also ends with activation of factor X, which aids
the platelet plug in response to vascular injury. (1) Second- in the generation of thrombin and then fibrin. (4)(5) The in-
ary hemostasis is the deposition of insoluble fibrin after trinsic and common pathways are represented in the activated
activation of hemostatic factors, and the fibrinolytic system partial thromboplastin time (aPTT) test. (6) Fibrin is the ter-
is responsible for the dissolution of thrombi. (2)(3) Such minal result of the common pathway, leading to hemostasis
disorders can be acquired, in response to medications or and preventing hemorrhage, but this thrombus is then regu-
other diseases, or can be congenital, arising from genetic lated by the fibrinolytic system, which eventually dissolves the
mutations and specific deficiencies. thrombus. (2) Plasmin is the primary regulator of fibrinolysis,
removing the thrombus when the blood vessel is healed and
HEMOSTASIS OVERVIEW its integrity is restored. (2)
Primary hemostasis relies on platelets adhering to areas of
vascular injury, attaching to the exposed matrix of collagen EPIDEMIOLOGY
and von Willebrand factor (vWF). (1) Platelets then be- Coagulopathy is relatively common in newborns, with
come activated, changing the phospholipids exposed on adults and children having relatively different coagulation
the cell surface and resulting in platelet aggregation, systems than infants. Until an infant has reached 32 weeks’
which subsequently creates the initial platelet plug. (1) Oc-
gestational age, their platelet count is reduced compared
curring simultaneously is the initiation of the coagulation
with older children, and platelet function is decreased. (9)
cascade, or secondary hemostasis, which results in insolu-
Many coagulation factors are also decreased in neonates,
ble fibrin generation from a series of protein reactions.
including factors II, VII, IX, X, XI, and XII, antithrombin,
(3)(4)(5) This cascade, composed of serine proteases and
and protein C. (9) In contrast, factors V, VIII, and XIII,
cofactors, can arise via 2 different pathways, the intrinsic
and fibrinogen have normal levels, whereas vWF is in-
or the extrinsic pathway, which converge on the common
creased. (9)(10) As a result of these alterations, neonates
pathway.
can have up to a 25% chance of bleeding during admis-
The extrinsic pathway is triggered when blood makes
sion to the NICU, with prematurity increasing risk. (11)
contact with extravascular cells, which possess tissue fac-
One of the most serious bleeding complications includes
tors, resulting in the activation of factor V, which then ac-
intraventricular hemorrhage, which can affect 23% of in-
tivates factor X, the first factor of the common pathway.
(3)(4) The extrinsic and common pathways are represented fants born at less than 32 weeks’ gestational age, with in-
in a prothrombin test (PT). (6) In the absence of exposure creasing gestational age being protective. (12) Infants with
to tissue factors, the coagulation cascade can also arise sepsis, lower birthweight, or the presence of a patent duc-
from the intrinsic pathway, where the contact system acti- tus arteriosus have an increased risk. (12)
vates after exposure to invasive pathogens and certain ma-
terials in the blood. (4)(7) The contact system is composed DISORDERS OF PRIMARY HEMOSTASIS
of factor XII, prekallikrein, and high-molecular-weight Impairment of primary hemostasis is frequently responsi-
kininogen, and reacts to substances including collagen, ble for serious bleeding events in infants. Various factors,

Table 1. Diagnosis Based on Coagulation Panel Abnormalities

Type of Disorder Platelet Count PT/INR aPTT
Disorders of Primary Hemostasis
Quantitative disorders Decreased Normal Normal
Qualitative disorders Normal or decreased Normal Normal
vWD Normal Normal Prolonged
Congenital thrombotic thrombocytopenic purpura Decreased Normal Normal
Collagen and vascular disorders Normal Normal Normal
Disorders of Secondary Hemostasis
Vitamin K deficiency Normal Prolonged Normal or prolonged
Hemophilia A: Factor VIII deficiency Normal Normal Prolonged
Hemophilia B: Factor IX deficiency Normal Normal Prolonged
Factor XIII deficiency Normal Normal Normal

aPTT5activated partial thromboplastin time, INR5international normalized ratio, PT5prothrombin time, vWD5von Willebrand disease.

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 including heredity, maternal acquisition, infections, and examination, coagulation testing, and potential hematology
drugs, can impair primary hemostasis in the neonate. consultation can help identify a disorder of primary hemo-
Gestational age (premature infants typically exhibit slightly stasis (Table 2 and Table 3).
lower platelet counts compared with those born at full
term), hypoxia, acidosis, higher vWF concentrations and Quantitative Disorders of Primary Hemostasis
enhanced function, lower plasma level and activity of other Impaired Platelet Production. Platelets are formed through
coagulation proteins, elevated hematocrit count, large eryth- the fragmentation of megakaryocytes in the bone marrow.
rocytes during the first day after birth, and platelet This process begins during early fetal life and increases in
hyperreactivity are other factors to consider. (9)(10) In ad- number to adult concentrations in the peripheral blood
dition to an accurate medical and family history, physical around 22 weeks’ gestation. (13) Newborns have developmental

Table 2. Quantitative Disorders of Primary Hemostasis

Pattern of Inheritance/ Clinical Signs and
Disorder Transmission Symptoms Diagnosis Management
Neonatal alloimmune Transfer of platelet- Thrombocytopenia Platelet count Donor-matched platelet
thrombocytopenia specific antibodies Risk of bleeding Plasma levels of anti- transfusion
ICH is common HPA-1A in parents Intravenous IgG
Immune Transfer of platelet- Thrombocytopenia Birthing parent and infant Intravenous IgG
thrombocytopenia in specific antibodies Risk of bleeding platelet counts Corticosteroids
the birthing parent ICH is rare
Thrombocytopenia from N/A Maternal hypertension with or Clinical history and Platelet transfusion
preeclampsia without thrombocytopenia platelet counts
Low birth weight infant
Congenital infection Congenital or perinatal Variable: Clinical manifestations Antiviral or antibacterial
transmission  Toxoplasmosis: petechiae, with viral or infectious treatments
hepatosplenomegaly, disease testing
jaundice, low birth weight,
hydrocephalus, intracranial
calcifications, microcephaly
 Rubella: microcephaly,
developmental delay, hearing
impairment,
hepatosplenomegaly,
retinopathy, congenital
glaucoma, cataracts,
intrauterine growth
restriction, congenital heart
defects, and purpura
 CMV: sensorineural hearing
loss, microcephaly,
intracranial calcifications,
hepatitis, purpura, retinitis
and severe
thrombocytopenia
 HIV: sepsis, growth faltering
 HSV: sepsislike illness,
thrombocytopenia,
consumptive coagulopathy,
and acute liver failure
Thrombocytopenia Autosomal recessive Bleeding and Clinical manifestations Platelet transfusion
absent radii thrombocytopenia that Genetic testing
syndrome improves over time
May have cardiac and renal
abnormalities
Wiskott-Aldrich X-linked recessive Thrombocytopenia Genetic testing Intravenous IgG
syndrome Eczema Platelet transfusion
Immunodeficiency Corticosteroids
Congenital Autosomal recessive Purpura, petechia, and bleeding Bone marrow biopsy Platelet transfusion
amegakaryocytic (early) Genetic testing Stem cell transplant
thrombocytopenia Aplastic anemia and leukemia
(late)

CMV5cytomegalovirus, HIV5human immunodeficiency virus; HSV, herpes simplex virus, ICH5intracranial hemorrhage, Ig5immunoglobulin,
N/A5not applicable.

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 Table 3. Qualitative Disorders of Primary Hemostasis
Pattern of Inheritance/ Clinical Signs and
Disorder Transmission Symptoms Diagnosis Management
Glanzmann Autosomal recessive Mild to severe bleeding Flow cytometry with the Factor VIIa
thrombasthenia absence of GPIIb/IIIa Aminocaproic acid
receptor Platelet transfusion
Platelet aggregation
studies
Bernard-Soulier Autosomal recessive Mild to severe bleeding Flow cytometry: absence Platelet transfusion
syndrome of glycoprotein IB, V,
and IX on platelet
surfaces and platelet
aggregation studies
Gray platelet Autosomal dominant, Bleeding Peripheral smear review Platelet transfusion
syndrome autosomal recessive, or Splenomegaly and no a-granules on Desmopressin
X-linked electron microscopy Splenectomy
Hermansky-Pudlak Autosomal recessive Bleeding Clinical findings Platelet transfusion
syndrome Oculocutaneous albinism Lack of platelet d Desmopressin
Vision abnormalities granules on electron
Possible immunodeficiency microscopy
von Willebrand Autosomal dominant Frequent mucocutaneous aPTT and FVIII activity Antifibrinolytics,
disease (type 1 and most type bleeding, with vWF ristocetin-cofactor desmopressin
2) or autosomal spontaneous joint or activity vWF concentrates alone
recessive (type 3) muscle bleeding and/or vWF antigen levels and/or a combination
hematomas in type 3 of FVIII:vWF
disease
Congenital Autosomal recessive Hyperbilirubinemia ADAMTS13 activity ADAMTS13 replacement
thrombotic Thrombocytopenia
thrombocytopenic Stroke and other arterial
purpura thromboembolic events,
ischemia, and renal
disease
Collagen and Typically autosomal Bleeding Clinical and family history Antifibrinolytics
vascular disorders dominant Skin and joint hypermobility
(Ehlers-Danlos syndrome)
Arteriovenous malformations
Telangiectasis (hereditary
hemorrhagic
telangiectasia)

aPTT5activated partial thromboplastin time, FVIII5factor VIII, vWD5von Willebrand disease.

immaturities in hematopoiesis and are thus more sus- and increasing their ploidy, thereby boosting megakaryocyte
pectable to peripheral cytopenia, particularly in high- mass. (18) However, neonates with thrombocytopenia can
demand states, if they have defects in thrombopoiesis augment the quantity of their megakaryocytes but are unable
and myelopoiesis. For instance, prolonged intrauterine to affect their size. (18) A small neonatal megakaryocyte may
hypoxia resulting from placental dysfunction might cause thus have limited ability to respond to increased demand and
both thrombocytopenia and polycythemia in small- thrombocytopenia. (18)
for-gestational-age (SGA) newborns owing to impaired When platelets adhere to areas of vascular damage,
thrombopoiesis. (14) Multiple studies indicate that plasma they release biological mediators and the contents of gran-
concentrations of thrombopoietin, which controls thrombo- ules to facilitate plasma coagulation reactions. (1) Follow-
poiesis, are elevated in both full-term and preterm neonates ing endothelial damage, platelets attach to the underlying
compared with healthy adults. (15) Conversely, neonatal basement membrane collagen, initiating the primary stage
megakaryocyte progenitors may have higher proliferative of hemostasis and engaging with subendothelial vWF. (1)
rate potential and more sensitivity to thrombopoietin than Glycocalicin serves as an indicator of heightened platelet
adult progenitors. (16) However, compared with adult mega- turnover, whereas interleukin 6 levels rise in reaction to
karyocytes, they produce fewer platelets per cell and are thrombocytopenia. (19) Neonates experiencing intrauterine
smaller. (17) growth restriction and thrombocytopenia exhibited undetect-
In normal circumstances, the adult bone marrow adapts to able levels of glycocalicin in their plasma, indicating compro-
heightened platelet requirements by enlarging megakaryocytes mised thrombopoiesis. (19) In addition, alloimmunization

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 against platelets can occur during pregnancy or after receiv- measured through cordocentesis, with findings of severe
ing a transfusion, resulting in the swift destruction of incom- thrombocytopenia warranting treatment. (24) Postnatally,
patible platelets. (20) infants with platelet counts less than 50 × 103/mL (50 × 109/L)
should be screened for ICH with head ultrasonography and
Neonatal Alloimmune Thrombocytopenia. Neonatal alloim- given a platelet transfusion if platelets fall below 30 × 103/mL
mune thrombocytopenia (NAIT) is rare (1 in 1,000 births) (30 × 109/L). (24) The threshold for transfusion decreases if
and is triggered by the transfer of platelet-specific alloanti- the newborn is actively bleeding or has an intracranial or ex-
bodies or human leukocyte antigen antibodies from the tracranial hemorrhage, and it is important not to postpone
pregnant person across the placenta, which then recognize treatment while waiting for confirmation testing. (24) Infants
the corresponding antigens in the infant. (21) The human should be given donor-matched platelet transfusions, because
platelet alloantigens (HPAs) from the non–birth parent antibodies from the birth parent might persist in the infant's
may differ from those of the birth parent, leading to the bloodstream, and platelets may not stabilize until these anti-
production of antibodies in the pregnant person against bodies are cleared from the infant's circulation. (24) In addi-
an unfamiliar antigen. As early as 15 weeks of gestation, tion, intravenous immunoglobin may be necessary while
these immunoglobin G antibodies can be transplacentally antibodies are cleared. (24)
transmitted to the fetal circulation, causing thrombocyto-
penia, and can persist until they are cleared. (22)(23) The ITP in the Pregnant Person. ITP in the pregnant person
likelihood of NAIT recurring in subsequent pregnancies causes neonatal thrombocytopenia because of active trans-
has been projected to exceed 80%, with subsequent pre- placental transport of antiplatelet antibodies from the
sentations having greater severity and an increased risk of pregnant person, which then act against fetal platelet sur-
bleeding. (24) face glycoproteins. In ITP, platelet counts in the birth par-
NAIT is diagnosed based on clinical and serologic find- ent are low whereas infant platelet counts are variable. If
ings. Clinical findings related to thrombocytopenia include platelet counts in the infant are initially decreased, plate-
ecchymosis, petechiae, purpura, and bleeding. Intracranial lets should continue to be monitored after birth as platelet
hemorrhage (ICH) stands out as one of the most critical counts may continue to fall postnatally. (26) Platelet
complications and can be detected during pregnancy as counts will typically normalize by 4 to 6 weeks after
early as the 20th week of gestation. (25) However, NAIT birth. (26) Thrombocytopenia is significant enough in
frequently remains undetected during prenatal screening 9% to 15% of infants born to persons with ITP that treat-
because universal screening is not routinely conducted. ment is required but fortunately, only 0% to 1.5% of in-
Screening tools include the detection of plasma levels of fants have ICH. (26) Infants with platelet counts less
anti-HPA-1a, the most common antigen involved in white than 50 × 103/mL (50 × 109/L) may need to be monitored
pregnant persons. (24) Fetal HPA genotyping through am- even though the risk for ICH is low. (26)
niocentesis is rarely used given the invasive nature of the
procedure. (24) Congenital Neonatal Infections.
Postnatally, NAIT should be considered in a newborn Cytomegalovirus
with thrombocytopenia within 48 hours of delivery after Cytomegalovirus (CMV) can cause neonatal infection from
excluding other factors contributing to thrombocytopenia. congenital or perinatal transmission, and can manifest as
The birth parent’s platelet count should be obtained if a sensorineural hearing loss, microcephaly, intracranial cal-
neonate has thrombocytopenia without an identified cause cifications, hepatitis, pneumonia, purpura, retinitis, SGA,
because it can distinguish NAIT from other autoimmune and severe thrombocytopenia. Diagnosis is achievable by
thrombocytopenias such as immune thrombocytopenia detecting CMV in both urine and saliva of the neonate
(ITP). (24) Final diagnosis can then be made with platelet through polymerase chain reaction, with sensitivities rang-
immunologic testing of both parents. (24) In addition to ing from 93% to 100%. (27) Pregnant persons with mono-
this testing, anti-HPA antibodies in blood in the birth par- nucleosislike illness and/or with fetal anomalies suggestive
ent and genotyping in the non–birth parent can identify of congenital CMV should be tested. (27)(28) Treatment
the risk of recurrence in subsequent pregnancies. (23)(24) includes 6 months of valganciclovir therapy in newborns
For prenatal management, intravenous immunoglobin showing symptoms with CNS involvement between 32 weeks’
with or without steroid administration is the preferred gestation and less than 1 month of age. (28) It is important
treatment and can be given to pregnant persons as early to monitor for myelosuppression during the full course of
as 18 weeks’ gestation. (24) Fetal platelet counts can be treatment. (28)

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 Toxoplasmosis an earlier onset and present with symptoms resembling
Neonatal toxoplasmosis presents with petechiae, hepato- sepsis. (35) The infant may have thrombocytopenia, con-
splenomegaly, jaundice, low birthweight, hydrocephalus, sumptive coagulopathy, and acute liver failure within the
intracranial calcifications, microcephaly, seizures, retinitis, initial 30 days after birth. (35) Diagnosis is completed
and microphthalmia. (29) Diagnosis is achieved through through HSV polymerase chain reaction assays from any
anti-Toxoplasma gondii immunoglobulin (Ig)M/IgA and skin vesicles, cerebrospinal fluid, whole blood, and surface
IgG, indirect ophthalmoscopy to identify retinochoroiditis, swabs of the conjunctiva, nasopharynx, mouth, and anus.
and the detection of calcification and hydrocephalus via (35) When HSV infection is suspected or confirmed,
brain magnetic resonance imaging and computed tomogra- prompt treatment with intravenous acyclovir should be
phy. (30) If pregnant persons are diagnosed during gestation initiated.
through serologic or amniotic fluid testing, treatment with spi-
ramycin can be offered early in pregnancy, or pyrimethamine Preeclampsia. With an incidence of 2% to 6% in the
and sulphonamide in the third trimester through delivery. United States, preeclampsia is the most common pregnancy-
(30) In the infant, therapy includes a combination of pyri- related complication in pregnant patients. (36) Its primary
methamine and sulfonamide for 12 months. (30) It is impor- pathologic characteristics result from the activation of plate-
tant to monitor for bone marrow suppression throughout the lets and a widespread ischemic disorder due to endothelial
treatment course because of folate metabolism inhibition. (30) dysfunction. Mechanisms considered for the etiology of
thrombocytopenia include decreased platelet production
Rubella
and decreased circulating megakaryocyte progenitors, as
Congenital rubella syndrome is an uncommon cause of
well as increased immune-mediated platelet consumption.
thrombocytopenia in infants. Clinical characteristics include
(36) Thrombocytopenia is observed in SGA infants, possi-
microcephaly, developmental delay, hearing impairment, hep-
bly stemming from consumptive coagulopathy, platelet de-
atosplenomegaly, retinopathy, congenital glaucoma, cataracts,
struction, and vascular pathology. (36) In SGA newborns,
intrauterine growth restriction, congenital heart defects, and
elevated erythropoietin levels and impaired thrombopoiesis
purpura. (31) Thrombocytopenia can be secondary to bone
may be the result of intrauterine hypoxia. (14) In addition, in-
marrow suppression (particularly in SGA infants) but the ex-
fants born to persons with preeclampsia have significantly
act etiology remains unknown. (32)
lower platelet counts, lower megakaryocyte colony-forming
units, and decreased megakaryocyte counts. (36)
Human Immunodeficiency Virus
Human immunodeficiency virus (HIV) type 1 infection re-
Congenital Thrombocytopenia Syndromes. Congenital throm-
mains a major contributor to morbidity and mortality
bocytopenia syndromes should be considered in infants
among children in low- and middle-income nations, with
who present with bleeding near birth that is out of propor-
over a third of HIV-1–positive infants succumbing to the
tion to their thrombocytopenia, have an associated family
infection during childhood if left untreated. (33) Thrombo-
history, and have additional nonhematologic clinical find-
cytopenia, sepsis, and failure to thrive have been identified
as common findings in symptomatic patients. (34) Early ings. Thrombocytopenia absent radii (TAR), amegakaryo-
diagnosis and immediate treatment via the initiation of an- cytic thrombocytopenia, and Wiskott-Aldrich syndrome
tiretroviral therapy are imperative and critical for children are the primary platelet disorders with these manifesta-
younger than 18 months who have been exposed to perinatal tions but rare inborn errors of metabolism, such as
HIV-1. Diagnosis is established by using molecular virologic Gaucher disease and methylmalonic acidemia, can also be
assays, such as HIV-RNA or HIV-DNA tests. (33) considered. (26)
TAR is an autosomal recessive disorder in which in-
Herpes Simplex Virus fants have bilateral absent radii with thumbs and present
In infants, herpes simplex virus (HSV) infection can pre- with bleeding, petechial rash, and purpura near the time
sent as a widespread or disseminated disease affecting var- of birth. (37)(38) Bleeding and thrombocytopenia are more
ious organs, localized central nervous system involvement severe early in life and will often improve as the infant
with or without skin symptoms, or infection restricted to grows older. (38) Infants with TAR are predisposed to cow
the skin, eyes, and/or mouth. (35) Symptoms of HSV in- milk intolerance, which temporally correlates to worsening
fection may appear any time from birth to 6 weeks of age, thrombocytopenia. (38) Both cardiac and renal abnormali-
but infants with disseminated disease typically experience ties can be seen as part of TAR. (38) The diagnosis is

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 established through clinical observations, which can be VIIa and aminocaproic acid for mucosal hemorrhages.
validated via genetic testing. (37) Both platelet morphology and numbers are normal
Congenital amegakaryocytic thrombocytopenia is inher- during evaluation, and identification of defects in platelet
ited in an autosomal recessive fashion with severe (type 1) glycoprotein IIB/IIIa leads to a definitive diagnosis. (37)
and mild to moderate (type 2) types. (39)(40) Purpura, pe- Bernard-Soulier syndrome causes bleeding due to large
techiae, and bleeding can occur in the first month of age. platelets that have poor adhesion. (37) It has an incidence
(39)(40) Other hematologic manifestations include aplas- of less than 1 per million and can manifest in infancy,
tic anemia and leukemia as a late manifestation. (39)(40) though 16 years is the mean age of diagnosis. (37)(43) Af-
Bone marrow biopsy will show a reduction in megakaryo- fected patients can have severe life-threatening hemor-
cytes, and genetic testing of the c-MPL gene will lead to a rhage with an estimated 16% mortality rate but can also
definitive diagnosis. (39)(40) At present, hematopoietic have only unexplained purpura. (43) Life-threatening hemor-
stem cell transplantation stands as the only curative treat- rhage may be out of proportion to their thrombocytopenia.
ment option. (41) (37) Platelet transfusions are the mainstay of treatment, and
Wiskott-Aldrich syndrome has the clinical hallmarks of definitive diagnosis is via flow cytometry, showing an absence
thrombocytopenia, eczema, and immunodeficiency, with of glycoprotein IB, V, and IX on platelet surfaces. (37)(43)
an X-linked recessive inheritance pattern. (42) The small Gray platelet syndrome is named after the appearance
platelets and thrombocytopenia are thought to be due to of the washed-out gray platelets seen on peripheral smears. It
splenic destruction. (42) Infants can have failure to thrive is caused by an absence of platelet a-granules which leads to
and are susceptible to infections from encapsulated organ- bleeding, splenomegaly, and myelofibrosis. (44) Genetic inher-
isms. (42) Treatments may include intravenous immuno- itance can be autosomal dominant, autosomal recessive, or X-
globulin, platelet transfusions, and corticosteroids. (42) linked. (44) Patients present with bleeding diathesis near the
time of birth, easy bruising, and low platelet counts. (44) Diag-
Medications. Medications can also be a cause of quantita- nosis is made by the appearance of large, gray washed-out
tive platelet disorders, particularly in well-appearing in- platelets on peripheral smear and the lack of a-granules on
fants with no other identified causes of thrombocytopenia. the electron microscope. (37)(44)
Common causes include antibiotics, heparin, phenytoin, Inherited via an autosomal recessive pattern, patients
and indomethacin. (26)(37) with Hermansky-Pudlak syndrome present with bleeding
diathesis, oculocutaneous albinism, vision abnormalities,
Qualitative Disorders of Primary Hemostasis and in some variants, immunodeficiency and neutropenia.
Qualitative Platelet Disorders. Although rare, inherited qual- (45) Additional clinical findings are postprocedural bleed-
itative platelet disorders should be considered in infants ing, easy bruising, and colonic bleeding and may include
with early-onset bleeding that is persistent and dispropor- ocular conditions (ie, nystagmus, strabismus), pulmonary
tionate to the platelet count, and with an abnormal periph- fibrosis, and granulomatous colitis. (45) The diagnosis is
eral blood smear. There may be a family history of clinical, with additional findings of impaired secondary ag-
autosomal dominant, autosomal recessive, or X-linked in- gregation, and the absence of platelet d granules (dense
heritance. On peripheral blood smear, platelets can be bodies) on an electron microscope. (37)(45)
large or have abnormal morphology. (37) Definitive diag-
nosis can be challenging, with platelet function testing, Von Willebrand Disease. Von Willebrand disease (vWD) is
flow cytometry, and genetic testing all being used. Some the most prevalent hereditary bleeding disorder and re-
qualitative platelet disorders, such as Glanzmann throm- sults from an anomaly in vWF, a glycoprotein essential for
basthenia and Bernard-Soulier syndrome, carry an in- platelet adhesion to the subendothelium following vascu-
creased risk for isoimmunization or alloimmunization lar injury. (1) In addition, vWF stabilizes factor VIII
after platelet transfusions leading ultimately to ineffective (FVIII) in the coagulation cascade, shielding it from degra-
platelet transfusions. (37) dation. (46) Inheritance is autosomal dominant for type 1
Glanzmann thrombasthenia is an autosomal recessive vWD and most forms of type 2, and autosomal recessive
quantitative or a qualitative platelet disorder. It is found for type 3. (46) Type 1, a quantitative defect, is the most com-
more frequently in certain ethnic groups and consanguin- mon form, but can have a range of clinical severity. (46)(47)
ity. (37) The clinical signs of bleeding vary in severity, If symptomatic, the initial presentation includes frequent
from mild to potentially life-threatening. (37) Platelet mucocutaneous bleeding, with spontaneous joint or muscle
transfusions are the mainstay of treatment, with factor bleeding and/or hematomas in type 3 disease. (46)

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 Diagnosis is made through measurement of aPTT and from mutations in the genes for fibrillar collagen proteins
FVIII activity, vWF ristocetin-cofactor activity, and vWF (collagen type I, III, and V) and presents with skin and
antigen levels. Therapies include tranexamic acid, desmo- joint hypermobility, spontaneous hematomas secondary to
pressin, high-purity vWF concentrates alone, and/or a minimal trauma, delayed wound healing, and fragility of
combination of FVIII:vWF, based on the severity of the the blood vessels and internal organs. (50)
disease. (46) There is a relative contraindication to the use Hereditary hemorrhagic telangiectasia, also known as
of desmopressin in children younger than 2 years, but it may Osler-Weber-Rendu syndrome, is a genetic disorder inher-
be considered if accompanied by careful management with ited in an autosomal dominant pattern, characterized by
fluid restriction, prevention of hyponatremia, and monitoring bleeding resulting from abnormal blood vessels. (51) Pa-
of both electrolyte levels and urine output. (46) tients usually have subclinical arteriovenous malforma-
tions in the lungs and liver, and carry a high risk for
Thrombotic Thrombocytopenia Purpura. Congenital throm- bleeding and other complications including pulmonary hy-
botic thrombocytopenia purpura is a rare autosomal reces-
pertension and hemorrhagic stroke. (51) Other symptoms
sive inherited condition of ADAMTS13 metalloprotease
include epistaxis, anemia from gastrointestinal bleed-
deficiency. (48) Symptoms include hyperbilirubinemia,
ing, and telangiectasias of the lips, fingertips, and buc-
thrombocytopenia, stroke and other arterial thromboem-
cal mucosa. (51)
bolic events, ischemia, and renal disease. (48) Treatment
with ADAMTS13 replacement reduces the incidence of
DISORDERS OF SECONDARY HEMOSTASIS
end-organ damage. (48)
Secondary hemostasis refers to the process of fibrin for-
Collagen and Vascular Disorders. Collagen is a key compo- mation via the coagulation cascade, primarily involving co-
nent of basement membrane function and provides structural agulation factors and activated cell surfaces. Diagnosis of
support for cellular behavior and signaling. Mutations in colla- inherited bleeding disorders affecting secondary hemosta-
gen IV, VI, VII, XV, XVII, and XVIII are rare but cause dis- sis relies on a combination of coagulation tests, family his-
eases affecting multiple systems. (49) Collagen IV mutations, tory, and clinical history (Table 4).
being the most prevalent structural basement membrane
element, can lead to a range of multisystemic disorders, Hemophilia A: Factor VIII Deficiency
encompassing cerebral small vessel disease, intracerebral Hemophilia A is a hereditary coagulation disorder linked
hemorrhage, kidney disorders, ocular abnormalities, and to the X chromosome, resulting from a deficiency in
myopathy. (49) FVIII, with an incidence of around 1 in 5,000 males. (52)
Distinguishing features of other inherited connective Approximately 30% of mutations arise de novo, therefore
tissue disorders such as Ehlers-Danlos syndrome, consist absence of a family history does not exclude the possibility
of susceptibility to easy bruising and bleeding. This arises of the condition. (53)

Table 4. Disorders of Secondary Hemostasis

Pattern of Inheritance/
Disorder Transmission Clinical Signs and Symptoms Diagnosis Management
Hemophilia A: X-linked recessive or de Bleeding episodes, often involving Prolonged aPTT Desmopressin
factor VIII novo mutations joints and muscles, circumcision Low factor VIII level Factor VIII replacement
deficiency site bleeding, ICH is rare. Non-factor therapies
Hemophilia B: X-linked recessive Frequent bleeding episodes in the Prolonged aPTT Factor IX replacement
factor IX neonatal period, muscle and Low factor IX level
deficiency joint bleeding, occasional
spontaneous hemorrhages
Factor XIII Autosomal recessive Skin bruising, subcutaneous Low Factor XIII level Fresh-frozen plasma or
deficiency bleeding, bleeding from the Normal PT, aPTT, and cryoprecipitate
umbilical cord, ICH, and soft platelet count Factor XIII replacement
tissue hematomas
Vitamin K Prevented by vitamin K Bleeding through the umbilical Prolonged PT with or Administration of a
deficiency prophylaxis at birth cord/stump, cephalohematoma, without aPTT elevation parenteral dose of
ICH, gastrointestinal and Normal platelets and vitamin K
mucocutaneous bleeding fibrinogen

aPTT5activated partial thromboplastin time, ICH5intracranial hemorrhage, PT5prothrombin time.

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 A suspected diagnosis due to bleeding episodes, often The goal of treatment involves exogenous FIX concen-
involving joints and muscles, or a family history, should trates to achieve hemostasis and prevent recurrent bleed-
prompt further testing. A prolonged aPTT alongside a nor- ing and joint destruction. Prophylactic treatment entails
mal PT and platelet count is typical of hemophilia A. (54) regular administration of FIX concentrate to maintain a
Severity is based on factor level compared with normal, minimum trough FIX activity of 1% between doses. (54)
with mild being 5% to 40%, moderate 1% to 5%, and se- Emerging treatment approaches for hemophilia include
vere less than 1%. (54) The earliest and most serious com- subcutaneous FIX products and gene therapy based on ad-
plication in neonates with severe hemophilia is ICH, eno-associated viral vectors. (54)
which occurs in 1% to 4% of cases. (54) Extracranial hem-
orrhage, including subgaleal bleeding and cephalohema- Factor XIII (FXIII) Deficiency
toma formation, can also occur. (53)(54) Circumcision site Congenital FXIII deficiency is a rare autosomal recessive
bleeding is common and severe hemophilia can present bleeding disorder, affecting roughly 1 in 2 million individ-
with spontaneous muscle hemorrhage in the lower ex- uals. (55) Activated FXIII is critical in the final phase of co-
tremities, iliopsoas muscle buttocks, and forearms, as well agulation by enhancing the stability of the fibrin clot. (2)
as intra-articular bleeding. (54) Symptoms can vary from severe, potentially life-threaten-
Treatment goals are to achieve hemostasis during acute ing bleeding to milder manifestations such as skin bruis-
bleeds and avoid rebleeding. Desmopressin is the pre- ing, subcutaneous bleeding, bleeding from the umbilical
ferred hemostatic treatment of individuals with mild dis- cord, and soft tissue hematomas. Patients with FXIII defi-
ease along with early rehabilitation and pain management. ciency will initially form a clot, but this will be unstable
(54) ICH should be suspected with new hypertension, and they will have rebleeding. (55) The severity of bleeding
change in mental status or level of alertness, lethargy, or is associated with the level of FXIII activity and the severe
increased fussiness, and treated accordingly. For moderate phenotype has the highest rate of ICH of any bleeding dis-
to severe disease, and for joint bleeds, consecutive days of order. (56) Diagnosis is difficult because PT, aPTT, platelet
factor replacement is required. (54) Other novel therapies count, and thrombin time are normal; specific FXIII as-
have become available and include nonfactor therapies says are required for the diagnosis. (57) In the event of
and gene therapy. (54) acute bleeding, fresh-frozen plasma or cryoprecipitate can
be given if the diagnosis is suspected. If the diagnosis is
Hemophilia B: Factor IX Deficiency made, treatment is factor infusions.
Hemophilia B is a rare genetic bleeding disorder linked to
the X chromosome, characterized by a deficiency in coagu- Vitamin K Deficiency
lation factor IX (FIX), occurring in 5 in 100,000 males. Vitamin K deficiency bleeding disorder (VKDB) was ini-
(54) Clinical bleeding often corresponds with the levels of tially identified in the 1800s as a hemorrhagic disease of
FIX activity in the plasma, but certain patients may exhibit the newborn. (58) In 1961, the American Academy of Pe-
variability in the severity of bleeding symptoms. (54) Dis- diatrics, recommended that all infants be given a single
ease severity is based on the same thresholds as hemo- parenteral dose of vitamin K at birth, which has dramati-
philia A, with severe being less than 1% of normal. (54) If cally reduced the mortality rate of VKDB and the inci-
severe, presentation is similar to severe hemophilia A, dence of ICH. (58)(59)
with frequent bleeding episodes in the neonatal period. VKDB should be considered in all infants who present
(54) Patients with mild to moderate hemophilia B have a with a bleeding diathesis in the first 6 months of age.
wider bleeding phenotype, ranging from bleeding with mi- Newborns are particularly vulnerable to deranged vitamin
nor trauma to more severe muscle and joint bleeding and K metabolism because of limited vitamin K acquisition
occasional spontaneous hemorrhages. (54) during gestation and initial lack of gut flora to produce ad-
At birth, there is a reduction in all vitamin K–depend- ditional vitamin K. (60) ICH, a bleeding umbilical stump,
ent factors, including FIX, and this reduction is even gastrointestinal and mucocutaneous bleeding, and bleed-
more pronounced in preterm neonates, posing challenges ing circumcisions should prompt the clinician to consider
in diagnosing hemophilia B at birth. (9)(10) Diagnosis can the possibility of VKDB. (58)(60)
be made by measuring plasma FIX activity levels; genetic The etiology and time frame of VKDB is divided into
analysis is then recommended to establish a causative mu- early, classic, and late presentations. Early VKDB occurs in
tation. (54) the first 24 hours after birth and is secondary to the

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 transplacental acquisition of drugs from the pregnant per- quantitative (type 1) deficiencies or qualitative (type 2) dysfunc-
son that interfere postnatally with the infant’s metabolism tional proteins, from 3 possible genes (FGA, FGB, and FGG).
of vitamin K. (58)(60) Clinical findings consist of cephalo- (61) The rarest form, afibrinogenemia, usually manifests dur-
hematoma, umbilical stump bleeding, and ICH with a his- ing infancy, with prolonged bleeding seen after circumcision
tory of medications administered to the pregnant person and bleeding from the umbilical cord. (61)
that reduce the infant’s available vitamin K, such as war- Nearly all instances of afibrinogenemia result from null
farin, anticonvulsants, and antituberculosis medications. mutations in the FGA gene. (62) Although bleeding is the
(58)(60) more common manifestation, thrombosis can also occur
Classic VKDB occurs between 2 and 7 days after birth because of the impaired antithrombin function of fibrin.
and arises from insufficient vitamin K intake in newborns. (61) Hypofibrinogenemia and dysfibrinogenemia disorders
(58)(60) In addition to the impact of medications taken by are associated more commonly with mild bleeding tenden-
the pregnant person, classic VKDB deficiency occurs in in- cies, but most patients are asymptomatic and are inciden-
fants who exclusively drink breast milk, have limited en- tally identified on abnormal screening coagulation tests.
teral intake, and have received inadequate vitamin K (61) Most hypofibrinogenemias are missense mutations
supplementation (ie, zero vitamin K or a single oral dose) found equally in all 3 genes whereas dysfibrinogenemias
at birth. (58) The birth parents of infants with classic are mainly missense mutations in genes FGA and FGG. (61)
VKDB will often have a diet that is low in vitamin K, Fibrinogen concentrate, cryoprecipitate, or fresh-frozen
which occurs in green, leafy vegetables. (60) plasma is most used in patients with afibrinogenemia and
Late VKDB manifests between 2 weeks and 6 months hypofibrinogenemia, whereas antifibrinolytic drugs (ie,
of age with ICH and gastrointestinal and mucocutaneus aminocaproic acid and tranexamic acid) are used more fre-
bleeding. (58)(60) Infants with an exclusive mother’s own quently in dysfibrinogenemia. (61)
milk diet continue to be at higher risk of late VKDB as
well as infants with poor absorption of vitamin K. (60) Plasminogen Activator Inhibitor 1 Deficiency
This includes infants with prolonged diarrhea, liver dis- Plasminogen activator inhibitor 1 (PAI-1) functions as a
ease, pancreatic insufficiency, cystic fibrosis, and biliary urokinase-type plasminogen activator and inhibits tissue-
atresia. (58)(60) Late VKDB has an increased risk in the type plasminogen activator as a protease inhibitor. PAI-1
summer months and in male infants. (58)(60) inhibits fibrinolysis, but when absent or nonfunctional,
A prolonged PT increases suspicion for VKDB, though clots are unstable and prematurely break down. (62)
if the duration is sufficient, aPTT may be increased as Bleeding typically only happens as a result of surgical pro-
well. (60) If both are prolonged, the PT prolongation will cedures or trauma, though it can be serious and life-
be out of proportion to the aPTT. (37)(60) Factor II, VII, threatening, and difficult to predict as PT and aPTT are
IX, and X concentrations will be decreased while platelets normal. (62) Medications like tranexamic acid and amino-
and fibrinogen are normal. (37)(58)(60) Head imaging caproic acid, which inhibit fibrinolysis, are successful in
should be conducted to assess for possible ICH. both treating and preventing instances of bleeding. (62)
Management of the acute complications of VKDB con-
sists of administration of a parenteral dose of vitamin K. α-2 Antiplasmin Deficiency
With adequate treatment, PT and aPTT corrects in 2 to a-2 Antiplasmin (a2-AP) is another protease inhibitor of fibri-
6 hours, which helps to confirm the diagnosis. (60) As nolysis which acts as a primary inhibitor of plasminogen. (2)
prophylaxis, term infants should receive a single dose of Fibrinolysis takes place when activating agents act on plasmin-
0.5 to 1.0 mg of vitamin K whereas preterm infants should ogen to transform it into the active serine protease plasmin,
receive a dose of 0.3 to 0.5 mg/kg if birthweight is below predominantly tissue plasminogen activator. a2-AP deficiency
1,000 g. (58) Oral prophylaxis is less efficacious than intra- is an autosomal recessive condition. (63) Aminocaproic acid
muscular prophylaxis because of lower parental compli- and tranexamic acid, alongside other inhibitors of fibrinolysis,
ance and inconsistent drug absorption. (58) can be beneficial in treatment. (63)

DISORDERS OF FIBRINOLYSIS ACQUIRED COAGULOPATHIES

Qualitative/Quantitative Fibrinogen Disorders Disseminated Intravascular Coagulation
Fibrinogen is a glycoprotein synthesized by the liver and Disseminated intravascular coagulation (DIC) is a multi-
present in the plasma. Rare mutations can lead to either factorial condition involving coagulation and immune and

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 Key
= Acvaon
= Inhibion

Intrinsic Pathway – Acvated Paral Thromboplasn Time (aPTT) Extrinsic Pathway – Prothrombin Time (PT)

CAS External Injury

XII XIIa
TF
XI XIa
Anthrombin VIIa VII

IX IXa X

VIII VIIIa X Xa
XIII
IIa Prothrombin (II) Thrombin (IIa)
XIIIa Crosslinked Fibrin
V Va Fibrinogen (I) Fibrin
(Stable Clot)
Common Pathway – PT and PTT
Protein S IIa
tPA
PAI-1 uPA
Protein C and Acvated TAFIa TAFI
Thrombomodulin Protein C
Plasminogen Plasmin
Alpha2 anplasmin

Figure. The classic coagulation cascade. The intrinsic pathway, which is tested by the aPTT, is encompassed in red, the extrinsic pathway, which is tested
by the PT, is encompassed in green and the common pathway, which affects both PT and aPTT, is encompassed in purple. aPTT5activated partial
thromboplastin time, CAS5contact activation system, composed of prekallikrein, kallikrein, and high-molecular-weight kininogen, PAI-15plasminogen
activator inhibitor 1, PT5prothrombin time, PTT 5 partial thromboplastin time, TAFI5thrombin activatable fibrinolysis inhibitor, TF5tissue factor,
tPA5tissue plasminogen activator, uPA5urokinase plasminogen activator.

inflammatory pathways with excessive thrombin generation. neonates, platelets <100 × 103/mL [100 × 109/L]), decreased
(64) Underlying conditions, including infection, trauma, or natural killer cell function, triglycerides greater than 265 mg/dL
malignancy, trigger hemostatic processes and thrombin gener- (3 mmol/L), ferritin greater than 500 ng/mL (500 mg/L), fibrin-
ation. Thrombin then leads to fibrin formation, involves the ogen less than 15,000 mg/dL (150 g/L), hemophagocytosis, and
fibrinolytic pathway, and depletion of hemostatic factors (pro- soluble IL-2R levels/CD25 levels greater than 2,400 U/mL.
teins C/S, antithrombin) causing small vessel thrombosis and (66) Given that the result of many of these diagnostic tests
organ dysfunction, significant bleeding, and capillary leak, re- take time, clinical judgment is critical. Because of the poor spe-
sulting in third-spacing. (64) As DIC is caused by other un- cificity and sensitivity, the hallmarks of hemophagocytosis are
derlying disease states, the definitive treatment is based on not required to make the diagnosis. Several genetic conditions
the underlying disorder. (65) Supportive care can be offered predispose individuals to HLH, such as familial HLH, pigmen-
with transfusions, through modulating thrombin generation tary disorders, and disorders that increase susceptibility to
(heparin or low-molecular-weight heparin), and with anti- Epstein-Barr virus infection. (67) Management of HLH involves
thrombin/anticoagulant factor concentrates. a combination of immunosuppressive and chemotherapy medi-
cations, along with biological agents, to suppress the cytokine
Hemophagocytic Lymphohistiocytosis storm and target activated T-cells and macrophages. (66)(67)
Hemophagocytic lymphohistiocytosis (HLH) may be caused
by the mutual atypical activation of both type 1 lymphocytes Liver Disease
(ie, natural killer and CD8 cells) and mononuclear phagocytes Liver disease causes changes in all 3 phases of hemostasis
(ie, dendritic cells and macrophages). (66) It consists of a con- (primary and secondary hemostasis and fibrinolysis). (68)
stellation of symptoms, and one must meet 5 of 8 criteria for Portal hypertension can cause congestive splenomegaly
diagnosis. (66) These criteria are both clinical, such as spleno- and sequestration, limiting the number of circulating platelets.
megaly and fever and abnormal laboratory values such as (68) Impairment in hepatic synthesis of thrombopoietin,
cytopenias ($2 lineages; hemoglobin <10 g/dL [100 g/L] in which acts as the main regulator of platelet generation, leads

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 to dysregulation of platelet production. (68) The hepatic pa-
• A comprehensive family and pregnancy history
renchymal cells produce all the necessary factors except for
and physical examination can aid in identifying
FVIII, which is produced by endothelial cells, making the re-
the cause of newborn coagulopathy.
duced production of many factors (II, V, VII, IX, XI, and XIII)
a hallmark of liver disease. (68) Conversely, the liver synthe- • Initial laboratory screening should include a complete
sizes all profibrinolytic and antifibrinolytic proteins, except for blood cell count with differential, PT, aPTT, and
tissue plasminogen activator and PAI-1, which are produced fibrinogen, with additional studies as clinically
by endothelial cells. (68) The homeostasis between bleeding indicated. Abnormalities in the platelet count, PT,
and clotting is therefore even more precarious, and predicting and aPTT will be beneficial in identifying the most
whether a patient will bleed or develop thrombosis is common coagulopathic conditions, though there
challenging. are severe bleeding disorders in which these
laboratory findings are normal.
Vascular Anomalies
• Hematology consultation can be beneficial in
Vascular anomalies encompass a wide range of disorders
assisting with diagnostic evaluation and
marked by atypical development of lymphatic, arterial, ve-
management.
nous, and capillary vessels. In vascular tumors, there is
an abnormal increase in endothelial cell proliferation,
whereas malformations primarily involve normal endothe-
lial cells but display abnormal vessel arrangements. (69)
Kaposiform hemangioendothelioma (KHE) and tufted
angiomas (TA) are benign vascular tumors commonly ob-
served in infancy. KHEs tend to be more locally aggressive
American Board of Pediatrics
and burrow into deeper structures, whereas TAs tend to Neonatal-Perinatal Content
be more superficial (dermis and subcutis). (69) Kasabach- Specifications
Merritt phenomenon (KMP) occurs in roughly 70% of pa- • Know the causes and pathophysiology of neonatal
tients with KHE and 10% to 20% of those with TA. (69) thrombocytopenia and thrombocytosis.
KMP is characterized by thrombocytopenia, low fibrinogen • Know the clinical and laboratory manifestations and
levels, increased D-dimer, and prolonged PT and aPTT. management of neonatal thrombocytopenia and
This is likely caused by platelet entrapment within the ab- thrombocytosis.
normal blood vessels of the tumor, leading to the deple- • Know the inheritance patterns of the common coagu-
lation factor deficiencies.
tion of platelets and coagulation factors. (69)(70) KMP
• Know the causes and pathophysiology of acquired de-
lesions are red/deep purple, warm, tense, and painful.
fects in hemostasis.
Treatment is complete resection if able or with sirolimus,
• Know the clinical and laboratory features and manage-
oral steroids, and vincristine. (70) ment of acquired defects in hemostasis including intra-
Kaposiform lymphangiomatosis is similar to KHE/TA vascular coagulation and hemorrhagic disease of the
but involves lymphatic vasculature and is mainly found in newborn.
the soft tissues, bones, spleen, and thoracic cavity. (71) Ka- • Know the causes and pathophysiology of congenital
posiform lymphangiomatosis typically is severe, presents defects in hemostasis.
early in life, and displays progression. (70)(71) Coagulop- • Know the clinical manifestations, laboratory findings,
athy is akin to KMP and is treated similarly. (71) and management of congenital defects in hemostasis.

Summary
Coagulation disorders in infants can be
References
challenging to diagnose given the physiologic 1. Broos K, Feys HB, De Meyer SF, Vanhoorelbeke K, Deckmyn H.
Platelets at work in primary hemostasis. Blood Rev.
differences in newborns and susceptibility to
2011;25(4):155–167
pregnancy conditions. When concerned about a
2. Chapin JC, Hajjar KA. Fibrinolysis and the control of blood
coagulopathic condition, clinicians should be coagulation. Blood Rev. 2015;29(1):17–24
aware that: 3. Gale AJ. Current understanding of hemostasis. Toxicol Pathol.
2011;39(1):273–280

Vol. 25 No. 11 N O V E M B E R 2 0 2 4 e705

Downloaded from /neoreviews/issue/25/11

by Almoosa Hospital user
 4. Smith SA, Travers RJ, Morrissey JH. How it all starts: Initiation of 25. Bertrand G, Kaplan C. How do we treat fetal and neonatal
the clotting cascade. Crit Rev Biochem Mol Biol. 2015;50(4):326–336 alloimmune thrombocytopenia? Transfusion (Paris).
5. Furie B. Pathogenesis of thrombosis. Hematology Am Soc Hematol 2014;54(7):1698–1703
Educ Program. 2009;2009(1):255–258 26. Gleason CA, Juul SE. Avery’s Diseases of the Newborn. Tenth Edition;
6. Winter WE, Flax SD, Harris NS. Coagulation testing in the Core 2017
Laboratory. Laboratory Med. 2017;48(4):295–313 27. Yamamoto AY, Mussi-Pinhata MM, Marin LJ, Brito RM, Oliveira
7. Wu Y. Contact pathway of coagulation and inflammation. Thromb J. PFC, Coelho TB. Is saliva as reliable as urine for detection of
2015;13:17 cytomegalovirus DNA for neonatal screening of congenital CMV
infection? J Clin Virol. 2006;36(3):228–230
8. Caen J, Wu Q. Hageman factor, platelets and polyphosphates: early
history and recent connection. J Thromb Haemost. 28. Rawlinson WD, Boppana SB, Fowler KB, et al. Congenital
2010;8(8):1670–1674 cytomegalovirus infection in pregnancy and the neonate: consensus
recommendations for prevention, diagnosis, and therapy. Lancet
9. Campbell SE, Bolton-Maggs PHB. Congenital and acquired bleeding
Infect Dis. 2017;17(6):e177–e188
disorders in infancy. Early Hum Dev. 2015;91(11):637–642
29. Hampton MM. Congenital toxoplasmosis: a review. Neonatal Netw.
10. Kenet G, Chan AKC, Soucie JM, Kulkarni R. Bleeding disorders in
2015;34(5):274–278
neonates. Haemophilia. 2010;16(suppl 5):168–175
30. Carellos EVM, de Andrade JQ, Romanelli RMC, et al. UFMG
11. Venkatesh V, Curley A, Khan R, et al. A novel approach to
Congenital Toxoplasmosis Brazilian Group (UFMG-CTBG). High
standardised recording of bleeding in a high risk neonatal
frequency of bone marrow depression during congenital
population. Arch Dis Child Fetal Neonatal Ed. 2013;98(3):F260–263 toxoplasmosis therapy in a cohort of children identified by neonatal
12. Poryo M, Boeckh JC, Gortner L, et al. PROGRESS study consortium screening in Minas Gerais, Brazil. Pediatr Infect Dis J.
and NGFN - Nationales Genomforschungsnetz Deutschland. Ante-, 2017;36(12):1169–1176
peri- and postnatal factors associated with intraventricular 31. Gudeloglu E, Akillioglu M, Bedir Demirdag T, Unal NA, Tapisiz
hemorrhage in very premature infants. Early Hum Dev. 2018;116:1–8 AA. Congenital rubella syndrome: a short report and literature
13. K€
uhne T, Imbach P. Neonatal platelet physiology and review. Trop Doct. 2023;53(1):171–175
pathophysiology. Eur J Pediatr. 1998;157(2):87–94 32. Zinkham WH, Medearis DN, Osborn JE. Blood and bone-marrow
14. Wasiluk A, Mantur M, Kemona H, Szczepa nski M, Jasi
nska E, findings incongenital rubella. J Pediatr. 1967;71(4):512–524
Milewski R. Thrombopoiesis in small for gestational age newborns. 33. Golemba MD, Mecikovsky D, Ortız de Zarate M, et al. Unraveling
Platelets. 2009;20(7):520–524 HIV-1 diagnosis in special pediatric cases. J Clin Virol.
15. Saxonhouse MA, Sola-Visner MC. Thrombocytopenia in the 2020;131:104343
neonatal intensive care unit. Neoreviews. 2009;10(9):e435–e445 34. Diaz C, Hanson C, Cooper ER, et al. Disease progression in a cohort
16. Sola-Visner M. Platelets in the neonatal period: developmental of infants with vertically acquired HIV infection observed from
differences in platelet production, function, and hemostasis and the birth: the Women and Infants Transmission Study (WITS). J Acquir
potential impact of therapies. Hematology Am Soc Hematol Educ Immune Defic Syndr Hum Retrovirol. 1998;18(3):221–228
Program. 2012;2012:506–511 35. Fernandes ND, Arya K, Ward R. Congenital Herpes Simplex. In:
17. Murray NA, Roberts IA. Circulating megakaryocytes and their StatPearls. StatPearls Publishing; 2024. Accessed March 17, 2024.
progenitors in early thrombocytopenia in preterm neonates. Pediatr [Link]
Res. 1996;40(1):112–119 36. Yang J, Zhang H, Niu J, et al. Impact of preeclampsia on
18. Ferrer-Marin F, Liu ZJ, Gutti R, Sola-Visner M. Neonatal megakaryocytopoesis and platelet homeostasis of preterm infants.
thrombocytopenia and megakaryocytopoiesis. Semin Hematol. Platelets. 2016;27(2):123–127
2010;47(3):281–288 37. Martin RJ, Fanaroff AA, Walsh MC. Fanaroff and Martin’s Neonatal-
19. Sciscione AC, Bessos H, Callan N, Blakemore K, Kickler T. Perinatal Medicine. 11th ed. Philadelphia, PA: Elsevier; 2019.
Indicators of platelet turnover in thrombocytopenic infants. Br J 38. Cowan J, Parikh T, Waghela R, et al. Thrombocytopenia with absent
Obstet Gynaecol. 1997;104(6):743–745 radii (TAR) syndrome without significant thrombocytopenia. Cureus.
20. Salama A. Alloimmune thrombocytopenias. J Pediatr Hematol Oncol. 2020;12(9):e10557
2003;25 Suppl 1:S39–41 39. Tirthani E, Said MS, De Jesus O. Amegakaryocytic Thrombocytopenia.
21. Kjeldsen-Kragh J, Killie MK, Tomter G, et al. A screening and In: StatPearls. StatPearls Publishing; 2024. Accessed March 13, 2024.
intervention program aimed to reduce mortality and serious [Link]
morbidity associated with severe neonatal alloimmune 40. Al-Qahtani FS. Congenital amegakaryocytic thrombocytopenia: a
thrombocytopenia. Blood. 2007;110(3):833–839 brief review of the literature. Clin Med Insights Pathol. 2010;3:25–30
22. Ferro M, Macher HC, Fornes G, et al. Noninvasive prenatal 41. Cancio M, Hebert K, Kim S, et al. Outcomes in hematopoietic stem
diagnosis by cell-free DNA screening for fetomaternal HPA-1a cell transplantation for congenital amegakaryocytic thrombocytopenia.
platelet incompatibility. Transfusion (Paris.). 2018;58(10):2272–2279 Transplant Cell Ther. 2022;28(2):101.e1-101–e6
23. Donato H. Neonatal thrombocytopenia: A review. I. Definitions, 42. Malik MA, Masab M. Wiskott-Aldrich Syndrome - StatPearls - NCBI
differential diagnosis, causes, immune thrombocytopenia. Arch Bookshelf. Accessed March 13, 2024. [Link]
Argent Pediatr. 2021;119(3):e202–e214 books/NBK539838/
24. Norton T, Newberry D, Jnah A. Neonatal alloimmune 43. Almomani MH, Mangla A. Bernard-Soulier Syndrome. In:
thrombocytopenia: a concise review. Adv Neonatal Care. StatPearls. StatPearls Publishing; 2024. Accessed March 13, 2024.
2021;21(2):115–121 [Link]

e706 NeoReviews

Downloaded from /neoreviews/issue/25/11

by Almoosa Hospital user
 44. Gunay-Aygun M, Zivony-Elboum Y, Gumruk F, et al. Gray platelet 58. Hand I, Noble L, Abrams SA. Vitamin K and the newborn infant.
syndrome: natural history of a large patient cohort and locus Pediatrics. 2022;149(3):e2021056036
assignment to chromosome 3p. Blood. 2010;116(23):4990–5001 59. Committee on Nutrition. Report of Committee on Nutrition: vitamin
45. Introne WJ, Huizing M, Malicdan MCV, O’Brien KJ, Gahl WA, et al. K compounds and the water-soluble analogues. Pediatrics.
Hermansky-Pudlak Syndrome. In: Adam MP, Feldman J, Mirzaa GM 1961;28(3):501–507
eds. GeneReviewsV
R . University of Washington, Seattle; 1993. Accessed
[Link] S, Shirahata A. Vitamin K deficiency bleeding in infancy.
March 13, 2024. [Link] Nutrients. 2020;12(3):780
46. Echahdi H, El Hasbaoui B, El Khorassani M, Agadr A, Khattab M. 61. Mohsenian S, Palla R, Menegatti M, et al. Congenital fibrinogen
Von Willebrand’s disease: case report and review of literature. Pan disorders: a retrospective clinical and genetic analysis of the
Afr Med J. 2017;27:147 Prospective Rare Bleeding Disorders Database. Blood Adv.
47. Eikenboom JC. Congenital von Willebrand disease type 3: clinical 2024;8(6):1392–1404
manifestations, pathophysiology and molecular biology. Best Pract 62. Fay WP, Parker AC, Condrey LR, Shapiro AD. Human plasminogen
Res Clin Haematol. 2001;14(2):365–379 activator inhibitor-1 (PAI-1) deficiency: characterization of a large kindred
48. Scully M. Congenital TTP: next stop, acuity and therapy. Blood. with a null mutation in the PAI-1 gene. Blood. 1997;90(1):204–208
2021;137(25):3469–3471 63. Carpenter SL, Mathew P. a2-Antiplasmin and its deficiency:
49. Gatseva A, Sin YY, Brezzo G, Van Agtmael T. Basement membrane fibrinolysis out of balance. Haemophilia. 2008;14(6):1250–1254
collagens and disease mechanisms. Essays Biochem. 2019;63(3):297–312 64. Toh CH, Alhamdi Y. Current consideration and management of
50. Key NS, DE Paepe A, Malfait F, Shovlin CL. Vascular haemostasis. disseminated intravascular coagulation. Hematology Am Soc Hematol
Haemophilia. 2010;16 Suppl 5:146–151 Educ Program. 2013;2013(1):286–291
51. Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria 65. Wada H, Thachil J, Di Nisio M, et al. The Scientific Standardization
for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber Committee on DIC of the International Society on Thrombosis
syndrome). Am J Med Genet. 2000;91(1):66–67 Haemostasis. Guidance for diagnosis and treatment of DIC from
52. Soucie JM, Evatt B, Jackson D, The Hemophilia Surveillance System harmonization of the recommendations from three guidelines.
Project Investigators. Occurrence of hemophilia in the United J Thromb Haemost. 2013 Published online February 4
States. Am J Hematol. 1998;59(4):288–294 [Link] JI, Horne A, Arico M, et al. HLH-2004: Diagnostic and
53. Peyvandi F, Garagiola I, Young G. The past and future of therapeutic guidelines for hemophagocytic lymphohistiocytosis.
haemophilia: diagnosis, treatments, and its complications. Lancet. Pediatr Blood Cancer. 2007;48(2):124–131
2016;388(10040):187–197 67. Canna SW, Marsh RA. Pediatric hemophagocytic lymphohistiocytosis.
54. Srivastava A, Santagostino E, Dougall A, et al. WFH Guidelines for Blood. 2020;135(16):1332–1343
the Management of Hemophilia panelists and co-authors. WFH 68. Kujovich JL. Coagulopathy in liver disease: a balancing act.
Guidelines for the management of hemophilia, 3rd edition. Hematology Am Soc Hematol Educ Program. 2015;2015(1):243–249
Haemophilia. 2020;26 Suppl 6:1–158 [Link] KW, Brand~ao LR. Coagulation issues in vascular anomalies.
55. Pelcovits A, Schiffman F, Niroula R. Factor XIII deficiency: A review Semin Pediatr Surg. 2020;29(5):150966
of clinical presentation and management. Hematol Oncol Clin North 70. Adams DM, Brand~ao LR, Peterman CM, et al. Vascular anomaly
Am. 2021;35(6):1171–1180 cases for the pediatric hematologist oncologists—An
56. Hsieh L, Nugent D. Factor XIII deficiency. Haemophilia. 2008;14(6): interdisciplinary review. Pediatr Blood Cancer. 2018;65(1):e26716
1190–1200 71. Croteau SE, Kozakewich HPW, Perez-Atayde AR, et al. Kaposiform
57. Karimi M, Peyvandi F, Naderi M, Shapiro A. Factor XIII deficiency lymphangiomatosis: a distinct aggressive lymphatic anomaly. J Pediatr.
diagnosis: Challenges and tools. Int J Laboratory Hematol. 2018;40(1):3–11 2014;164(2):383–388

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 NEOREVIEWS QUIZ

NEO
QUIZ
1. Coagulation factors are developmentally regulated and neonates, particularly
those born preterm, are at increased risk of bleeding. While multiple
coagulation factor levels are decreased in neonates, some are within normal
range or increased. Which of the following coagulation factors is increased in
neonates compared to adults and children?

A. Factor II.
B. Von Willebrand factor.
C. Factor VIII.
D. Protein C.
E. Antithrombin.
2. Coagulation disorders are classified as disorders of primary hemostasis, disorders REQUIREMENTS: Learners can
of secondary hemostasis, or disorders of the fibrinolytic system. Neonatal take NeoReviews quizzes and
alloimmune thrombocytopenia (NAIT) is a disorder of primary hemostasis caused claim credit online only at:
by the transplacental transfer of platelet-specific antibodies or human leukocyte [Link]
antigen antibodies. NAIT occurs in approximately 1 in 1,000 births and presents neoreviews.
with thrombocytopenia within 48 hours of birth. NAIT is an important diagnosis
To successfully complete 2024
that must not be missed because subsequent pregnancies will need to be closely
NeoReviews articles for AMA PRA
monitored for recurrence. What is the projected risk of NAIT recurrence in a
Category 1 Credit™, learners
subsequent pregnancy? must demonstrate a minimum
A. 40%. performance level of 60% or
higher on this assessment. If
B. 50%.
you score less than 60% on the
C. 60%. assessment, you will be given
D. 70%. additional opportunities to
E. 80%. answer questions until an
overall 60% or greater score is
3. A term male neonate has prolonged bleeding after a circumcision. He was achieved.
born after an uncomplicated pregnancy via cesarean section for breech
presentation. He received 1 dose of intramuscular vitamin K at birth. His This journal-based CME activity
laboratory evaluation reveals a prolonged activated partial thrombin time is available through Dec. 31,
(aPTT) with normal prothrombin time (PT) and platelet count. Which of the 2026, however, credit will be
recorded in the year in which
following diagnoses is most consistent with this clinical presentation?
the learner completes the quiz.
A. Factor VIII deficiency.
B. Von Willebrand disease.
C. Bernard-Soulier syndrome.
D. Glanzmann thrombasthenia.
E. Factor XIII deficiency.
2024 NeoReviews is approved
4. A 3-day-old exclusively breastfed neonate born at 41 weeks’ gestation develops
for a total of 10 Maintenance of
irritability and altered mental status. He was born at home via uncomplicated vaginal Certification (MOC) Part 2
delivery after an uncomplicated pregnancy. Brain imaging reveals the presence of an credits by the American Board
intracranial hemorrhage and you suspect classic vitamin K deficiency bleeding of Pediatrics (ABP) through the
disorder (VKDB). Which of the following statements regarding VKDB is CORRECT? AAP MOC Portfolio Program.
NeoReviews subscribers can
A. Classic VKDB presents between 3 and 21 days after birth. claim up to 10 ABP MOC Part 2
B. The presence of prolonged aPTT and normal PT on laboratory evaluations is points upon passing 10 quizzes
consistent with the diagnosis of VKDB. (and claiming full credit for
C. Correction of coagulation test abnormalities within 2 to 6 hours of each quiz) per year. Subscribers
can start claiming MOC credits
vitamin K administration helps confirm the diagnosis.
as early as October 2024. To
D. Classic VKDB more commonly occurs in males and during the winter months. learn how to claim MOC points,
E. Late VKDB is characterized by spontaneous muscle hemorrhage, particularly go to: [Link]
of the lower extremities. org/journals/pages/moc-credit.

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 5. Liver disease can be associated with abnormalities in all 3 phases of
hemostasis including primary and secondary hemostasis as well as
fibrinolysis. All of the following factors are produced by the liver EXCEPT:
A. Factor XIII.
B. Factor VII.
C. Factor II.
D. Factor VIII.
E. Factor IX.

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 ARTICLE

Thrombotic Disorders in the Newborn

Karyssa Knopoff, MD,* Lorena Ostilla, MD,† Perry Morocco, MD,* Patrick Myers, MD†
*Section of Pediatric Hematology, Oncology and Stem Cell Transplant, Department of Pediatrics, University of Chicago, Chicago, IL
†
Section of Neonatology, Department of Pediatrics, Northwestern University, Chicago, IL

EDUCATION GAP

Thrombus formation is common in neonates and can arise from both

congenital and acquired causes, ranging from genetic abnormalities to
indwelling catheters. Given this, neonatologists need to be able to identify
when a thrombus is provoked, or when additional work is required, and
how best to treat it.

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

1. Recognize which common coagulation abnormalities correspond to

patterns of laboratory tests.
2. Recognize the common congenital conditions that place infants at risk
for venous thromboembolism.
3. Identify the risk factors for an acquired venous thromboembolism.

ABSTRACT
The coagulation and thrombotic systems of an infant are fundamentally
AUTHOR DISCLOSURES Dr Myers serves different from those of adults and older children. Hemostatic factors have
on the executive committee for the
inherently lower circulation levels in infants and are also affected prenatally
Council of Pediatric Sub-Specialists and
has served as chair of the Organization of by conditions of pregnancy. The unique physiology of neonates can
Neonatal Training Program Directors. Drs contribute to a procoagulant state, which can result in a high level of
Ostilla, Knopoff, and Morocco have morbidity and mortality. This review outlines the epidemiology, clinical
disclosed no financial relationships
relevant to this article. This article does characteristics, diagnosis and management, and etiologies of congenital
not contain a discussion of an and acquired forms of thrombotic disorders, with a discussion of the
unapproved/investigative use of a evaluation for hypercoagulation.
commercial product/device.

ABBREVIATIONS

aPL antiphospholipid
The coagulation system involves a careful biological balancing act between co-
aPTT activated partial thromboplastin
time agulation and thrombosis, with a visual representation of the coagulation cas-
AT antithrombin cade and the main pathways involved (Fig 1). (1) The figure shows the pathways
CVL central venous line
and associated coagulation tests that clinicians can use to assist in identifying a
DVT deep vein thrombosis
LMWH low molecular weight heparin coagulopathy or a procoagulant state. Primary and secondary hemostasis involve
PT prothrombin time platelet aggregation and insoluble fibrin deposition, respectively, which in turn
UAC umbilical artery catheter
leads to a mature thrombus at the site of an injury or in response to an insult.
UFH unfractionated heparin
UVC umbilical vein catheter (2)(3)(4) A disruption in these pathways can lead to a procoagulant state, in
VTE venous thromboembolism which hemostasis is shifted toward coagulation and thrombus formation, and

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 The classical coagulation cascade.
Key
= Acvaon
= Inhibion

Intrinsic Pathway – Acvated Paral Thromboplasn Time (aPTT) Extrinsic Pathway – Prothrombin Time (PT)

CAS External Injury

XII XIIa
TF
XI XIa
Anthrombin VIIa VII

IX IXa X

VIII VIIIa X Xa
XIII
IIa Prothrombin (II) Thrombin (IIa)
XIIIa Crosslinked Fibrin
V Va Fibrinogen (I) Fibrin
(Stable Clot)
Common Pathway – PT and PTT
Protein S IIa
tPA
PAI-1 uPA
Protein C and Acvated TAFIa TAFI
Thrombomodulin Protein C
Plasminogen Plasmin
Alpha2 anplasmin

Figure 1. The classic coagulation cascade. The intrinsic pathway, which is tested by the aPTT, is encompassed in red; the extrinsic pathway, which is
tested by the PT, is encompassed in green; and the common pathway, which affects both PT and aPTT, is encompassed in purple. aPTT5activated partial
thromboplastin time, CAS5contact activation system, composed of prekallikrein, kallikrein, and high-molecular-weight kininogen, PAI-15plasminogen activator
inhibitor 1, PT5prothrombin time, PTT5partial thromboplastin time, TAFI5thrombin activatable fibrinolysis inhibitor, TF5tissue factor, tPA5tissue
plasminogen activator, uPA5urokinase plasminogen activator. (Reprinted with permission from Ostilla L, Knopoff K, Myers P, Morocco P. Disorders of
coagulation in the newborn. NeoReviews. 2024;25(11):e694.

arise via either a congenital or an acquired cause, such as among others. These proteins exist on the other end of
a line-associated deep vein thrombosis (DVT). the coagulation cascade, working to block thrombus for-
mation. Protein C and protein S are vitamin K–dependent
HEMOSTASIS OVERVIEW glycoproteins that work to inactivate activated factor V and
The first step in thrombosis involves primary hemostasis, in
which platelets bind to the exposed matrix of collagen and
von Willebrand factor at sites of vessel injury. (2) These pla-
telets are then activated, causing aggregation and the initial
platelet plug, which combines with insoluble fibrin gener-
ated by secondary hemostasis, or the coagulation cascade
(Fig 2). (2)(4)(5)(6) These steps lead to a stable thrombus,
which is resistant to degradation. The 2 main pathways of
secondary hemostasis, intrinsic and extrinsic, converge on
the common pathway, and are represented by the prothrom-
bin test (PT; encompasses extrinsic and common pathway)
and the activated partial thromboplastin time (aPTT; encom-
passes the intrinsic and common pathway). (7) Once the
thrombus is formed, the fibrinolytic system works to eventu-
ally dissolve the thrombus after the vessel endothelium has
recovered from its injury. (3)
The body contains its own natural anticoagulants in the
form of protein C, protein S, and antithrombin (AT), Figure 2. Overview of the infant’s response to vascular injury.

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 Table. Overview, Management, and Key Points for Thrombotic Disorders in Infants
DISEASE/DISORDER TAKE HOME POINTS MANAGEMENT, IF APPLICABLE
AT deficiency Autosomal dominant Factor Xa inhibitors
Venous and/or arterial thrombosis resistant to heparin AT replacement
treatment
Diagnosis made through qualitative functional AT assays
Protein C/S deficiency Autosomal dominant Protein C replacement (FFP or Protein C
Disseminated intravascular coagulation and neonatal concentrate)
purpura fulminans shortly after birth if homozygous Protein S treated with anticoagulation
or compound heterozygous
Diagnosis by plasma levels or functional assays
Factor V Leiden Autosomal recessive
The most common genetic risk factor for thrombosis
Diagnosis by activated protein C resistance and direct
gene analysis testing
Prothrombin G20210A mutation Arterial thrombus and central nervous system
thrombosis seen in children <2yo
Thrombocytosis Primary–genetic mutation induces megakaryocytic Secondary – benign, usually resolves
hyperplasia; rare spontaneously
Secondary – infection, inflammation, anemia; related to
thrombopoietin produced by the liver in times of stress
Indwelling catheters Most common cause of acquired thrombosis in Short-term anticoagulation prior to line
neonates removal, treatment course varying from
Higher risk with larger lumens, multiple lumens, femoral 6 wk 3 mo with repeat imaging
insertion sites, and temporary lines (peripherally
inserted central catheter > port)
Nephrotic syndrome Hypercoagulability related to hypovolemia and Anticoagulation (LMWH) for thrombus and
hemoconcentration future prophylactic anticoagulation
Urinary loss of anti-thrombotic proteins and increased during flares
platelet activation
Antiphospholipid syndrome Antibody-mediated hypercoagulability Anticoagulation for 3 mo or longer with
Venous and arterial thrombosis ongoing risk factors
Confirmatory testing done 12 wk after suspicion/outside
of illness
Prolonged PTT without bleeding symptoms and does
not correct with mixing study
Lupus anticoagulant stronger indicator of thrombotic
potential

AT5antithrombin, FFP5fresh-frozen plasma, LMWH, low-molecular-weight heparin, PTT5partial thromboplastin time.

factor VIII. (3) AT is another important part of coagula- factors for UVC-associated thrombi include blood trans-
tion, a serine protease with the ability to inactivate factor fusions, malposition of the UVC, increased duration of
IXa/Xa and thrombin (factor IIa). (4) catheter placement, maternal diabetes, sepsis, necrotizing
enterocolitis, family history of thrombus, and congenital
EPIDEMIOLOGY heart disease. (12)(13) UAC-associated thrombi are more
Thrombus formation is relatively common in infants in likely to occur in premature infants, with increased dura-
the NICU with the Pediatric Health Information System tion of catheter placement, sepsis, and perinatal asphyxia.
reporting that neonates had the second highest rate of ve- (13) However, thrombi can also develop in the absence of
nous thromboembolism (VTE) in admitted pediatric pa- a UVC or UAC; renal vein thrombi are the most common
tients, at 75 per 10,000 admissions in 2007, only behind type that accounts for about 10% of thrombotic events in
adolescents. (8) This number has only increased since the neonatal period. (9)(14)
2001, when there were only 44 per 10,000 admissions in
infants less than 28 days old, likely because of increased EVALUATION FOR HYPERCOAGULATION
survival among critically ill neonates and their increasing When there are concerns for a prothrombotic condition, he-
complexity. (8) In infants, an estimated 90% of throm- matology consultation is recommended to aid in diagnosis
botic incidents are linked to the use of a venous or arterial and management with an overview provided in the Table.
access device, with an umbilical vein catheter (UVC) con- The most important aspects of the initial diagnostic evaluation
ferring a 12% to 21% risk of thrombosis and an umbilical are family and personal history of thrombosis, thrombus type,
artery catheter (UAC) a 12% to 35% risk. (9)(10)(11) Risk and location, and whether the thrombus could be considered

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 provoked or unprovoked in the current clinical setting. Risk thrombosis, renal vein thrombosis, and cerebral vessel
factors, such as those described later in this review, help guide thrombosis, which can occur prenatally. (23) If the diagno-
the decision to a hypercoagulation evaluation for a congenital sis is suspected, protein levels can be measured in the
cause contributing to the thrombus. This initial laboratory test- plasma or via functional assays. (23)(24) It is important to
ing typically includes evaluation for deficiency in AT, protein C, take into consideration that in preterm, small-for-gestational-
and protein S, along with factor V Leiden and prothrombin age infants and infants of diabetic mothers, serum protein C
G20210A mutation analysis, and antiphospholipid antibod- levels are lower than those of adults. (25)
ies, including lupus anticoagulant. (15) Additional testing of Management of affected infants includes protein C re-
factor VIII levels, lipoprotein(a), and homocysteine can also placement therapy with plasma-derived viral inactivated
be considered, because all of these may lead to a higher protein C concentrate or fresh-frozen plasma if replace-
likelihood of thrombosis. (16) ment is unavailable. Protein S deficiency is treated via anti-
coagulation. (22) In the event of purpura fulminans or
CONGENITAL THROMBOTIC DISORDERS large vessel thrombosis, unfractionated heparin (UFH) or
AT Deficiency low-molecular-weight heparin (LMWH) can be used with
AT deficiency has an autosomal dominant pattern of in- caution. (22)
heritance. (17) AT is an endogenous anticoagulant, and its
shortage leads to the most severe type of thrombophilia, Factor V Leiden
with a 300-fold increase in risk of VTE compared with the Factor V Leiden thrombophilia is an autosomal recessive
normal population. (17) AT functions to inhibit thrombin condition leading to hypercoagulation and elevated throm-
(factor IIa), activated factor X (Xa), factor IXa, and other bosis risk. It is the most common genetic risk factor for
serine proteases. (18) Symptoms include unexplained and VTE and the homozygous mutation occurs in 1 in 5000
recurrent venous and/or arterial thromboembolism, which individuals of Caucasian origin where it is most common
are highly resistant to heparin treatment, DVT, pulmonary
compared with other ethnic groups. (26)(27) The mutation
embolism, and other hypercoagulable events that can
is defined by an inadequate anticoagulant response to acti-
manifest after trauma, shock, sepsis, critical care admis-
vated protein C and symptoms include recurrent and/or
sion, or surgical procedures. (19)
unprovoked DVT, pulmonary emboli, and Budd-Chiari
Diagnosis is difficult in the neonate as the mean AT-III
syndrome. (26)(28) Budd-Chiari syndrome arises from a
levels in term newborns are 56% of those in the adult,
thrombosis causing blockage of the hepatic veins, and fac-
and even lower in premature infants. (20) A thorough ex-
tor V Leiden testing should be sent on any neonate who
amination of family medical records along with quantita-
presents with, or develops this condition. (29)
tive laboratory functional tests can be conducted to help
Diagnosis of factor V Leiden requires testing for acti-
with diagnosis. Laboratory testing is done to assess plasma
vated protein C resistance as well as direct DNA analysis
AT’s capability to inhibit the chromogenic activity of exog-
of the gene F5, which codes for factor V, to identify a mu-
enous factor IIa or factor Xa. (20)(21) These tests lack sen-
tation. Management depends on clinical manifestations
sitivity to detect mild forms of the disease and formal
and is treated according to standard guidelines with UFH
diagnosis is made through qualitative functional AT assays
or LMWH. (26)
that are best performed after recovery from clinical illness.
(21) Treatment of symptomatic infants includes AT-III re-
placement, factor Xa inhibitors (such as rivaroxaban or Prothrombin G20210A Mutation
apixaban), and AT replacement products in patients with The prothrombin G20210A mutation is another well-
severely low AT levels. (21) described cause of thrombosis, and can result in arterial
thrombosis and central nervous system thrombosis in
Protein C and S Deficiency children younger than 2 years. (30) With increased levels
Both protein C and protein S deficiencies are autosomal of prothrombin, about 133% of normal, this mutation con-
dominant conditions with varying degrees of penetrance. tributes to thrombotic risk. (30)(31) Like factor V Leiden,
(22) If homozygous or compound heterozygous, both con- the mutation is seen most commonly in white popula-
ditions will show symptoms of disseminated intravascular tions, in whom it is found in 3% to 17% of patients with
coagulation and neonatal purpura fulminans shortly after VTE. (31) Although most patients are heterozygous car-
delivery. (22)(23) Other manifestations include retinal riers, in very rare instances a patient can be homozygous

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 for the mutation, which seems to increase the likelihood function despite high circulating platelet counts, and have a
of thrombosis. (30)(32) low risk of thrombotic complications (4%). (35)(39)
The mutation can cause venous or arterial thrombosis,
but in patients younger than 2 years, arterial thrombosis is ACQUIRED THROMBOTIC DISORDERS
more common, especially in neonates. (30) In any neonate Indwelling Catheters
with an unprovoked arterial thrombus, or finding of a central Thrombosis associated with central venous lines (CVLs) is
nervous system thrombus, prothrombin gene analysis should “classified into three types: pericatheter sheath, thrombotic
be performed to evaluate for the mutation. (30) occlusion of the catheter lumen, and mural thrombosis, ei-
ther superficial or deep vein.” (40) In neonates, these
THROMBOCYTOSIS CVLs are in the form of UVCs/UACs, peripherally in-
Thrombocytosis, or increased platelet production, can be serted central catheter lines, and Hickman catheters (eg,
defined as either a primary or secondary process with sec- Broviacs).
ondary (reactive) thrombocytosis being more common Thromboses can begin forming within hours of line in-
among infants. (33) Sick infants face an increased risk of sertion due to venous injury activating coagulation cas-
complications due to thrombocytosis because of their in- cades, fibrin deposition on foreign catheter material, and
herently low AT, protein C, and protein S levels as well as almost immediate regrowth of surrounding endothelial
the smaller diameter of their blood vessels. (30) A family and smooth muscle cells. (40) Blood flow can be de-
history of thrombotic events should be evaluated in any in- creased up to 60% around lines, which disrupts laminar
fant with an unexplained thrombotic event. flow and then causes additional adhesion of coagulation
Secondary thrombocytosis is a reactive process in which factors and platelets around the catheter itself. (40) The
infection, inflammation, or anemia causes an increase in risk for thromboses is greater in newborns compared with
an infant’s platelet production. Reactive thrombocytosis is other populations because of their small vessel size and
more common among preterm infants, is generally be- immaturity of their clotting mechanisms especially in the
nign, and resolves spontaneously. (34) Thrombopoietin is face of hemostatic imbalance caused by fluid status, con-
the growth factor responsible for platelet production and genital heart disease, or hypoxia. (41)
is produced primarily by the liver. During times of stress Known patient-related risk factors for line-associated
or infection, hepatic thrombopoietin increases in response clots are malignancy, previous history of thrombosis, and
to inflammatory interleukins, driving the reactive throm- systemic infection. (9)(10)(11)(13)(40)(41) Risk factors asso-
bocytosis commonly observed. (35) ciated with the line itself are related to type/lumen size,
Primary thrombocytosis is uncommon and arises from access location, and time from insertion. Higher risk is
a genetic mutation that induces hyperplasia of megakaryocytes conveyed to larger diameter of the catheter, multilumen
in the bone marrow. (36) Unlike reactive thrombocytosis, pri- lines, temporary lines (peripherally inserted central cathe-
mary thrombocytosis can lead to arterial thrombosis and ters more than ports), and femoral insertion sites. (40)
myocardial infarctions, though affected patients are typically Long-term total parenteral nutrition as well as hyperosmo-
asymptomatic. (35) Patients with chronic myeloproliferative lar solutions convey a higher risk of thrombosis due to
neoplasm essential thrombocythemia present with an in- catheter-induced occlusion of vessels and increased risk of
creased platelet count; this condition is extremely rare with a endothelial vessel damage. (41)
global incidence of 0.6 per 100,000 patients per year in pe- Frequently, in neonates, UFH infusions are started
diatric patients. (37) Diagnosis is challenging and is based on alongside CVL insertion to allow infants to complete their
the World Health Organization 2016 criteria that requires a needed treatments (antibiotics, parenteral nutrition, etc).
combination of thrombocytosis (platelet count $450 × 103/mL However, these infusions do not decrease the rate of
[450 × 109/L]); bone marrow with megakaryocyte prolifera- thrombosis but rather reduce occlusion. (41)
tion; a JAK2, CALR, or MPL gene mutation; and lack of crite- Although most thromboses related to catheter events
ria to diagnose chronic myeloid leukemia, other chronic are asymptomatic, clinical manifestations include edema
myeloproliferative neoplasms (such as polycythemia vera), (localized or including surrounding areas/drainage path-
myelodysplastic syndromes, or a myeloid malignancy. (38) ways), erythema, and pain/tenderness. The primary treat-
This must all occur in the absence of reactive thrombocyto- ment approach involves anticoagulation, and the decision
sis. (38) Pediatric patients with essential thrombocythemia to remove the CVL is made on an individual basis. Short-
may experience minor hemorrhage because of poor platelet term anticoagulation is recommended before line removal.

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 (41) Thromboses in an artery should prompt removal of antibodies alone is insufficient for the diagnosis of aPL syn-
the line and initiation of LMWH or UFH for at least 10 days. drome, and patients with aPL antibodies require another in-
(41) Provoked VTEs are treated for 6 weeks to 3 months with sult, such as trauma or a congenital prothrombotic disorder,
anticoagulation and reimaged before discontinuing therapy to for thrombus formation to occur. (48) Primary aPL syndrome
ensure that the thrombosis has completely resolved, or be- occurs without any associated disease, whereas secondary
come chronic. (40) Goal anti–factor Xa levels of 0.5 to aPL syndrome is associated with another condition, such
1.0 IU/mL when using LMWH and 0.35 to 0.7 IU/mL if us- as systemic lupus erythematosus or another autoimmune
ing UFH. Of note, neonates require higher doses of enoxa- condition. (48)
parin, in the range of 1.7 to 2.0 mg/kg every 23 hours, aPL antibodies bind and activate endothelial cells, neu-
because of the lower levels of AT and large volume of distri- trophils, and platelets, resulting in proinflammatory cyto-
bution. (41)(42) kines and complement activation. (48) They also interfere
with anticoagulant pathways including fibrinolysis by in-
Nephrotic Syndrome hibiting protein C and inhibiting b2GPI, which normally
Patients diagnosed with nephrotic syndrome are at in- blocks factor Xa formation, thrombin activation, and plate-
creased risk for thrombosis (2%–3%), particularly DVTs let aggregation. (48) The summation of these effects re-
and renal vein thrombosis. (43) Hypercoagulability stems sults in a prothrombotic state, and an increased risk of
from thrombocytosis arising from hypovolemia and hemo- stroke is seen more often in pediatric cases compared
concentration; increased platelet activation; urinary losses with adult cases, where there is typically an underlying au-
of AT; deficiency of protein C, protein S, and plasmino- toimmune condition and more VTE events. (49) Lupus
gen; and increased levels of fibrinogen and factors V and
anticoagulant is the stronger indicator of thrombotic po-
VIII caused by dysregulated compensatory protein synthe-
tential compared with anticardiolipin antibody, which does
sis. (43) Congenital nephrotic syndrome is rare and is
not appear to confer thrombotic risk, but triple-positive
most commonly found in infants of Finnish descent, with
aPL syndrome has the highest risk. (47)(48) aPL syndrome
an incidence of 1 in 8,200 live births. (44)
in pregnant persons can result in the transfer of these
Anticoagulation is usually initiated with LMWH in re-
antibodies to the fetus via the placenta, but this does not
sponse to a thrombus, as it has more predictable pharmaco-
appear to result in perinatal thrombosis. (50)
kinetics and there is no need for intravenous access. (43)
After a thromboembolic event in the setting of positive
UFH can be used if there is a need for quick reversal or tight
aPL, anticoagulation is recommended for at least 3 months
titration. (43) Anticoagulation at prophylactic doses should
or longer if there is an ongoing risk factor. (45) If there
then be used when patients have flares of nephrotic syn-
are recurrent episodes of thromboembolism, anticoagula-
drome, to prevent further thrombotic events. (45)
tion is advised for as long as the risk factor is present. (45)

Antiphospholipid Syndrome
Antiphospholipid (aPL) syndrome is an antibody-mediated
hypercoagulability with repeated venous and/or arterial Summary
thrombotic events, along with other hematologic manifesta-
tions, including thrombocytopenia and/or hemolytic anemia. Thrombophilia is common in infants, especially
(46) aPL antibodies are a diverse set of immunoglobulins tar- neonates hospitalized in the NICU, which confers
geting proteins that bind to phospholipids; common screening additional morbidity and mortality. Clinicians
aPL assays include anticardiolipin antibody, anti-b2 glycopro- caring for such patients should be aware that:
tein, and lupus anticoagulant. (47) Because in some instances • Hypercoagulability testing may not be indicated
aPL syndrome can be a transient phenomenon in reaction to based on the clinical scenario surrounding the
infection, underlying autoimmune disorders, medications, diagnosis of an acute thrombus.
and/or malignancy, initial testing is done at the time of the
• CVLs are the most common cause of thrombosis
event, and repeat confirmatory testing is completed 12 weeks
in neonates, but congenital and other acquired
or more later. (46) A prolonged aPTT in the absence of bleed-
prothrombotic states contribute to a small subset
ing symptoms or a bleeding history could be from positive
of arterial or venous thromboembolism.
aPL antibodies, which can be confirmed if an aPTT mixing
study does not appropriately correct. The presence of aPL

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 catheter thrombosis: diagnosis, management and outcome. Blood
American Board of Pediatrics Coagul Fibrinolysis Int J Haemost Thromb. 2014;25(2):97–106
13. Gibson K, Sharp R, Ullman A, Morris S, Kleidon T, Esterman A.
Neonatal-Perinatal Content Risk factors for umbilical vascular catheter-related adverse events:
Specifications a scoping review. Aust Crit Care. 2022;35(1):89–101
• Know the causes and pathophysiology of congenital 14. Bacciedoni V, Attie M, Donato H, Comit
e Nacional de Hematolog
ıa,
and acquired thrombotic disorders. Oncolog
ıa y medicina transfusional. Thrombosis in newborn infants.
Arch Argent Pediatr. 2016;114(2):159–166
• Know the clinical and laboratory features, manage-
ment, and potential adverse effects of treatment of 15. Middeldorp S, Nieuwlaat R, Baumann Kreuziger L, et al. American
congenital and acquired thrombotic disorders. Society of Hematology 2023 guidelines for management of venous
thromboembolism: thrombophilia testing. Blood Adv. 2023;7(22):
• Know the causes and pathophysiology of acquired de-
7101–7138
fects in hemostasis.
16. Raffini L, Thornburg C. Testing children for inherited thrombophilia:
• Know the clinical and laboratory features and manage-
more questions than answers. Br J Haematol. 2009;147(3):277–288
ment of acquired defects in hemostasis including intra-
vascular coagulation and hemorrhagic disease of the 17. de la Morena-Barrio B, Orlando C, de la Morena-Barrio ME, Vicente
V, Jochmans K, Corral J. Incidence and features of thrombosis in
newborn.
children with inherited antithrombin deficiency. Haematologica.
• Know the causes and pathophysiology of congenital
2019;104(12):2512–2518
defects in hemostasis.
18. Bianchini EP. Antithrombin deficiency: no sugar, no diagnosis!. Blood.
• Know the clinical manifestations, laboratory findings,
2022;140(2):83–85
and management of congenital defects in hemostasis.
19. Ehrhardt JD, Boneva D, McKenney M, Elkbuli A. Antithrombin
• Know the pathogenesis and complications of catheter-
deficiency in trauma and surgical critical care. J Surg Res. 2020;
related thrombi including umbilical arterial and central
256:536–542
venous catheters.
20. Seguin J, Weatherstone K, Nankervis C. Inherited antithrombin III
deficiency in the neonate. Arch Pediatr Adolesc Med. 1994;148(4):
389–393
21. Smith N, Warren BB, Smith J, et al. Antithrombin deficiency: a pediatric
disorder. Thromb Res. 2021;202:45–51
References 22. Wypasek E, Undas A. Protein C and protein S deficiency: practical
1. Ostilla L, Knopoff K, Myers P, Morocco P. Disorders of coagulation diagnostic issues. Adv Clin Exp Med Off Organ Wroclaw Med Univ.
in the newborn. NeoReviews. 2024;25(11):e694 2013;22(4):459–467
2. Broos K, Feys HB, De Meyer SF, Vanhoorelbeke K, Deckmyn H. 23. Minford A, Brand~ao LR, Othman M, et al. Diagnosis and management
Platelets at work in primary hemostasis. Blood Rev. 2011;25(4): of severe congenital protein C deficiency (SCPCD): communication
155–167 from the SSC of the ISTH. J Thromb Haemost. 2022;20(7):1735–1743
3. Chapin JC, Hajjar KA. Fibrinolysis and the control of blood coagulation. 24. Hepner M, Protein KV. Protein S. Methods Mol Biol. 2013;992:
Blood Rev. 2015;29(1):17–24 373–381 doi: 10.1007/978-1-62703-339-8_30 PMID: 23546730
4. Gale AJ. Current Understanding of Hemostasis. Toxicol Pathol. 25. Campbell SE, Bolton-Maggs PHB. Congenital and acquired bleeding
2011;39(1):273–280 disorders in infancy. Early Hum Dev. 2015;91(11):637–642
5. Smith SA, Travers RJ, Morrissey JH. How it all starts: Initiation of 26. Kujovich JL. Factor V Leiden thrombophilia. Genet Med. 2011;13(1):1–16
the clotting cascade. Crit Rev Biochem Mol Biol. 2015;50(4):326–336 27. Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic
6. Furie B. Pathogenesis of thrombosis. Hematology Am Soc Hematol distribution of factor V Leiden in 4047 men and women. Implications
Educ Program. 2009;2009(1):255–258 for venous thromboembolism screening. JAMA. 1997;277(16):1305–1307
7. Winter WE, Flax SD, Harris NS. Coagulation testing in the core 28. Piersigilli F, Auriti C, Seganti G. Budd–Chiari syndrome and factor
laboratory. Laboratory Med. 2017;48(4):295–313 V Leiden in a neonate. N Engl J Med. 2006;355(5):527–528
8. Raffini L, Huang YS, Witmer C, Feudtner C. Dramatic increase in 29. Zhang P, Zhang J, Sun G, et al. Risk of Budd-Chiari syndrome
venous thromboembolism in children’s hospitals in the United associated with factor V Leiden and G20210A prothrombin mutation:
States from 2001 to 2007. Pediatrics. 2009;124(4):1001–1008 a meta-analysis. PLoS One. 2014;9(4):e95719
9. Greenway A, Massicotte MP, Monagle P. Neonatal thrombosis and 30. Young G, Manco-Johnson M, Gill JC, et al. Clinical manifestations
its treatment. Blood Rev. 2004;18(2):75–84 of the prothrombin G20210A mutation in children: a pediatric
10. Bersani I, Piersigilli F, Iacona G, et al. Incidence of umbilical vein coagulation consortium study. J Thromb Haemost. 2003;1(5):
catheter-associated thrombosis of the portal system: A systematic 958–962
review and meta-analysis. World J Hepatol. 2021;13(11):1802–1815 31. Jadaon MM. Epidemiology of Prothrombin G20210A mutation in
11. Hwang JH, Chung ML, Lim YJ. Incidence and risk factors of the Mediterranean region. Mediterr J Hematol Infect Dis. 2011;3(1):
subclinical umbilical catheter-related thrombosis in neonates. e2011054
Thromb Res. 2020;194:21–25 32. Bosler D, Mattson J, Crisan D. Phenotypic heterogeneity in patients
12. Park CK, Paes BA, Nagel K, Chan AK, Murthy P. Thrombosis and with homozygous prothrombin 20210AA genotype. J Mol Diagn.
Hemostasis in Newborns (THiN) Group. Neonatal central venous 2006;8(4):420–425

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 33. Gleason CA, Juul SE. Avery’s Diseases of the Newborn. 10th ed; 42. Malowany JI, Knoppert DC, Chan AKC, Pepelassis D, Lee DSC.
Philadelphia, PA: Elsevier; 2017 Enoxaparin use in the neonatal intensive care unit: experience over
34. Martin RJ, Fanaroff AA, Walsh MC. Fanaroff and Martin’s Neonatal- 8 years. Pharmacotherapy. 2007;27(9):1263–1271
Perinatal Medicine. 11th ed. Philadelphia, PA: Elsevier; 2019 43. Kerlin BA, Haworth K, Smoyer WE. Venous thromboembolism in
pediatric nephrotic syndrome. Pediatr Nephrol. 2014;29(6):989–997
35. Putti MC, Bertozzi I, Randi ML. Essential thrombocythemia in
children and adolescents. Cancers (Basel). 2021;13(23):6147 44. Rheault MN. Nephrotic and nephritic syndrome in the newborn.
Clin Perinatol. 2014;41(3):605–618
36. Jeon GW. Pathophysiology, classification, and complications of
common asymptomatic thrombocytosis in newborn infants. Clin 45. Monagle P, Chan AKC, Goldenberg NA, et al. Antithrombotic therapy
Exp Pediatr. 2021;65(4):182–187 in neonates and children: antithrombotic therapy and prevention of
thrombosis, 9th ed: American College of Chest Physicians Evidence-
37. Ianotto JC, Curto-Garcia N, Lauermanova M, Radia D, Kiladjian JJ,
Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e737S–e801S
Harrison CN. Characteristics and outcomes of patients with
essential thrombocythemia or polycythemia vera diagnosed before 46. Lim W. Antiphospholipid syndrome. Hematology Am Soc Hematol
Educ Program. 2013;2013(1):675–680
20 years of age: a systematic review. Haematologica. 2019;104(8):
1580–1588 47. Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are
stronger risk factors for thrombosis than anticardiolipin antibodies
38. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the
in the antiphospholipid syndrome: a systematic review of the
World Health Organization classification of myeloid neoplasms and
literature. Blood. 2003;101(5):1827–1832
acute leukemia. Blood. 2016;127(20):2391–2405
48. Islab~ao AG, Trindade VC, da Mota LMH, Andrade DCO, Silva CA.
39. Randi ML, Geranio G, Bertozzi I, et al. Are all cases of
Managing antiphospholipid syndrome in children and adolescents:
paediatric essential thrombocythaemia really myeloproliferative
current and future prospects. Paediatr Drugs. 2022;24(1):13–27
neoplasms? Analysis of a large cohort. Br J Haematol. 2015;169(4):
49. Avcin T, Cimaz R, Silverman EDED, et al. Pediatric antiphospholipid
584–589
syndrome: clinical and immunologic features of 121 patients in an
40. Geerts W. Central venous catheter–related thrombosis. Hematology international registry. Pediatrics. 2008;122(5):e1100-1107–e1107
Am Soc Hematol Educ Program. 2014;2014(1):306–311 50. Motta M, Boffa MC, Tincani A, Avcin T, De Carolis S, Lachassinne
41. Revel-Vilk S, Ergaz Z. Diagnosis and management of central- E. Follow-up of babies born to mothers with antiphospholipid
line-associated thrombosis in newborns and infants. Semin Fetal syndrome: preliminary data from the European neonatal registry.
Neonatal Med. 2011;16(6):340–344 Lupus. 2012;21(7):761–763

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 NEOREVIEWS QUIZ

NEO
QUIZ

1. An infant of 31 weeks’ gestation requires long-term venous access for

medication administration and fluid management. After the placement of an
umbilical venous catheter, there appears to be prolonged blood oozing at
the insertion site. The team suspects a defect in hemostasis. Of the 2 main
pathways of secondary hemostasis, testing which of the following would
demonstrate a defect in the intrinsic pathway?

A. Activated partial thromboplastin time (aPTT).

B. Antithrombin III level.
C. Bleeding time.
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neoreviews.
former 29-weeks gestation infant is found to have a thrombotic incident. Of
the following, which is most likely to be linked to this event? To successfully complete 2024
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A. Blood transfusions. Category 1 Credit™, learners
B. Chorioamnionitis. must demonstrate a minimum
C. Respiratory distress syndrome. performance level of 60% or
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you score less than 60% on the
E. Venous or arterial access devices.
assessment, you will be given
3. Shortly after delivery, a term infant develops diffuse bruising. On further additional opportunities to
investigation, the neonate demonstrates signs of disseminated intravascular answer questions until an
overall 60% or greater score is
coagulation and is found to have retinal thrombosis on ophthalmologic achieved.
examination. Of the following, which condition most likely contributed to
these findings? This journal-based CME activity
is available through Dec. 31,
A. Antiphospholipid syndrome. 2026, however, credit will be
B. Antithrombin deficiency. recorded in the year in which
C. Factor V Leiden. the learner completes the quiz.
D. Protein C and S deficiency.
E. Prothrombin G20210A mutation.
4. Unlike secondary thrombocytosis, which can be caused by infection,
inflammation, or anemia, primary thrombocytosis is a rare condition caused
by genetic mutations in the JAK2, CALR, or MPL genes, leading to hyperplasia 2024 NeoReviews is approved
of megakaryocytes in the bone marrow and thrombocytosis. What platelet for a total of 10 Maintenance of
count is required to meet the diagnostic criteria of primary thrombocytosis? Certification (MOC) Part 2
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org/journals/pages/moc-credit.

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 5. Nephrotic syndrome places an infant at increased risk for thrombosis
(particularly renal and deep vein thrombosis). This hypercoagulable state
stems from thrombocytosis due to hypovolemia and an increase of all of the
following except:

A. Factor V.
B. Factor VII.
C. Fibrinogen.
D. Plasminogen.
E. Platelet activation.

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 ARTICLE

Hemoglobinopathies in the Neonate

Katrina Blankenhorn, MD,* Kaitlin Strumph, DO, MS*
*Division of Hematology/Oncology, Department of Pediatrics, Children’s Hospital at Montefiore, Albert Einstein College of Medicine, New York, NY

EDUCATION GAPS

Neonatologists should know how to recognize and assess for both

quantitative and qualitative hemoglobin disorders. Early diagnosis of
moderate to severe hemoglobinopathies is crucial as it can prevent
morbidity and mortality in patients affected by these conditions.

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

1. Describe the pathophysiology, typical presentation, and general

complications associated with common quantitative and qualitative
hemoglobin disorders.
2. Recognize the difference between A-globin and b-globin mutations and
know when each of these related disorders present in the in utero or
neonatal period.
3. Interpret newborn screening hemoglobinopathy results to provide early
diagnosis and counseling to families.

ABSTRACT
Hemoglobinopathies in neonates constitute a group of disorders
influenced by genetic mutations in the human globin genes. They are
often broadly categorized into quantitative defects or qualitative defects,
though they are not mutually exclusive. In quantitative defects, the
mutation causes insufficient production of a normal globin chain, which
can range from no production to mild deficiency. These are typically
referred to as thalassemias. In qualitative defects, the structure of the
hemoglobin is altered. The most common structural hemoglobinopathy is
AUTHOR DISCLOSURES Drs Blankenhorn sickle cell disease. During fetal development, distinct globin chains are
and Strumph have disclosed no financial synthesized, which undergo a progressive switch to adult globin chains
relationships relevant to this article. This perinatally. This affects the timing of the clinical presentation of these
article does not contain a discussion of
an unapproved/investigative use of a disorders and thus, our ability to diagnose them. In this review, we focus
commercial product/device. on the epidemiology, genetic causes, clinical presentation, and general
overview and management of common hemoglobin disorders that may be
ABBREVIATIONS encountered in the neonatal period.
HPFH hereditary persistence of fetal
hemoglobin
NTDT nontransfusion dependent Hemoglobinopathies are disorders caused by abnormal production or struc-
SCD sickle cell disease
TDT transfusion-dependent ture of the hemoglobin protein. Many of these disorders are present in utero or
b-thalassemia during the neonatal period. In this review, we focus on the structure and

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 function of the hemoglobin molecule and then provide a (4)(5)(6) Due to the timing of globin chain switching during
comprehensive discussion of the more common types of development, a premature infant will predominantly express
hemoglobinopathies. hemoglobin F, which slowly decreases as the infant ap-
proaches term gestational age. In adults, hemoglobin F ac-
HEMOGLOBIN PRODUCTION counts for less than 1% of total hemoglobin, and the most
Hemoglobin is a heterotetrametric protein consisting of 2 common hemoglobin in adults is hemoglobin A (a2b2) with
polypeptide globin a subunits and 2 polypeptide globin b a minimal amount of the minor hemoglobin A2 (a2d2). (4)
subunits. The globin subunits are encoded by multigene
clusters on chromosome 16 for a-globin and chromosome HEMOGLOBINOPATHIES
11 for b-globin (Fig 1). (1)(2)(3)(4) These globin polypepti- Hemoglobinopathies are a heterogenous group of disorders
des each contain a heme group that can reversibly bind ox- caused by genetic mutations in the globin genes. They are of-
ygen, allowing it to be delivered to the tissues. Different ten broadly categorized into quantitative defects or qualitative
a-like and b-like globin chains are synthesized during fetal defects, but they are not mutually exclusive. (4) In quantitative
development and neonatal development. The order in defects, the mutation causes insufficient production of a nor-
which different b-globins are expressed generally follows mal globin chain, which can range from no production to
the order in which they are arranged along chromosome mild deficiency. These are typically referred to as the thalasse-
11: 50 -e-gG-gA-d-b30 . (2)(4) In the first 8 weeks of gesta- mias. In qualitative defects, the structure of the hemoglobin
tion, there is a brief period of embryonic globin gene ex- is altered. The most common structural hemoglobinopathy is
pression. The embryonic chains z and e are the first to be sickle cell disease.
produced during early embryonic life, producing hemoglobin
Gower 1, hemoglobin Gower 2, and hemoglobin Portland. EPIDEMIOLOGY OVERVIEW
After 8 weeks’ gestation, the a-globin and g-globin chains Historically, hemoglobinopathy variants have been natu-
are predominantly expressed, which creates hemoglobin F rally selected because of their protective advantage against
(a2g2), termed fetal hemoglobin. Fetal hemoglobin is the severe malaria, resulting in the highest prevalence seen in
most common hemoglobin at birth, accounting for 70% to tropical and subtropical regions affected by malaria. (7)(8)
90% of hemoglobin in the neonatal period. After birth, the
g-globin chain of fetal hemoglobin is progressively replaced THALASSEMIAS
by the b-globin chain of adult hemoglobin termed hemoglo- Thalassemias are a group of disorders generally character-
bin A, or a2b2, which occurs around 3 to 6 months of age. ized by ineffective erythropoiesis and hemolysis. The dis-
This is referred to as the hemoglobin switch (see Fig 2). orders are often classified based on the type of globin

Figure 1. a- and b-globin gene clusters. Diagram of a- and b-globin gene clusters and their expression within the adult hemoglobin protein. The ar-
rangement of genes corresponds with the order of their expression during development. Early fetal life is characterized by the expression of f a chains
and e b chains. In adults, hemoglobin chains are predominantly a chains combined with b chains and a smaller amount of c and d chains.

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 Figure 2. Hemoglobin switch. Schematic diagram depicting the change in hemoglobin chain expression through fetal and early postnatal life. By 6
months of age, c chains drop precipitously and b chains increase, which corresponds to the time when clinical manifestations of b-thalassemias present.

chain that is affected: a-thalassemias are caused by de- a-Thalassemia

creased production of a chains, whereas b-thalassemias a-Thalassemia is caused by mutations in 1 or more of the
are caused by decreased production of b chains. Thalasse- 4 a-globin genes. These can range in severity from 1 muta-
mias have a wide range of clinical severities based on the tion causing a slightly decreased a-globin production, to a
number of genes affected, the types of mutations involved, 4-gene mutation leading to no a-globin production. The ma-
and the subsequent effect on globin production. jority of mutations are deletional, but point mutations have
also been reported. When mutations occur on the same
Epidemiology of Thalassemias chromosome, they are considered to be in cis configuration.
a-Thalassemia is seen in approximately 5% of the world’s When mutations occur on opposite chromosomes, they are
population. It is most prevalent in Southeast Asia, specifically considered to be in trans configuration (see Table 1).
Laos and Cambodia; however, it is also present in Africa and a-globin gene expression begins in utero, therefore se-
regions of the Mediterranean and Middle East. (9) The more vere mutations in these genes can be clinically apparent in
severe cis-mutations are seen in Southeast Asia, whereas sin- utero and at birth. a-thalassemia carrier status occurs
gle gene mutations or trans mutations are more commonly when 1 a-globin gene is mutated (-a/aa). This is clinically
seen in Africa. If both parents have a cis mutation, their off- benign as there are 3 other normal-functioning a-globin
spring will have a 25% chance of having a-thalassemia major genes. Mutations of 2 a-globin genes are classified as
leading to hydrops fetalis. Hemoglobin constant spring, the a-thalassemia trait, which causes low mean corpuscular
most common type of nondeletional a-thalassemia, is pre- volume, low mean corpuscular hemoglobin, and normal
dominantly seen in northeastern Thailand, southern China, hemoglobin levels or very mild anemia. Affected individu-
and minority populations in Vietnam. (10) als have normal growth and development.
b-thalassemias are less prevalent than a-thalassemias; Three a-globin deletions with only 1 active a-globin
however, they still affect 1.5% of the global population. gene (- -/-a) is called deletional hemoglobin H disease. In
Each year approximately 40,000 infants are born with the hemoglobin H disease, the significant decrease in a-globin
condition, and half will require regular blood transfusion chains leads to an imbalance with the b-like chains. The ex-
therapy. Most people with b-thalassemias reside in a geo- cess g chains (in utero) and b chains (neonatal) form tet-
graphic region stretching from Africa, through southern ramers called hemoglobin Bart (g4) and hemoglobin H (b4),
Europe and the Middle East, to Southeast Asia. Hemoglo- respectively. (10)(13) These tetramers are highly unstable,
bin E- b-thalassemia is most commonly found in South- leading to precipitation of the hemoglobin in red blood cells,
east Asia. (11)(12) causing direct damage to the red cell membrane and leading

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 Table 1. Alpha Thalassemia Mutations

Nomenclature Gene mutaons Presentaon

a1 a2 Asymptomac
D-thalassemia carrier Borderline low MCV
a1 a2 Normal Hemoglobin
D-thalassemia trait
a2 a2
Cis mutaon
a1 a2 Asymptomac
Mild anemia
a2 Low MCV
a1
Trans mutaon
a1 a2

a1 a2 Mild to moderate microcyc anemia

Deleonal Hemoglobin H disease Chronic hemolysis
a2 a2 Rarely require transfusions

Moderate to severe microcyc anemia

Non-deleonal a1 CS Chronic hemolysis
Hemoglobin H – Constant Spring Splenomegaly
a2 a2
Oen requires transfusions

a2 a2 Hydrops fetalis
D-thalassemia major Not compable with life unless fetus
a2 a2 receives intrauterine transfusions

A list of the common types of a-thalassemia with their corresponding genetic mutations and the resultant phenotypes. a-thalassemia
carriers have 1 mutation. a-thalassemia trait refers to persons with 2 mutations, either in a cis or trans configuration. Deletional hemo-
globin H disease is due to deletions of 3 of 4 genes. Nondeletional hemoglobin H disease is the result of 2 deletions and a third muta-
tion such as hemoglobin constant spring, which leads to more severe anemia and chronic hemolysis. a-thalassemia major occurs when
there are no a genes, which is not compatible with life unless the fetus receives intrauterine transfusions. MCV5mean corpuscular
volume.

to chronic hemolysis. Patients often develop hyperbilirubine- of a 4 a-globin gene deletion, die in utero or shortly after
mia from the hemolysis and splenomegaly due to compensa- birth. (14)
tory extramedullary hematopoiesis. Patients with deletional For patients with a-thalassemia, management depends on
hemoglobin H often have mild to moderate anemia but do the severity of the phenotype. Most people with hemoglobin
not usually require transfusions. (14)(15) There is a form of H are not transfusion-dependent. However, during acute in-
nondeletional hemoglobin H disease in which a cis mutation fections, particularly with parvovirus, that can trigger an aplas-
is inherited with a nondeletional mutation of a third a-globin tic crisis, they may require support with transfusions. Folic
gene. Examples include hemoglobin constant spring, Pakse, acid supplementation can be recommended because of the
and Quong Sze mutations, which, if inherited with 2 a-gene rapid cell turnover and thus higher folic acid consumption.
deletions, can result in nondeletional hemoglobin H syn- (16) In patients with severe phenotypes, additional complica-
drome. (14) The constant spring mutation causes the produc- tions, such as iron overload, growth delay, splenomegaly, and
tion of an abnormally long a-globin protein, which is highly cholelithiasis, should be monitored. (15)(16)
unstable, thus leading to more clinically significant symp- Diagnosis of a-thalassemia cannot be determined based
toms compared with the deletional form of hemoglobin H on hemoglobin electrophoresis. Genetic testing is required
disease. People with nondeletional hemoglobin H often and often done based on family history or clinical suspicion
require frequent transfusions. (14)(15) Almost all fetuses in a patient with microcytic anemia. Preconception counsel-
with hemoglobin Barts hydrops fetalis syndrome, because ing is extremely important for those with a-thalassemia. If

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 both parents are carriers of a cis mutation, there is a 25% 3. the presence of a mutation that enhances hemoglobin
risk in each pregnancy that the fetus will inherit all 4 muta- F production, offering partial compensation for the de-
tions and therefore lack all a-globin genes. When all a ficiency in b-globin chains. (11)(14)
chains are deleted (–/–) the lack of a-globin production is
not compatible with life. Affected fetuses may survive the Children with TDT will clinically present around 6 to
first and second trimesters because of the persistence of 12 months of age, coinciding with the time of hemoglobin
embryonic z-globin chains, but unless given transfusions, switch and subsequent drop in hemoglobin F levels with
they will go on to develop hydrops fetalis. In addition to hy- minimal to no hemoglobin A production. Children with
drops fetalis of the fetus, placentomegaly can occur, as well NTDT present later in childhood, usually during routine ex-
as potentially life-threatening complications in the pregnant aminations which reveal a microcytic anemia. (2) Diagnosis
patient (eg, preeclampsia, hemorrhage, and disseminated of b-thalassemia is based on hemoglobin electrophoresis
intravascular coagulation). In utero transfusions have been showing elevations in hemoglobin F and hemoglobin A2
an effective treatment of these fetuses if detected early with a reduction or absence of hemoglobin A. Genetic se-
enough in pregnancy followed by life-long transfusions in quencing of the b-globin gene can confirm the diagnosis.
the surviving infants. (16) These couples should receive ge- Without treatment, children with TDT will develop hep-
netic counseling with prenatal diagnosis in future pregnan- atosplenomegaly and marrow expansion from ineffective
cies. Prenatal diagnosis can be performed using DNA-
erythropoiesis and will suffer from growth and developmen-
based diagnosis via amniocentesis. (15)(16)(17)
tal delays, complications of iron overload, and a shortened
lifespan. Treatment of TDT consists of red cell transfusions
b-Thalassemia
typically made every 3 to 4 weeks. Transfusions are given to
b-Thalassemias are most commonly caused by point mu-
target a goal hemoglobin nadir of greater than 9 to 9.5 g/dL
tations in 1 of the 2 b-globin genes. These mutations can
(90–95 g/L) to suppress innate erythropoiesis and support
affect transcription, translation, or post-translation modifi-
oxygen-carrying capacity. Transfusion therapy results in im-
cations, hence leading to a wide array of clinical severities
proved growth, decreased skeletal abnormalities, reduced hy-
because of the varying effects on b-globin production. Mu-
tations that lead to mild reductions in b-globin synthesis persplenism, and decreased gut iron absorption. Generally,
are denoted as b 1 whereas mutations leading to the com- children with NTDT do not require transfusions except dur-
plete absence of b-globin synthesis are denoted as b0. Ho- ing special circumstances such as surgeries, acute infections,
mozygous b0 mutations lead to no detectable b-chain or to support growth during childhood. (18)
synthesis. As a result of excess a chains, red cell precur- In 2019, the US Food and Drug Administration ap-
sors are prematurely destroyed, resulting in chronic hemo- proved the medication luspatercept for adults older than
lysis. (2)(3) 18 years with TDT. The medication improves late-stage
Classification of b-thalassemia was previously based on erythroid maturation, and thus increases hemoglobin lev-
the symptoms of the patient as well as the degree of anemia. els, leading to a reduction in transfusion requirements.
Individuals were classified as having b-thalassemia major, in- (19) In 2022, gene therapy for thalassemia was approved,
termedia, or minor. More recently, classification has focused the first transformative therapy that allows individuals
on whether the patient requires transfusions or not, a treat- with TDT to become transfusion-independent. (20)(21)
ment that is initiated based on the severity of an individual’s
anemia and/or symptoms. Transfusion-dependent b-thalasse-
COMMON STRUCTURAL HEMOGLOBIN VARIANTS
mia (TDT) is usually caused by homozygous b0 mutations
Epidemiology of Structural Variants
or compound heterozygous b1/b0 mutations. Individuals
Structural hemoglobin variants arise from genetic muta-
with only 1 b-globin mutation, or homozygous b1 muta-
tions, generally do not require transfusions and are classified tions that cause an abnormal globin chain structure in the
as non–transfusion-dependent b-thalassemia (NTDT). Pheno- hemoglobin. Hemoglobin S, the most prevalent, is seen in
types can be influenced by 3 primary factors: high frequencies across sub-Saharan Africa, the Mediterra-
nean, the Middle East, and India, regions with a significant
1. the quantity of b-globin chain synthesized by the individual malaria burden. (8)(22) Hemoglobin C is prevalent in West
2. the concurrent inheritance of a-thalassemia, which al- Africa and Southeast Asia and within diverse populations
ters the ratio of a- to b-globin chains, thereby alleviating in Africa, South and Central America, and Southern Europe.
certain hemolytic effects (23) Hemoglobin E predominantly affects individuals from the

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 Indian subcontinent and Southeast Asia, with Thailand, Laos, Hemoglobin C
and Cambodia exhibiting frequencies approaching 60%. (9) Hemoglobin C results from a single amino acid mutation
leading to glutamic acid being replaced by lysine in the
Hemoglobin S Syndromes sixth position of the b-globin chain. Individuals with the
Hemoglobin S is caused by a point mutation in codon 6 hemoglobin C trait (hemoglobin AC) are phenotypically
of the b-globin gene on chromosome 11, resulting in an normal whereas individuals who inherit 2 copies of the
amino acid substitution in which glutamic acid is replaced hemoglobin C allele (hemoglobin CC disease) often have
by valine. Upon deoxygenation inside the red cell, hemoglo- mild chronic hemolytic anemia. Because of chronic hemo-
bin S will polymerize, leading to a conformational change lysis, individuals have an increased risk of gallstones. Folic
in the red cell shape into a “sickle.” Individuals who inherit acid is often provided to prevent folate deficiency. Typi-
1 hemoglobin S gene have sickle cell trait. These individuals cally, transfusions are not needed. (23)
are generally asymptomatic. Sickle cell disease (SCD) is an
autosomal recessive group of disorders caused by either the Hemoglobin E
homozygous inheritance of the hemoglobin S gene or a Hemoglobin E is caused by a mutation in the b-globin
compound heterozygous mutation involving hemoglobin S gene that creates an alternate splice site leading to de-
and another b-globin mutation that can influence sickling. creased production of an abnormal b chain. Individuals
Homozygous inheritance, termed hemoglobin SS, causes with hemoglobin E trait can have mild microcytosis and
the more severe form of the disease. If a patient coinherits a are asymptomatic. Individuals with coinheritance of hemo-
sickle mutation and a hemoglobin C allele, they will have globin E and a b-thalassemia mutation can present with
hemoglobin SC disease, which is typically milder than he- an array of phenotypes ranging from mild anemia to se-
moglobin SS. When a sickle mutation is inherited with vere anemia requiring transfusion support. Modifiers such
b-thalassemia, the severity of the resulting sickling disorder as the type of b-thalassemia mutation, and whether the in-
depends on the severity of the coinherited b-thalassemia dividual coinherited a-thalassemia, can affect the pheno-
mutation. Coinheritance of a b0 mutation, which produces type. (2) Individuals who coinherit hemoglobin S and
no hemoglobin A, results in severe SCD similar to hemoglo- hemoglobin E (hemoglobin SE) exhibit a mild sickle cell
bin SS. (24)(25)(26) phenotype similar to hemoglobin S/b1 thalassemia.
Children with SCD typically do not present with symp-
toms until 6 to 12 months of age when fetal hemoglobin OTHER VARIANTS
levels begin to decrease and hemoglobin S production in- Unstable Hemoglobins
creases. Sickling of the red cells leads to a combination of Unstable hemoglobins can result from a mutation in any
intermittent vaso-occlusion in the vasculature as well as of the globin chains. Mutations are often inherited in an
chronic hemolysis. This leads to acute complications and autosomal dominant pattern. These mutations cause changes
chronic organ damage. Common complications include in the solubility of the hemoglobin, thus leading to instability
strokes, retinopathy, acute chest syndrome, nephropathy, and hemoglobin precipitation referred to as Heinz bodies.
functional asplenia, and subsequent increased risk for in- These precipitates can bind to the red cell membrane causing
fections, avascular necrosis, and episodes of acute vaso-oc- a change in the membrane leading to breakdown and clear-
clusive pain crises. (22)(24) ance of the affected cells in the spleen. The red cell lifespan
Early diagnosis of SCDs is important because early ini- can be severely shortened leading to anemia. (29)
tiation of prophylactic penicillin, usually by the age of Clinical presentation of unstable hemoglobins is vari-
2 months, has been shown to decrease mortality from bac- able, and the severity is linked to the causative variant and
teremia. (27) Disease-modifying therapies such as hydroxy- its influence on hemoglobin stability. As a result, the spec-
urea and blood transfusions have been shown to decrease trum of clinical manifestations can be broad, ranging from
complications. Curative therapy includes stem cell trans- no symptoms to severe chronic hemolytic anemia. Of par-
plantation. In 2023, gene therapy for SCD was approved. ticular importance to the neonatologist, unstable g-globin
Through ex-vivo genetic modification, these treatments offer mutations can cause transient neonatal hemolytic anemia,
patients a transformative opportunity to drastically amelio- which resolves between 6 and 9 months of age because of
rate their disease. Results from ongoing clinical trials have the transition from fetal to adult hemoglobin. Generally,
shown drastic improvement in hemoglobin levels and a re- unstable hemoglobinopathies manifest as mild phenotypes
duction of vaso-occlusive crises. (28) and patients may exhibit mild chronic hemolytic anemia.

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 Patients should be educated about prevention, including HPFH and db-thalassemia are clinically important be-
avoidance of oxidant drugs and prompt evaluation during cause elevated hemoglobin F levels can attenuate the disease
hemolytic episodes. Infections can often precipitate hemoly- severity of coinherited b-chain hemoglobinopathies, such as
sis. In patients with severe hemolysis, transfusion support in patients with combined hemoglobin S and HPFH.
may be required. Others only require transfusions during
hemolytic crises, often prompted by infections. Splenec- NEWBORN SCREENING
tomy can be considered in severe cases, but not as the pre- Newborn screening programs have the ability to diagnose
ferred option because it can cause a hypercoagulable state hemoglobinopathies at birth, thus allowing for early im-
in some people. (29) plementation of preventive care. The US newborn screen-
ing program began screening for SCD in 1975. Since
Methemoglobins: Hemoglobin M 2006, all 50 states have adopted universal screening for
Some types of hemoglobin variants, termed hemoglobin SCD. However, screening for a- and b-thalassemia is not
M, can result in methemoglobin. Methemoglobin is a con- yet universal in all states. (33)(34)
dition in which heme iron becomes oxidized. As a result, Advancements in diagnostic technology have led to the
the oxygen-carrying capacity of blood decreases because adoption of isoelectric focusing or high-performance liquid
oxidized iron cannot reversibly bind oxygen. In most chromatography for detecting hemoglobinopathy in new-
cases, a tyrosine is substituted for a histidine in the proxi- born screening programs. Both technologies have high sen-
mal and distal sites of the a or b chains, leading to an sitivity and specificity for the diagnosis of SCD and severe
iron-phenolate complex. (30) thalassemia. (35)
Inheritance of hemoglobin M is autosomal dominant. Af- Interpretation of newborn screening results is based on the
fected individuals often have chronic methemoglobinemia. order in which the hemoglobin types are reported (Table 2).
As a result, they typically present with cyanosis. Patients can The diagnostic report lists the primary hemoglobin type
also have hemolysis and may present with neonatal jaun- detected with the highest concentration, followed by sub-
dice. Depending on which chain is mutated, individuals will sequent variants in descending order based on the amount
present at different time points. In the case of a-globin var- present. For example, a child with a normal hemoglobin
iants, the dusky color of affected infants will be noted at phenotype would have the results “FA,” signifying the pre-
birth. When there is a b-globin variant, the symptoms be- dominant hemoglobin at birth first, hemoglobin F, followed
come apparent only after b chains have replaced the fetal g by the smaller amount of hemoglobin A that is detected.
chains at 6 to 9 months of age. (31) A child with hemoglobin SS would have the results
Hemoglobin M can be diagnosed with electrophoresis. “FS,” again signifying the predominant hemoglobin at
No effective treatment exists for cyanosis in patients with birth, hemoglobin F, followed by the lesser amount of he-
hemoglobin M, however, individuals are often otherwise moglobin S that is being produced, and no hemoglobin A.
asymptomatic.
Table 2. Newborn Screen Hemoglobinopathy
Interpretation
Hereditary Persistence of Fetal Hemoglobin and db-
NEWBORN
Thalassemia SCREEN RESULT PRESUMED DIAGNOSIS
Hereditary persistence of fetal hemoglobin (HPFH) and
FA Normal
db-thalassemia are benign conditions in which individuals FAS Sickle cell trait
exhibit markedly elevated levels of hemoglobin F into FS Sickle cell anemia: Hemoglobin SS or
hemoglobin S/b0 thalassemia
adulthood. db-Thalassemia results from a large deletion FSA Hemoglobin S/b1 thalassemia
encompassing both the d- and b-globin genes. (32) Hetero- FSC Hemoglobin SC disease
F Transfusion-dependent b-thalassemia
zygotes often are characterized by hemoglobin F levels be- (b-thalassemia major)
tween 5% and 20% and mild microcytic anemia. HPFH FA Barts Hemoglobin H disease
mutations are caused by a large deletion in the region be- Newborn screening results for hemoglobinopathy. The diagnostic
tween the g- and b-globin genes or a point mutation in newborn screening report lists the primary hemoglobin type de-
the g-globin gene promoter. (32) Deletional HPFH is char- tected with the highest concentration, followed by subsequent
variants in descending order based on the amount present.
acterized by hemoglobin F levels of 10% to 20% with no F5hemoglobin, A5hemoglobin A, S5hemoglobin S, C5hemoglobin
effect on red blood cell indices. (32) C, Barts5tetramer of c-globin chains.

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 Carriers of hemoglobin S will have the result “FAS,” signi- References
fying the higher production of normal adult hemoglobin
1. Higgs DR. The molecular basis of a-thalassemia. Cold Spring Harb
A compared with the amount of hemoglobin S being
Perspect Med. 2013;3(1):a011718
produced.
2. Taher AT, Musallam KM, Cappellini MD. b-Thalassemias. N Engl J
Newborn screening results for a child with severe Med. 2021;384(8):727–743
b-thalassemia (ie, Cooley anemia) would show only hemoglo- 3. Thein SL. The molecular basis of b-thalassemia. Cold Spring Harb
bin F and no hemoglobin A, thus signifying the complete lack Perspect Med. 2013;3(5):a011700
of normal adult hemoglobin production. Newborns with the 4. Harteveld CL, Achour A, Arkesteijn SJG, et al. The
b-thalassemia trait often go undetected. Severe a-thalassemia hemoglobinopathies, molecular disease mechanisms and
diagnostics. Int J Laboratory Hematol. 2022;44(suppl 1):
(hemoglobin H disease) can be detected, as the screening 28–36
methods can detect the fast migrating hemoglobin Barts bands. 5. Wang X, Thein SL. Switching from fetal to adult hemoglobin. Nat
However, a-thalassemia trait and a-thalassemia carriers often Genet. 2018;50(4):478–480
go undetected as the small amount of hemoglobin Barts pro- 6. Forget BG. Progress in understanding the hemoglobin switch.
duced is often below the level of detection. (35) N Engl J Med. 2011;365(9):852–854
Universal newborn screening in the United States is an 7. Taylor SM, Parobek CM, Fairhurst RM. Haemoglobinopathies and
the clinical epidemiology of malaria: a systematic review and meta-
important public health advancement; however, states of-
analysis. Lancet Infect Dis. 2012;12(6):457–468
ten have limited capacity to implement systems to ensure
8. Aidoo M, Terlouw DJ, Kolczak MS, et al. Protective effects of the
access to comprehensive follow-up care. Therefore, it is sickle cell gene against malaria morbidity and mortality. Lancet.
imperative that neonatologists and general pediatricians 2002;359(9314):1311–1312
are equipped at interpreting the results and appropriately 9. Vichinsky EP. Changing patterns of thalassemia worldwide. Ann N
counseling patients on the diagnoses. Y Acad Sci. 2005;1054:18–24
10. Fucharoen S, Viprakasit V. Hb H disease: clinical course and
disease modifiers. Hematology Am Soc Hematol Educ Program.
CONCLUSIONS
2009:26–34
Hemoglobinopathies in neonates encompass a broad range 11. Weatherall DJ. The definition and epidemiology of non-transfusion-
of hemoglobin disorders with a wide array of phenotypes. dependent thalassemia. Blood Rev. 2012;26 Suppl 1:S3–6
Children can present perinatally, around 6 to 12 months of 12. Angastiniotis M, Modell B, Englezos P, Boulyjenkov V. Prevention
age, or later in life, depending on the specific mutations in- and control of haemoglobinopathies. Bull World Health Organ.
1995;73(3):375–386
herited. As a result, neonatologists often have the opportunity
13. Chui DH. Alpha-thalassemia: Hb H disease and Hb Barts hydrops
to diagnose these disorders. Understanding the physiology of fetalis. Ann N Y Acad Sci. 2005;1054:25–32
hemoglobin development, having an awareness of the clinical 14. Lal A, Vichinsky E. The clinical phenotypes of alpha thalassemia.
spectrum of hemoglobinopathies, along with the ability to ac- Hematol Oncol Clin North Am. 2023;37(2):327–339
curately interpret newborn screening results, can lead to early 15. Vichinsky EP. Alpha thalassemia major–new mutations, intrauterine
diagnoses and better outcomes in children with more se- management, and outcomes. Hematology Am Soc Hematol Educ
Program. 2009:35–41
vere phenotypes. As novel treatments such as gene ther-
apy continue to arrive on the scene, prompt diagnosis 16. Carr S, Rubin L, Dixon D, Star J, Dailey J. Intrauterine therapy for
homozygous alpha-thalassemia. Obstet Gynecol. 1995;85(5 Pt 2):876–879
will be paramount to providing children with early access
17. Pongtanakul B, Sanpakit K, Chongkolwatana V, Viprakasit V.
to these transformative therapies. Normal cognitive functioning in a patient with Hb Bart's hydrops
successfully cured by hematopoietic SCT. Bone Marrow Transplant.
2014;49(1):155–156
18. Rachmilewitz EA, Giardina PJ. How I treat thalassemia. Blood.
American Board of Pediatrics 2011;118(13):3479–3488
19. Cappellini MD, Taher AT. The use of luspatercept for thalassemia in
Neonatal-Perinatal Content adults. Blood Adv. 2021;5(1):326–333
Specifications 20. Leonard A, Tisdale JF, Bonner M. Gene therapy for
• Know the developmental biology of hemoglobin types. hemoglobinopathies: beta-thalassemia, sickle cell disease. Hematol
Oncol Clin North Am. 2022;36(4):769–795
• Know the clinical and laboratory features of neonatal
hemoglobinopathies, including the thalassemias. 21. Locatelli F, Lang P, Wall D, et al. CLIMB THAL-111 Study Group.
Exagamglogene autotemcel for transfusion-dependent b-thalassemia.
• Know the indications for and approaches to screening N Engl J Med. 2024;390(18):1663–1676
for hemoglobinopathies in the newborn population.
22. CDC. Sickle Cell Disease: Data and Statistics. [Link]
sickle-cell/data/?CDC_AAref_Val=[Link]
sicklecell/[Link]. Published 2024. Accessed May 4, 2024.

Vol. 25 No. 11 N O V E M B E R 2 0 2 4 e727

Downloaded from /neoreviews/issue/25/11

by Almoosa Hospital user
 23. Bibek Karna SKJ, Al Zaabi E. Hemoglobin C disease. In: Island T, 29. Gallagher PG. Diagnosis and management of rare congenital
ed.: StatPearls; 2024: [Link] nonimmune hemolytic disease. Hematology Am Soc Hematol Educ
NBK559043/. Accessed May 1, 2024. Program. 2015;2015:392–399
24. Serjeant GR. The natural history of sickle cell disease. Cold Spring 30. Mansouri A, Lurie AA. Concise review: methemoglobinemia.
Harb Perspect Med. 2013;3(10):a011783 Am J Hematol. 1993;42(1):7–12
25. Frenette PS, Atweh GF. Sickle cell disease: old discoveries, 31. Alonso-Ojembarrena A, Lubian-L opez SP. Hemoglobin M disease as a
new concepts, and future promise. J Clin Invest. 2007;117(4): cause of cyanosis in a newborn. J Pediatr Hematol Oncol. 2016;38(3):173–175
850–858 32. Bollekens JA, Forget BG. Delta beta thalassemia and hereditary
26. Bainbridge R, Higgs DR, Maude GH, Serjeant GR. Clinical persistence of fetal hemoglobin. Hematol Oncol Clin North Am.
presentation of homozygous sickle cell disease. J Pediatr. 1985; 1991;5(3):399–422
106(6):881–885 33. Consensus conference. Newborn screening for sickle cell disease
27. Gaston MH, Verter JI, Woods G, et al. Prophylaxis with oral and other hemoglobinopathies. JAMA. 1987;258(9):1205–1209
penicillin in children with sickle cell anemia. A randomized trial. 34. US Preventive Services Task Force. Screening for sickle cell disease
N Engl J Med. 1986;314(25):1593–1599 in newborns: recommendation statement. Am Fam Physician.
28. Sharma A, Boelens JJ, Cancio M, et al. CRISPR-Cas9 Editing of the 2008;77(9):1300–1302
HBG1 and HBG2 Promoters to Treat Sickle Cell Disease. N Engl J 35. Hoppe CC. Newborn screening for non-sickling hemoglobinopathies.
Med. 2023;389(9):820–832 Hematology Am Soc Hematol Educ Program. 2009:19–25

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 INDEX OF SUSPICION IN THE NURSERY

Term Neonate With Right-Sided

Limb Swelling: A Potpourri of Etiology
and Complication
Tehsin Patel,* Abhilasha Kumari,* Prashanth Ranya Raghavendra,* Sruthi Nair,* Anitha Haribalakrishna,*
Sumeet Anant Dhulshette,† Hemangini Thakkar,† Patil Varun Praveen,* Shivam Sushilkumar Shukla*
*Department of Neonatology, Seth G.S. Medical College and King Edward Memorial Hospital, Mumbai, India
†
Department of Radiology, Seth G.S. Medical College and King Edward Memorial Hospital, Mumbai, India

CASE PRESENTATION
A male neonate weighing 2,800 g (appropriate for gestational age) is born to a non-
consanguineous couple at 39 weeks of gestation via vaginal delivery in an outside
hospital. The mother is 28 years old, and antenatal ultrasonography findings are nor-
mal. Her blood group is A negative, and she has had no additional antenatal tests.
The neonate is vigorous at birth with Apgar scores of 9 and 9 at 5 and 10 minutes, re-
spectively. Anthropometric measurements at birth include length and head circum-
ference of 52 cm and 37 cm, respectively, both between the 50th and 95th percentiles
as per a modified Fenton chart. Physical and systemic examination findings at birth
are normal and the infant is receiving exclusive breast milk.
On day 3 after birth, diffuse jaundice is noted. An evaluation reveals the infant’s
blood type is B positive and the mother’s blood group O negative, the direct Coombs
test is positive, and total serum bilirubin (25 mg/dL [427.6 mmol/L]) is within the ex-
change transfusion range (cutoff, as per 2022 American Academy of Pediatrics
[AAP] hyperbilirubinemia management guideline: 22 mg/dL [376.3 mmol/L]). A dou-
ble-volume exchange transfusion via umbilical venous catheter is performed in an
outside hospital and intensive phototherapy is initiated. The neonate is discharged
from the hospital on day 8, exclusively breastfeeding. However, he is later readmitted
because of swelling in the right lower extremity, which progressively enlarged over
the next 48 hours. In addition, diffuse swelling is observed in the right scapular re-
gion and 2 distinct areas of swelling on the scalp. The neonate is referred to our insti-
tution for further management on day 12 after birth.
Examination findings at admission to our NICU are summarized in Table 1.

DIFFERENTIAL DIAGNOSIS AUTHOR DISCLOSURES Drs Patel, Kumari,

Raghavendra, Nair, Haribalakrisha,
• Venous thrombosis: Catheter-induced thrombosis, sepsis, prothrombotic disorder Dhulshette, Thakkar, Praveen, and Shukla
• Immunodeficiency disorder: Primary immune deficiency disorders, chronic have disclosed no financial relationships
relevant to this article. This article does
granulomatous disease
not contain a discussion of an
• Disseminated bacterial sepsis unapproved/investigative use of a
• Portal vein thrombosis commercial product/device.

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 Table 1. Clinical Examination of the Neonate at the Time of Admission to the NICU
EXAMINATION FINDINGS
Vital signs
Temperature 97.7 F (36.5 C)
Heart rate 170 beats/min
Respiratory rate 64 breaths/min
Capillary refill time <3 s
Oxygen saturation 88%
General examination Marked pallor, jaundice, and edema of the right lower extremity
Head Two well-defined erythematous, tender cystic fluctuant lesions in
the scalp in the right parietal region
Right shoulder Ill-defined tender erythematous swelling measuring 5 × 7 cm with
normal axillary artery pulsation
Right upper limb Normal brachial, radial, and ulnar artery pulsation
Right lower limb Ill-defined tender swelling extending from the upper thigh
including the foot, associated with paucity of movements.
Femoral and dorsalis pedis pulsation well felt. Limb perfusion:
normal
Rest of musculoskeletal examination (contralateral limb and back) Normal
Central nervous system Lethargic with poor spontaneous activity, cry, and tone secondary
to bilirubin-induced neurologic dysfunction
Abdomen Hepatosplenomegaly with liver palpable 4 cm below right costal
margin, firm and non-tender. Spleen palpable 3 cm below the
left costal margin.
Respiratory and cardiovascular system Normal

FURTHER COURSE with the portal vein and lower limb thrombus resolving by
Noninvasive respiratory support was initiated (continuous pos- day 21 after birth with the aforementioned measures.
itive airway pressure of 6 and fraction of inspired oxygen 30%) For the management of sepsis, the neonate was initially
and milk feeding started via an orogastric tube. The cause of started on intravenous antibiotics meropenem and amika-
multiple abscesses, limb edema, and anemia was evaluated cin based on a local antibiogram, and ultrasound-guided
aspiration of abscess with orthopedic intervention for right
with laboratory and radiologic investigations (Table 2).
Following initial evaluation, the comorbidities included femur osteomyelitis was planned.
Scalp abscesses were drained on day 14, following which
multiple scalp abscesses, right shoulder abscess, osteomyelitis
there was no recurrence. Shoulder abscess required 2 set-
of the right femur, right lower limb venous thrombosis, portal
tings of ultrasound-guided drainage on days 20 and 22, after
vein thrombosis, and anemia secondary to sepsis. A multidis-
which the abscess subsided. The purulent matter culture
ciplinary team including neonatology, orthopedic surgery, he-
from these sites showed methicillin-resistant Staphylococcus
matology, radiology, occupational therapy, social work, and
aureus (MRSA) growth which required broadening the anti-
lactation counselor were involved in the care of the neonate.
biotic spectrum to vancomycin and gentamycin.
Management of venous thrombosis of limb and portal
On confirmation of the right femur osteomyelitis with frac-
vein thrombosis included the use of unfractionated hepa-
ture noted on radiography and ultrasonography (Fig 3), surgical
rin with a bolus dose of 28 IU/kg followed by a mainte-
debridement of right femur granulation tissue with insertion
nance dose of 30 IU/kg given for 48 hours (1), with close
of antibiotic (vancomycin and gentamycin)–impregnated stim-
monitoring of activated partial thromboplastin time as rec- ulant beads was done during surgery. Granulation tissue cul-
ommended by the pediatric hematologist, and guided by ture sent during surgery grew MRSA. On discussion with the
serial limb ultrasonography and Doppler imaging. The ne- microbiologist, intravenous linezolid was added to the regi-
onate was switched to low-molecular-weight heparin after men, which along with gentamycin, was continued for 6
48 hours at a dose of 1.5 mg/kg administered subcutane- weeks. Limb movement gradually improved, with normal
ously twice a day, which was continued for 12 weeks. (1) movements achieved by day 66 after birth (Fig 4).
The infant’s lower limb was elevated and scrotal support Early intervention was initiated and the parents were
was provided. Monitoring for limb edema, limb girth, and encouraged to participate in the neonate’s care throughout
arterial pulsation was conducted every 3 hours because of the NICU stay. Further evaluation for an underlying pro-
the risk of compartment syndrome. The neonate had no ev- thrombotic state, other immunodeficiencies, brain mag-
idence of ascites or features of decompensated liver disease, netic resonance imaging, and brainstem-evoked response

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 Table 2. Laboratory and Radiological Investigations of the Index Neonate
LABORATORY INVESTIGATION PATIENT VALUE NORMAL REFERENCE RANGE
Complete blood cell count
Hemoglobin, g/dL (g/L) 7.3 (73) 13.4–23.7 (134–237)
Packed cell volume (%) 21.7 45–65
Mean corpuscular volume, µm3 (fL) 80.9 (80.9) 90–112 (90–112)
Mean corpuscular hemoglobin, pg 25.4 32.5
Mean corpuscular hemoglobin concentration, g/dL 30 32.1
Red cell distribution width, % 16.3 16.18 ± 1.23
Reticulocyte count, % 1.2 0–1
Total leukocyte count, /µL (×109/L) 42,800 (42.8) 5000–20,000 (5–200)
Platelets, ×103/µL (×109/L) 6 (6) 1.5–4.7 (1.5–4.7)
Peripheral smear Microcytic hypochromic anemia.
No evidence of hemolysis
C-reactive protein, mg/dL (mg/L) 11.3 (113) Up to 1 (10)
Blood culture Methicillin-resistant Staphylococcus aureus
Blood glucose, mg/dL (mmol/L) 94 (5.2) 60–125 (3.3–6.9)
Blood gas (venous)
pH 7.36 7.35–7.45
PCO2, mm Hg (kPa) 44 (5.8) 35–45 (4.7–6)
PO2 (mm Hg) 46 (6.1) 50–70 (6.6–9.3)
Bicarbonate, mEq/L (mmol/L) 22.8 18–24
Liver enzymes
Aspartate aminotransferase, U/L (µkat/L) 34 (0.57) 9–80 (0.15–1.34)
Alanine aminotransferase, U/L (µkat/L) 22 (0.37) 13–45 (0.22–0.75)
Total bilirubin, mg/dL (µmol/L) 2.51 (42.9)
Direct bilirubin, mg/dL (µmol/L) 1.51 (25.9)
Prothrombin time (s)/activated partial
thromboplastin time (s)/international 14.7/27/1.07
normalized ratio
Total protein, g/dL (g/L) 5.8 (58) 6–7.5 (60–75)
Serum albumin, g/dL (g/L) 2.6 (26) 3–5 (30–50)
Serum lactate, mg/dL (mmol/L) 7.21 (0.8) 4.5–19.8 (0.5–2.2)
Thyroid-stimulating hormone, µIU/mL (mIU/L) 5.040 Up to 20
Cranial ultrasonography Two discrete scalp abscesses. Normal brain
parenchyma and cerebral Doppler
Ultrasonography of the abdomen and kidney- Normal Doppler-showing hypoechoic
ureter-bladder with a screening of the thrombus in the main portal vein, left
pancreas (Fig 1) portal vein. No ascites. No liver abscess
Ultrasonography of the right lower limb (Fig 5) Complete thrombus within the right
common femoral vein, right external iliac
vein, and a small part of common iliac vein,
with normal flow and compressibility of
superficial femoral, popliteal, and tibial veins
Ultrasonography of the right shoulder (Fig 5) Abscess in a subcutaneous and
intramuscular plane near right shoulder
Ultrasonography of hip (Fig 2) Osteomyelitis of the right femur, with a
collection of 0.5 mL of purulent material in
the femoral area. The hip joint is normal
Fundus evaluation Normal
Immunodeficiency evaluation Nitroblue tetrazolium test 98% burst cells.
(normal)
Dihydrorodamine test normal
Lymphocyte subset analysis normal
B memory and naïve T cell analysis normal

audiometry for bilirubin-induced neurologic dysfunction The investigations of the neonate from admission to
was planned on follow-up. At the time of discharge 74 days discharge have been summarized in Table 3.
after birth, the neonate weighed 4,350 g with normal move-
ments at the right shoulder, right upper and lower limb FINAL DIAGNOSIS
(Fig 6), no purulent matter collection on ultrasonography, MRSA sepsis with multiple abscesses and right femur os-
and normal neurodevelopment; he continues to receive teomyelitis and venous thrombosis in a neonate after um-
follow-up care. bilical venous catheterization.

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 Figure 1. Color Doppler showing hypoechoic thrombus. A. Main portal vein. B. Left portal vein. C. Ultrasonographic scan in B-mode showing thrombus
in the main portal vein. D. Resolution of thrombus after treatment.

DISCUSSION Neonates differ in concentration, production rate of most

Neonatal thrombosis is a rare complication occurring in coagulation factors, and their ability to regulate thrombin
5.1 in 100,000 live births, with more than 95% of cases hav- and plasmin, placing them at risk for a relative prothrom-
ing an identifiable risk factor. (2) Catheter-related thrombosis botic state. Sepsis causes further dysregulation of the innate
and bloodstream infection–associated venous thrombosis immune process, predisposing them to immune thrombosis.
(VT) account for 9.2% of cases. (3) The index neonate (4) The clinical manifestations vary from swelling, hyper-
had an umbilical venous catheter inserted for exchange emia, tenderness, and cyanosis in cases of lower extremity
transfusion and subsequently developed MRSA infection, thrombosis to hepatosplenomegaly and ascites with impaired
compounding the risk of VT. liver function in portal hypertension.

Figure 2. Ultrasonographic scans. A. Normal left femoral head contour (white arrow). B. Distorted irregular right femoral head contour (black arrow) with
collection around it, with irregular cortex of the shaft of femur (white arrowhead).

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 Figure 3. Radiographs. A. Signs of osteomyelitis of right femur with periosteal reaction and cortical irregularity (white arrow) with soft tissue edema sur-
rounding it. B. Antibiotic beads (STIMULANT) in right hip joint after arthrotomy and purulent matter drainage and joint lavage.

The management of VT in neonates is largely based on This is an emergency condition requiring arthrotomy for
consensus guidelines. Factors such as severity of thrombo- purulent matter drainage along with the insertion of ce-
sis, possibility of organ or limb impairment, presence of mented antibiotic beads. (9) This was similarly done in our
comorbidities, and risk for bleeding influence the decision case for prolonged local delivery of antibiotics, as the bone
to treat or to observe VT. (5) The first-line therapy com- sequestrum and its surroundings make it difficult for intra-
monly used for catheter and sepsis-related VT is typically venous antibiotics to penetrate. AAP recommends combina-
unfractionated or low-molecular-weight heparin adminis- tion therapy with parenteral vancomycin plus nafcillin or
tered for 3 months. (6) Thrombolysis therapy with recom- oxacillin plus gentamycin for 14 days for S aureus bacter-
binant tissue plasminogen activator is reserved for life-, emia and 4 to 6 weeks in case of osteoarticular infection.
limb-, and organ-threatening events, including pulmonary (10) In the index case, after arthrotomy, the orthopedic
embolism with hemodynamic compromise. Drugs such as team advised conservative management of the pathologic
streptokinase and urokinase are used only on a selective fracture of the femur with passive limb immobilization in
case-to-case basis. (7) the extended position, no application of harness was sug-
The annual incidence of osteomyelitis in developed gested. Oral paracetamol was given for pain relief.
countries is around 4 to 5 cases per 100,000 children, with Etiologic evaluation for VT and multiple abscesses in the
S aureus being the most common organism isolated. (8) neonatal period is quite challenging. Although inherited

Figure 4. A. Central figure of the infant showing right lower limb swelling from thigh to foot caused by osteomyelitis of the femur and cellulitis (methicillin-
resistant Staphylococcus aureus infection). B. Postarthrotomy purulent matter drainage and intravenous antibiotics led to subsiding of the swelling of the
right lower limb.

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 Figure 5. Ultrasonographic scans. A. Thrombosis of the right external iliac vein and common femoral vein (white arrow). B. Scapular abscess (white
arrow).

thrombophilia appears to be present in some neonates with management and prognostication of such unusual cases,
both catheter- and sepsis-related VT, the role of thrombo- early screening and diagnosis of primary immune deficiency
philia testing in neonates with VT is still debatable as it particularly that of phagocytic cell defect is of paramount im-
does not appear to acutely influence the type or duration portance in neonates with multiple abscesses. (12)
of treatment. Hence, the American Society of Hematol- VT, including portal VT, can be prevented by properly
ogy guidelines endorse thrombophilia testing mainly in inserting an umbilical venous catheter and preventing dis-
neonates with non–catheter-related VT. (11) For better placement of the catheter tip into the portal venous system
which might have occurred in our index case. (13) Preven-
tion of MRSA infection with strict infection control practi-
ces is of paramount importance as each additional day of
exposure in an uncolonized infant increases the acquisi-
tion risk of MRSA infection by 6%. (14)
Data on the prognosis of VT in neonates are lacking
and follow-up studies in general have shown mortality
ranging from 5% to 18%. (15) Long-term complications
such as post-thrombotic syndrome and portal hyperten-
sion with portal vein thrombosis are to be identified early
and managed as per standard recommendations.

LESSONS FOR THE CLINICIAN

• Critically ill neonates and those with sepsis are at major
risk of venous thromboembolic events.
• Timely intervention for venous thrombosis can salvage
limbs and prevent organ-threatening complications.
• Neonatal osteomyelitis is an emergency that requires
prompt medical and surgical intervention.
• Multifocal abscess in a neonate due to MRSA needs to
be evaluated for immunodeficiency and needs multidis-
Figure 6. Neonate at the time of discharge. ciplinary care and long-term follow-up

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by Almoosa Hospital user
Table 3. Table Summarizing the Course in the Hospital
DAY AFTER BIRTH 12 14 19 23 28 46 51
Hemoglobin, g/dL

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(g/L) 7.3 (73) 6.7 (67) 9.4 (94) 7.7 (77) 10 (10) 12.1 (121) 9.3 (93)
Total leukocyte
count, /µL (×109/L) 42,800 (42) 25,900 (25.9) 12,800 (12.8) 19,300 (19.3) 16,100 (16.1) 28,200 (28.2) 21,600 (21.6)
3
Platelet, ×10 /µL
(×109/L) 60 (60) 20 (20) 2.0 (2.0) 4.0 (4.0) 4.2 (4.2) 4.2 (4.2) 4.0 (4.0)
Body fluid culture and sensitivity
Blood Methicillin-resistant
Staphylococcus
aureus (MRSA)
Cerebropinal fluid No growth
culture
Urine culture No growth
Purulent matter MRSA
culture MRSA
Ultrasonography of The right common Resolution of Intramuscular and Bilateral lower limb
the lower limb femoral vein, right thrombus in subcutaneous arterial and
(Fig 2) external iliac vein, femoral and iliac edema in the right venous Doppler
and a small part vein. Persistent thigh. Collection shows normal
of the common thrombosis of the of 0.5 mL purulent flow velocity
iliac vein show left portal vein matter around hip
complete and umbilical vein joint associated
thrombus with cortical
irregularities of the
shaft of the femur
Radiography (Fig 3) Signs of osteomyelitis Antibiotic beads
of right femur (stimulant) in the
with periosteal right hip joint
reaction with after arthrotomy
cortical irregularity and purulent
with edema matter drainage
and joint lavage
Ultrasonography of Heterogenous Abscess in the Right parascapular An organized thick Resolution of
the shoulder hypoechoic subcutaneous and collection in the collection of 0.3 collection, mild
collection of size intramuscular form of mL near the right inflammation
5–6 mL just plane of 20–25 mL heterogenous scapular region present
superior to the near the right hypoechoic
right spine of the shoulder (uniquified 20 mL)
scapula in the
infraspinatus
muscle and
extending through
the spine of the
scapula

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 4. Engelmann B, Massberg S. Thrombosis as an intravascular
American Board of Pediatrics effector of innate immunity. Nat Rev Immunol. 2013;13(1):34–45
Epub 2012 Dec 7.
Neonatal-Perinatal Content 5. Greenway A, Massicotte MP, Monagle P. Neonatal thrombosis and
Specifications its treatment. Blood Rev. 2004;18(2):75–84
6. Chan AK, Monagle P. Updates in thrombosis in pediatrics: where
• Know the causative infectious agents and pathogene-
are we after 20 years? Hematology Am Soc Hematol Educ Program.
sis of osteomyelitis and septic arthritis.
2012;2012:439–443
• Know the clinical and laboratory features and differen-
7. Monagle P, Chan AKC, Goldenberg NA, et al. Antithrombotic
tial diagnosis of osteomyelitis and septic arthritis.
therapy in neonates and children: antithrombotic therapy and
• Know the management and complications of osteomy- prevention of thrombosis, 9th ed: American College of Chest
elitis and septic arthritis. Physicians Evidence-Based Clinical Practice Guidelines. Chest.
2012;141(2 suppl):e737S–e801S
8. Saavedra-Lozano J, Falup-Pecurariu O, Faust SN, et al. Bone and
joint infections. Pediatr Infect Dis J. 2015;36(8):788–799
Acknowledgments 9. Fisher R. Neonatal osteomyelitis. NeoReviews. 2011;12(7):e374–e380
The authors thank Dr Sangeeta Ravat, Dean, Seth GS 10. McMullan BJ, Campbell AJ, Blyth CC, et al. Clinical Management of
Medical College, and KEM Hospital, Mumbai, India, for Staphylococcus aureus bacteremia in neonates, children, and
granting permission for publication. adolescents. Pediatrics. 2020;146(3):e20200134
11. Klaassen IL, van Ommen CH, Middeldorp S. Manifestations and
clinical impact of pediatric inherited thrombophilia. Blood. 2015;
References 125(7):1073–1077

1. Sparger KA, Gupta M. Neonatal thrombosis. In: Eric C. Eichenwald, 12. O’Connell AE. Primary immunodeficiency in the NICU. Neoreviews.
Anne R Hansen, Camilia [Link], Ann R. Stark, Navin Jain, eds. 2019;20(2):e67–e78
Cloherty and Stark’s Manual of Neonatal Care. South Asia, India: 13. Kim JH, Lee YS, Kim SH, Lee SK, Lim MK, Kim HS. Does umbilical
Wolters Kluwer, 2021: 616–634 vein catheterization lead to portal venous thrombosis? Prospective US
2. Nowak-G€ ottl U, von Kries R, G€
obel U. Neonatal symptomatic evaluation in 100 neonates. Radiology. 2001;219(3):645–650
thromboembolism in Germany: two year survey. Arch Dis Child 14. Dong Y, Glaser K, Speer CP. New threats from an old foe:
Fetal Neonatal Ed. 1997;76(3):F163–7 methicillin-resistant Staphylococcus aureus infections in neonates.
3. Park CK, Paes BA, Nagel K, Chan AK, Murthy P; Thrombosis and Neonatology. 2018;114(2):127–134
Hemostasis in Newborns (THiN) Group. Neonatal central venous 15. Schmidt B, Andrew M. Neonatal thrombosis: report of a
catheter thrombosis: diagnosis, management and outcome. Blood prospective Canadian and international registry. Pediatrics. 1995;
Coagul Fibrinolysis. 2014;25(2):97–106 96(5 Pt 1):939–943

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 INDEX OF SUSPICION IN THE NURSERY

Term Neonate With Macrosomia and

Coarse Facies: An Overlapping Etiology
of Fetal Overgrowth
Prashanth Ranya Raghavendra, DM,* Medha Goyal, DM,† Shweta Mhatre, MD,* Anitha Haribalakrishna, MD, FRACP*
*Department of Neonatology, Seth G.S. Medical College and King Edward Memorial Hospital, Mumbai, India
†
Division of Neonatology, McMaster Children’s Hospital, Hamilton, Canada

THE CASE
A male infant is born to a 27-year-old gravida 3, para 1 mother with 2 spontaneous
abortions and 1 living child from a planned spontaneous pregnancy to nonconsangui-
neous parents. The cause of 2 spontaneous abortions has not been evaluated and the
older child is 3 years old with normal growth and development.
At 38 weeks of gestation, an ultrasonographic evaluation shows polyhydram-
nios with an amniotic fluid index of 28 and an estimated fetal weight of 4,500
g. There is no history of maternal diabetes, obesity, or exposure to medications,
smoking, alcohol, or recreational drugs. No other previous scan reports are avail-
able. She is referred to our center for delivery.
The infant is born at 39 weeks via cesarean delivery. His birthweight is 4,314 g,
length is 52 cm, head circumference is 36 cm, and the ratio of upper to lower seg-
ment is 1.6:1. Apgar scores are 9 and 9 at 1 and 5 minutes, respectively, and he
does not require any resuscitation after birth. Birth anthropometry on World Health
Organization growth charts suggested macrosomia, with all measurements between
2 and 3 standard deviations (SD).
Physical examination of the head confirms macrocephaly with 1 × 1.5 cm anterior
fontanel without overriding sutures and posterior fontanel admitting the fingertip.
The infant has coarse facial features with frontal bossing, bilateral infratemporal hol-
lowing, broad bulbous nose with flat philtrum, hypertelorism, and short broad nasal
root, macroglossia with a furrowed tongue, low-set ears, left ear skin tag, thick and
everted lower lip, and postaxial polydactyly (left upper and lower limbs) with overlap-
ping toes with a furrow. (Fig 1) There is no hepatomegaly, splenomegaly, or renome-
galy, and systemic examination findings are normal. He passes meconium within
24 hours after birth and is exclusively breastfed.
AUTHOR DISCLOSURES Drs
Raghavendra, Goyal, Mhatre, and
DIFFERENTIAL DIAGNOSIS
Haribalakrishna have disclosed no
• Congenital hypothyroidism financial relationships relevant to this
article. This article does not contain a
• Fetal overgrowth syndromes:
discussion of an unapproved/
A) Beckwith-Wiedemann spectrum investigative use of a commercial
B) Simpson-Golabi-Behmel syndrome product/device.

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 Figure 1. Clinical features noted in the index case: coarse facial features with frontal bossing, bilateral infratemporal hollowing, broad bulbous nose with
flat philtrum, hypertelorism, and short broad nasal root, macroglossia with a furrowed tongue, low-set ears, left ear skin tag, thick and everted lower lip,
and postaxial polydactyly (left upper and lower limbs) with overlapping toes with a furrow.

C) Sotos syndrome based on the temporal findings on examination, antenatal

• Infant of diabetic mother ultrasonography, and abnormal thyroid function test re-
• Storage disorder: sults, a final diagnosis of congenital hypothyroidism with
A) Mucopolysaccharidosis clinical Beckwith-Wiedemann spectrum is made (clinical
B) Lysosomal storage diseases score of 4—macroglossia [2], polyhydramnios [1], birth
weight >2 SD above the mean [1]).
ACTUAL DIAGNOSIS
The neonate underwent an extensive evaluation for the DISCUSSION
cause of fetal overgrowth (Table 1). Overgrowth syndromes are characterized by excessive
postnatal growth and tall stature, which is more than an
FINAL DIAGNOSIS individual’s genetic potential. This can be prenatal, postna-
Although genetic studies for fetal overgrowth and evalua- tal, or segmental. Prenatal overgrowth, which was seen in
tion for inborn errors of metabolism had normal results, this index neonate, refers to those who are born large for

Table 1. Investigations for Fetal Overgrowth in Index Neonate

INVESTIGATION RESULT
Complete blood cell count Normal
Blood glucose Normal
Serum calcium Normal
Radiographs of long bone (Fig 2) No other abnormality apart from left upper and lower limb
postaxial polydactyly
Normal bone age
Ultrasonography of abdomen No evidence of hepatosplenomegaly or renomegaly
Cranial ultrasonography Normal
Echocardiography Normal
Ophthalmologic examination No cataracts or cherry red spots
Inborn error of metabolism screening Negative
Karyotype Normal
Clinical exome sequencing for fetal overgrowth Normal
Methylation study Normal
Thyroid function test
Thyroid-stimulating hormone, µIU/mL (mIU/L) 17.17 (normal range, 0.72–11)
Free thyroxine, ng/dL (pmol/L) 1.25 (16.09) (normal range, 0.83–3.09 [10.68–39.77)
Free triiodothyronine, pg/mL (pmol/L) 3.710 (0.06) (normal range, 2.3–6.6 [0.04–0.10])
Ultrasonography of the thyroid Normal
Maternal hemoglobin A1C Normal
Histopathology of placenta Normal

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 (Table 3). (4) If the neonate has BWSp based on the scor-
ing system but has a negative test result, it is reasonable
to refer to a BWSp expert for further evaluation and man-
agement. The index neonate has a clinical score of 4 (mac-
roglossia [2], polyhydramnios [1], birth weight >2 SD
above the mean [1]).
The unique co-occurrence of congenital hypothyroidism
and overgrowth has been reported in a few case reports
and is often described as primary acquired hypothyroid-
ism. It has been hypothesized that the gene governing the
production of thyroxin-binding globulin might be in close
proximity to the one that governs the production of thy-
Figure 2. Radiographs of upper and lower limbs demonstrating normal roxin and also to the gene suppressing the manifestations
bone age and polydactyl. of BWSp. (5) Congenital hypothyroidism was reported in
gestational age, either macrosomic (>4,000 g) or with another case of a neonate with Sotos syndrome. (6)
length and weight greater than the 97th percentile. (1) In infants with suspected BWSp, the first-tier test is a
These neonates can continue to have accelerated postnatal methylation study which may show a gain of methylation
growth or follow a normal pace. The etiology commonly on IC1 (maternal), loss of methylation on IC2 (maternal),
includes maternal diabetes, Beckwith-Wiedemann spec- or both (paternal UPD); or a loss of chromosomal segment
trum (BWSp), Simpson-Golabi-Behmel, and Sotos syn- on 11p15.5 (along with its proper methylation) in nearly
drome. BWSp is the most common genetic overgrowth 75% cases. (4) If the methylation study is negative, se-
syndrome, with a prevalence of 1 in 10,340. (2) quence analysis or gene-targeted deletion-duplication anal-
Abnormal proliferation of chondrocytes and differentia- ysis of CDKN1C for loss of function on the maternal allele
tion into hypertrophic chondrocytes are seen. These are will detect 5% of cases with no family history and 40%
mediated by hormones such as parathyroid hormone– of cases with positive family history. (4) Karyotype may
related protein, growth hormone, insulinlike growth factor pick cytogenetic duplication, inversion, or translocation
1, fibroblast growth factor, and thyroid. (3) Various key of 11p15.5 in less than 1% of cases. (4) However, a chro-
causes of overgrowth syndromes seen in the neonatal pe- mosomal array (single nucleotide polymorphism based) can
riod are summarized in Table 2. pick small chromosomal deletions and duplications in 20%
Diagnosis of BWSp is made using the European Net- of cases. (4) When peripheral blood sample test results
work of Congenital Imprinting Disorders scoring system are negative, other tissues such as saliva, skin, or the

Table 2. Important Causes of Overgrowth Syndromes in the Neonatal Period

ETIOLOGY CLINICAL CHARACTERISTICS GENETIC BASIS
Beckwith-Wiedemann spectrum Hemihyperplasia, macroglossia, organomegaly, Chromosome 11p15.5 mutation
macrosomia, omphalocele
Simpson-Golabi-Behmel syndrome Macrosomia, macrocephaly, coarse facial features, Chromosome Xq26.2 (GPC3 mutation)
hypertelorism, ear lobe creases, macrostomia,
macroglossia, nipple anomalies, postaxial polydactyly
Sotos syndrome Prominent forehead, down slanting palpebral fissures, NDD1 mutation
malar flushing, macrosomia, joint laxity
Perlman Macrosomia, macrocephaly, hypotonia, abdominal wall DIS3L2 mutation
weakness, nephromegaly, cryptorchidism
Weaver syndrome Broad forehead and face, almond-shaped and down EZH2 gene
slanting palpebral fissures, wide philtrum, excess
loose skin, camptodactyly, stuck-on protruding chin
Bannayan-Riley-Ruvalcaba syndrome Macrosomia, macrocephaly, enlarged penis, PTEN-related disorders
supernumerary nipples, joint hypermobility, pectus
excavatum
MOMO syndrome Macrosomia, obesity, macrocephaly, ocular abnormalities LINC00237 gene
Primrose syndrome Enlarged and calcified external ears, distal muscle ZBTB20 mutation
wasting, microphthalmia, cataract, hypothyroidism,
corpus callosum agenesis

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 Table 3. Diagnosis of Beckwith-Wiedemann Spectrum (BWSp) is as per the European Network of Congenital
Imprinting Disorders Scoring System (4)
FINDINGS POINTS
Cardinal features
Macroglossia 2
Exomphalos 2
Lateralized overgrowth 2
Multifocal and/or bilateral Wilms tumor 2
Persistent hyperinsulinism (>1 wk) 2
Characteristic pathology: adrenal cortex cytomegaly, placental 2
mesenchymal dysplasia, pancreatic adenomatosis
Minor findings
Birthweight >2 standard deviations above the mean 1
Facial naevus simplex 1
Polyhydramnios 1
Ear creases and/or pits 1
Transient hyperinsulinism (<1 wk) 1
Characteristic tumor: Unilateral Wilms tumor, neuroblastoma, 1
rhabdomyosarcoma, hepatoblastoma, adrenocortical carcinoma,
or pheochromocytoma
Nephromegaly and/or hepatomegaly 1
Umbilical hernia and/or diastasis recti 1
Clinical Score Interpretation
41 BWSp confirmed
2–3 Diagnosis by genetic testing
0–1 BWSp rejected

hypertrophied tissue may identify low-level mosaic genetic The infant continues to exclusively breastfeed, with weight,
and epigenetic changes within 11p15.5 in up to 10% of affected length, and head circumference between 2 and 3 SD with nor-
patients. (7) mal development and continues to receieve close monitoring.
Short-term complications include the risk of hypoglycemia
and macroglossia-related feeding difficulty, the risk of apnea, Lessons for the Clinician
and persistent drooling. In the long term, the current guide- • Fetal overgrowth syndromes such as the BWSp present
lines of the American Association of Cancer Research recom- with inherited health concerns and risk of tumor predis-
mend uniform surveillance for all overgrowth syndromes with position necessitating prompt diagnosis at the earliest
an increased propensity for Wilms tumor (WT) and hepato- suspicion.
blastoma. (8) The overall risk of malignancy among BWSp pa- • The association of congenital hypothyroidism leads to
tients is approximately 7.5%: 4% WT, 1% hepatoblastoma, overlapping clinical findings because of the complex in-
terplay of genetic, epigenetic, and hormonal factors in
0.5% rhabdomyosarcoma, 0.5% neuroblastoma, and 1.3%
growth, which complicates the diagnosis.
all other tumors. (4)(9) a-fetoprotein (AFP) testing is currently
• A combination of methylation studies, karyotype, and
lacking in the international consensus statement as infants
clinical exome sequencing might still underdiagnose
with BWSp often have higher AFP levels. (7) The neurocogni-
those with BWSp, and these infants are required to be
tive development of BWSp patients is similar to that in the
followed up closely for growth and risk of malignancy.
general population, and therefore no additional surveillance is
recommended for development. (10)

Further Course American Board of Pediatrics

The infant has no complications during the hospital stay, Neonatal-Perinatal Content
is exclusively breastfeeding at the time of discharge, and Specifications
receives close follow-up by pediatrics genetics. At 3 months • Recognize the diagnostic implications of single vs.
and 6 months of follow-up, the coarse facial features and dys- multiple anomalies.
morphism persist. Repeat abdominal ultrasonography shows • Know the indications, limitations, and techniques
no evidence of organomegaly and thyroid function tests have for newborn screening for genetic disorders.
normalized with thyroid supplementation at 10 mg/kg per day.

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 3. Hartmann C, Tabin CJ. Dual roles of Wnt signaling during
chondrogenesis in the chicken limb. Development. 2000;127(14):
• Know the clinical features and inheritance 3141–3159
patterns of common syndromes or associations 4. Shuman C, Kalish JM, Weksberg R, et al. Beckwith-Wiedemann
that can be recognized in the newborn period (eg, syndrome. In: Adam MP, Feldman J, Mirzaa GM editors.
V
R
GeneReviews [Internet]. Seattle (WA): University of Washington,
VATER [vertebrae, anus, trachea, esophagus, and
Seattle; 2000:1993–2024.
limbs) association and DiGeorge syndrome).
5. Leung AKC, McArthur RG. EMG-syndrome and hypothyroidism.
• Know the disorders for which molecular genetic Clin Genet. 1989;36(4):269
studies are clinically indicated, such as cystic 6. Verma A, Salehi P, Hing A, Curda Roberts AJ. Sotos syndrome
fibrosis, and how to interpret test results. with a novel mutation in the NSD1 gene associated with congenital
hypothyroidism. Int J Pediatr Adolesc Med. 2021;8(3):191–194
7. Brioude F, Kalish JM, Mussa A, et al. Expert consensus document:
clinical and molecular diagnosis, screening and management of
Beckwith-Wiedemann syndrome: an international consensus
Acknowledgment statement. Nat Rev Endocrinol. 2018;14(4):229–249
The authors thank Dr Sangeeta Ravat, Dean, Seth GS 8. Kalish JM, Doros L, Helman LJ, et al. Surveillance recommendations
Medical College, and KEM Hospital, Mumbai, India, for for children with overgrowth syndromes and predisposition to wilms
granting permission for publication. tumors and hepatoblastoma. Clin Cancer Res. 2017;23(13):e115–e122
9. Brioude F, Toutain A, Giabicani E, Cottereau E, Cormier-Daire
References V, Netchine I. Overgrowth syndromes: clinical and molecular
aspects and tumour risk. Nat Rev Endocrinol. 2019;15(5):
1. Yachelevich N. Generalized overgrowth syndromes with prenatal 299–311
onset. Curr Probl Pediatr Adolesc Health Care. 2015;45(4):97–111 10. Barisic I, Boban L, Akhmedzhanova D, et al. Beckwith Wiedemann
2. Mussa A, Russo S, De Crescenzo A, et al. Prevalence of Beckwith- syndrome: a population-based study on prevalence, prenatal
Wiedemann syndrome in north west of Italy. Am J Med Genet A. diagnosis, associated anomalies and survival in Europe. Eur J Med
2013;161a(10):2481–2486 Genet. 2018;61(9):499–507

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 MATERNAL-FETAL CASE STUDIES

Alloimmunization in Pregnancy:
Implications for the Fetus and Neonate
Scott N. MacGregor, DO*
*Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Evanston Hospital - Endeavor Health, University of Chicago
Pritzker School of Medicine, Evanston, IL

ABSTRACT
Blood group or red cell alloimmunization occurs when a pregnant patient has
produced antibodies to a blood group antigen possessed by the fetus and
not possessed by the pregnant patient. Maternal antibodies are usually
produced as an immune response to fetal-maternal bleeding or blood
product transfusion. Prevention remains the most important strategy to avoid
the formation of maternal antibodies or alloimmunization. Maternal
alloimmunization may result in transplacental passage of these antibodies
into the fetal circulation and the potential for fetal or neonatal hemolysis and
anemia. Red cell alloimmunization can result in significant perinatal morbidity
and mortality. Management of alloimmunization in pregnant patients should
be protocol-driven. Current strategies for assessment and therapies allow for
more thorough and less invasive management with risks to mother and fetus.

THE CASE
A 37-year-old gravida 5, para 3-0-2-2-4 pregnant woman who conceived through in vitro
fertilization had anti-D antibodies with a titer of 1:1,024 at 10 weeks’ gestation. In her
last pregnancy, antibody screening had been negative, and she had received antepartum
Rh immune globulin at 28 weeks’ gestation. Her neonate was Rh positive and also re-
ceived intravenous immunoglobulin (IVIG) after delivery. Kleihauer-Betke testing per-
formed after delivery to assess for fetomaternal hemorrhage had negative results.
After the detection of anti-D antibodies in her current pregnancy, her husband
had D-antigen genotyping and was found to be heterozygous for D antigen. Given
that there was a 50% chance of her fetus being Rh positive, she underwent am-
niocentesis for fetal D-antigen genotyping. The amniocentesis results demon-
strated her fetus also to be D positive. In light of the low gestational age with high
risk of early-onset hemolytic disease of the fetus, Doppler assessments of the fetal
middle cerebral artery peak systolic velocity (MCA PSV), maternal plasmapheresis,
and IVIG therapy began at 13 weeks’ gestation.
AUTHOR DISCLOSURE Dr MacGregor has
disclosed no financial relationships
relevant to this article. This article does CASE PROGRESSION
not contain a discussion of an
unapproved/investigative use of a Her MCA PSV was initially just below the threshold of 1.5 multiples of the me-
commercial product/device. dian (MOM), providing reassurance that there was no significant fetal anemia.

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 She received 2 treatments of plasmapheresis and then be-
gan weekly IVIG therapy until 26 weeks’ gestation. Her
antibody titers decreased after plasmapheresis and IVIG
treatments. However, after IVIG at 26 weeks’ gestation,
her anti-D antibody titer again increased to 1:1,024. The
MCA PSV was elevated (>1.5 MOM) at 27 weeks, 2 days’
gestation, and she was scheduled for fetal blood sampling
with possible transfusion. She received betamethasone for
fetal lung maturity before her first transfusion. The blood
bank, maternal-fetal medicine, and neonatology specialists
coordinated a multidisciplinary preparation for a percuta-
neous umbilical blood sampling (PUBS) procedure.
Figure 2. Percutaneous umbilical blood sampling with needle inserted
At the time of her PUBS, a sinusoidal fetal heart rate pat- into the placental cord insertion of the posterior placenta.
tern was noted, consistent with severe fetal anemia (Fig 1).
PUBS was performed and the initial fetal hemoglobin A male infant was born at 29 weeks and 4 days’ gesta-
concentration was 4.1 g/dL (41 g/L). The fetus was given a tion via cesarean delivery, with Apgar scores of 6 and 8 at
transfusion and had a post-transfusion hemoglobin concen- 1 and 5 minutes, respectfully. The etiology of the fetal bra-
tration of 13.7 g/dL (137 g/L). The MCA PSV was 91 cm/s be- dycardia was most consistent with fetal vasospasm during
fore the transfusion and 44 cm/s after the transfusion. the PUBS procedure. He was noted to have respiratory dis-
The patient was scheduled to undergo repeat transfusion tress that was treated with continuous positive airway pres-
at 29 weeks, 4 days’ gestation because the MCA PSV in- sure. He had a birthweight of 1,788 g (82nd percentile). His
creased to greater than 1.5 MOM and a decrease in fetal he- admission hemoglobin concentration was 7.0 g/dL (70 g/L).
moglobin was calculated with advancing gestational age. In the NICU, the newborn received 2 doses of surfac-
The patient received a second course of betamethasone be- tant and was weaned to room air by 24 hours of age. He
fore the planned second PUBS. Fetal blood sampling was required 5 packed red blood cell transfusions during his
repeated, and the fetal hemoglobin was 6.5 g/dL (65 g/L). hospitalization in addition to phototherapy. He did not re-
During the procedure (Fig 2), a prolonged fetal bradycardia ceive IVIG and did not require an exchange transfusion.
He was eventually discharged at 41 days of age, with a he-
occurred before transfusion was initiated, which prompted
moglobin concentration of 11.2 g/dL (112 g/L).
an urgent delivery.

DISCUSSION
MATERNAL AND NEONATAL OUTCOMES
RhD alloimmunization occurs when RhD-positive cells en-
The pregnant patient underwent an urgent cesarean delivery ter the circulation of an RhD-negative person, stimulating
under spinal anesthesia without complications. Her postpar- an immune response with resulting production of anti-D
tum course was unremarkable. antibodies. The frequency of RhD-negative blood type
varies. The highest incidence is in the Basque region of
Spain (30%–35%). The incidence in other populations
varies, with an incidence of 15% in white North Americans
and Europeans, 8% in African Americans, 5% in Asian In-
dians, and less than 1% in non-Indian Asians. (1)
Most commonly, RhD alloimmunization occurs from
transplacental fetomaternal bleeding during pregnancy, if
the pregnant patient is RhD positive and the fetus is RhD
negative. Worldwide, the incidence of RhD alloimmuniza-
tion in pregnancy is 0.4% to 2.7%. (1) The incidence of
RhD alloimmunization historically was as high as 13% to
16% in RhD-positive pregnant patients. RhD immune
Figure 1. Fetal sinusoidal fetal heart rate at 27 weeks and 2 days’
globulin is administered to all RhD-positive pregnant pa-
gestation. tients to reduce the frequency of alloimmunization by

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 decreasing the likelihood of an immune response to RhD- blood group antigen and be at risk for developing HDFN. If
negative red blood cells. (1) Administration of RhD im- the father is heterozygous for the antigen, there is a 50%
mune globulin to pregnant persons with RhD-positive fe- risk that the fetus will inherit the antigen and be at risk. If
tuses reduces the incidence of RhD alloimmunization to the father is negative for the antigen, the fetus will not in-
0.4% to 1.8%.(1) The addition of routine antepartum RhD herit the antigen and will not be at risk for HDFN. In this
immune globulin administration to all RhD-negative preg- case, no further assessment and surveillance is required. (3)
nant patients at the beginning of the third trimester fur-
ther reduces the risk of RhD alloimmunization to 0.12% Fetal Antigen Testing
to 0.2%. (1) In patients with heterozygous or unknown paternal antigen
In infants born to pregnant persons with RhD alloim- status, it is possible to assess fetal antigen status using ei-
munization, 50% will be unaffected, 25% will be unaffected ther amniocentesis or noninvasive prenatal screening with
prenatally but require postnatal treatment of hyperbilirubi- fetal cell-free DNA from blood specimens from the preg-
nemia (phototherapy or exchange transfusion), and 25% nant person. Cell-free DNA testing can be performed for D,
will have severe fetal anemia requiring delivery or fetal c, C, E, Kell, and Duffy A antigens. (4) The sensitivity and
transfusion to avoid intrauterine fetal demise. (2) Proper specificity of cell-free DNA testing is very high. If the preg-
surveillance and treatment during pregnancy have greatly nant patient desires further confirmation, amniocentesis
reduced morbidity and mortality associated with RhD he- for fetal genotype can be performed. (4)
molytic disease of the fetus and newborn (HDFN). (2)
Screening for red cell alloimmunization in pregnant Antibody Titer Assessment
persons is routinely performed at the initial presentation If the fetus is at risk based on 1) fetal antigen testing (amnio-
for obstetric care. (1) If antibodies are present, identifica- centesis or cell-free DNA testing), 2) paternal antigen testing
tion of the specific antibody is routinely performed. If the without fetal antigen testing, or 3) unknown paternal antigen
antibody is against blood group antigens associated with testing, serial assessment of antibody titers in the pregnant
increased risk for HDFN, additional evaluation is required. person is performed every 4 weeks. The critical titer, or titer
(3) For pregnant patients, after identification of antibodies at which the fetus is considered at risk for hemolytic ane-
associated with HDFN, management involves a stepwise mia, varies among blood banks and most commonly is 1:16
approach to identify whether the fetus is at risk for HDFN or 1:32. (3) Fortunately, for most pregnant patients with al-
and to determine the degree of risk (Table). (3) loimmunization, the titer does not reach the level at which
additional evaluations are required before delivery. (3)
ASSESSMENT OF FETAL RISK AND ANEMIA
Paternal Antigen Testing Assessment of Severity of Fetal Anemia
After identifying antibodies in the pregnant person that may If the titer of the pregnant person reaches the critical level,
be associated with HDFN, the next step would be to assess additional evaluations are required. In the past, serial am-
for paternal antigen status. If the father of the fetus is homo- niocentesis was performed every 2 to 4 weeks to assess the
zygous for the antigen, the fetus will inherit the concerning amniotic fluid d OD450. The d OD450 reflects the spectro-
photometric deflection due to amniotic fluid bilirubin,
Table. Stepwise Assessment of a Pregnant Person with which is produced with fetal hemolysis. Doppler measure-
Blood Group Alloimmunization ment of fetal MCA PSVs has replaced amniotic fluid d
OD450 for the assessment of fetal anemia. As the fetal he-
Step 1: Antibody screening shows positive finding in the
pregnant person moglobin concentration decreases, the fetal blood becomes
Step 2: If antibody screening result positive, perform antigen less viscous, resulting in increased velocity that can be reli-
genotype testing in partner
Step 3: If partner is antigen heterozygous, determine fetal risk ably measured with Doppler ultrasonography.(5)(6) MCA
with antigen testing using cell-free DNA or amniocentesis PSV has similar or better sensitivity and specificity com-
Step 4: If fetal antigen is positive or unknown, obtain serial
antibody titer measurements in the pregnant person pared with amniotic fluid d OD450 and is noninvasive.
Step 5: If critical fetal antibody titer is reached, assess fetal anemia MCA PSV is considered normal if it is less than 1.5 MOM for
with weekly MCA PSV Dopplers
Step 6: If MCA PSV >1.5 MOM for gestational age, perform fetal
gestational age. (5)(6) If the MCA PSV is above 1.5 MOM,
PUBS with possible transfusion there is an increased risk of severe fetal anemia requiring ad-
MCA PSV5middle cerebral artery peak systolic velocity, MOM5multi- ditional diagnostic evaluation. MCA PSV is usually per-
ples of the median. formed weekly. (3)(5)(6)

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 Fetal Blood Sampling and Transfusion neonatal FcRn with similar actions as suggested for IVIG,
The standard approach to suspected fetal anemia with specifically, reduced transfer of IgG across the placenta and
MCA PSV greater than 1.5 MOM at preterm gestational age reduced circulating antibody. The advantage of the mono-
less than 34 weeks is to perform fetal blood sampling with clonal antibody compared with IVIG is that the monoclonal
possible transfusion. (5)(6) Under ultrasound guidance, a antibody has greater targeted blockage of the FcRN. (8)
spinal needle is introduced, preferably into the umbilical
cord at the placental cord insertion, and immediate fetal as-
sessment is performed to determine whether to proceed CONCLUSIONS
with transfusion (Fig 2). The procedure is usually per-
A systematic approach to the assessment and manage-
formed with local anesthesia and occasionally sedation of
ment of alloimmunization in pregnancy reduces the risk
the pregnant person. The amount of blood that is trans-
of fetal morbidity and mortality associated with HDFN. In
fused is based on a calculation using the estimated fetal
the future, it is possible that plasmapheresis and IVIG or
weight, the estimated fetoplacental blood volume, hemato-
monoclonal antibody–blocking neonatal Fc receptors could
crit of the transfused blood, and the initial hematocrit of
be more widely used to reduce the need for, and risks of,
the sampled fetal blood. The goal of transfusion would be
invasive procedures including fetal blood sampling and fe-
to increase the hemoglobin to approximately 15 g/dL (150
tal transfusion.
g/L). After 34 weeks’ gestation, antenatal steroids should
also be considered, as an option for lung maturity (if not al-
ready given) and delivery. (3)
American Board of Pediatrics
Delivery
Timing of delivery for patients with titers remaining below
Neonatal-Perinatal Content
the critical titer is based on routine obstetric management. Specifications
For patients with a critical titer resulting in weekly MCA • Know the effects on the fetus and/or newborn infant of
PSVs and not requiring fetal transfusion, delivery is usually maternal immunologic diseases and their management.

recommended at 37 weeks’ gestation.(3) For patients requir- • Know the general principles, applications, and limita-
tions of ultrasonography, including Doppler blood flow
ing frequent fetal transfusions, delivery is typically earlier.
measurements, in assessment of fetal conditions and
well-being.
UNCOMMON MANAGEMENT CONSIDERATIONS • Understand the rationale, interpretation, and limitations
This case illustrates an uncommon problem in a pregnant of maternal detection of fetal movement, of the bio-
physical profile, the non-stress test, and the contraction
patient with blood group alloimmunization. The case re-
stress test as means of assessing fetal well-being.
quired the uncommon use of plasmapheresis and IVIG early
• Know the diagnostic evaluation and perinatal manage-
in the second trimester given the high risk of early onset of ment of fetal-maternal blood group incompatibility.
HDFN. Data correlating MCA PSVs in the early second tri-
mester with fetal anemia are limited; however, there have
been some extrapolations of these data in unusual and se-
vere circumstances. These values could be used to suggest
the risk of fetal anemia before 18 weeks’ gestation. (5)(7)
References
One case series suggested that pregnant patients with 1. Prevention of RhD Alloimmunization during pregnancy Practice
Bulletin No. 181 American College of Obstetricians and
risk for, or suspected to have, severe fetal anemia before
Gynecologists. Obstet Gynecol. 2017;130:e57–e70
18 weeks’ gestation could be treated with plasmapheresis
2. Koelewijn JM, Vrijkotte TGM, van der Schoot CE, Bonsel GJ, de Haas
and IVIG therapy to reduce the risk of fetal hemolysis and M. Effect of screening for red cell antibodies, other than anti-D, to
anemia. (8) Plasmapheresis was used to reduce maternal detect hemolytic disease of the fetus and newborn: a population study
antibody. IVIG was used to bind to the neonatal Fc receptor in the Netherlands. Transfusion. 2008;48(5):941–952

(FcRn), reducing transfer of antibodies across the placenta, 3. Management of RhD Alloimmunization during pregnancy: practice
bulletin no 192. American College of Obstetricians and Gynecologists.
and decreasing circulating antibodies. There is currently a
Obstet Gynecol. 2018;113:e82–e89
multicenter, open-label study evaluating a monoclonal anti-
4. Alford B, Landry BP, Hou S, et al. Validation of a non-invasive
body in pregnant patients at high risk for early-onset severe prenatal test for fetal RhD, C, c, E, K and Fya antigens. Sci Rep.
HDFN. The monoclonal antibody specifically targets the 2023;13(1):12786

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 5. Mari G, Deter RL, Carpenter RL, et al. Noninvasive diagnosis by 7. Tongsong T, Wanapirak C, Sirichotiyakul S, Tongprasert F,
Doppler ultrasonography of fetal anemia due to maternal red-cell Srisupundit K. Middle cerebral artery peak systolic velocity of healthy
alloimmunization. N Engl J Med. 2000;342(1):9–14 fetuses in the first half of pregnancy. J Ultrasound Med.
6. Oepkes D, Seaward PG, Vandenbussche F, et al. DIAMOND 2007;26(8):1013–1017
Study Group. Doppler ultrasonography versus amniocentesis 8. Ruma MS, Moise KJ, Jr, Kim E, et al. Combined plasmapheresis and
to predict fetal anemia. N Engl J Med. 2006;355(2): intravenous immune globulin for the treatment of severe maternal red
156–164 cell alloimmunization. Am J Obstet Gynecol. 2007;196(2):138.e1–138.e6

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 VISUAL DIAGNOSIS

Unusual Dermatologic Findings in an

Extremely Low Birthweight Infant:
The Genetic Diagnosis
L. Elizabeth Ricker, MMS, PA-C,* Matthew Saxonhouse, MD,*† Lauren Carter, MD†‡
*Department of Neonatology, Atrium Health-Levine Children’s Hospital, Charlotte, NC
†
Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC
‡
Department of Medical Genetics, Atrium Health-Levine Children’s Hospital, Charlotte, NC

THE CASE
An extremely low-birthweight (ELBW) preterm neonate presents with unusual
dermatologic findings, atypical hair features, and extremity abnormalities.

PRENATAL AND BIRTH HISTORIES

• Born to a 26-year-old gravida 3, para 2 woman with normal results on prenatal
laboratory screening.
• Parents are from similar regions in Central America; no known consanguinity.
• The prenatal course is notable for limited prenatal care.
• Female infant born at 28 3/7 weeks’ gestation following premature rupture
of membranes, fetal bradycardia, and concern for placental abruption.
• Born in a vaginal delivery and had decreased tone and respiratory distress. The
infant required positive pressure ventilation initially and then underwent intuba-
tion; Apgar score of 2, 4, 6, and 8 at 1, 5, 10, and 15 minutes, respectively.
• Sepsis risk factors: Group B Streptococcus status unknown with inadequate
treatment.

PRESENTATION (NEWBORN DAY)

Vital Signs
• Heart rate: 170 beats/min
• Respiratory rate: 35 breaths/min
• Blood pressure: 39/24 (mean 31) mm Hg
• Oxygen saturation: 98% on synchronized intermittent mechanical ventilation
peak inspiratory pressure of 18 mm cm H2O, positive end-expiratory pressure
of 5 cm Hg, rate of 40 breaths/min, and fraction of inspired oxygen of 0.55 AUTHOR DISCLOSURE Dr Carter is
• Temperature: 97.7 F (36.5 C) vice-chair of the American College of
Medical Genetics Education Committee.
Dr Saxonhouse has attended meetings
Physical Examination with the support of Pediatrix. Ms Ricker
• Birthweight 860 g (20th percentile), head circumference 24 cm (15th percentile) has disclosed no financial relationships
relevant to this article. This article
• Head: Normocephalic with significant bruising; normal, open, flat fontanelles;
does not contain a discussion of an
prominent hyperpigmented eyebrows, scalp alopecia with hyperpigmentation, unapproved/investigative use of a
fused eyes commercial product/device.

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 • Oral cavity: Pink mucosae, intact palate, natal teeth
• Lungs: Clear, equal breath sounds; moderate retractions,
good aeration throughout
• Cardiovascular: Normal S1, S2; regular rate and rhythm;
no murmurs or gallops
• Abdomen: Soft, nontender, nondistended; no hepato-
splenomegaly
• Genitourinary: Normal preterm female genitalia; patent anus
• Skin: Severely friable, gelatinous, and immature skin out
of proportion to her level of prematurity
• Extremities: Large broad toes, long fingers
• Neurologic: Active, symmetric Moro reflex, normal strength
and tone

Laboratory Studies
• Complete blood cell count: White blood cell count 9.9 ×
103/mL (9.9 × 109/L), hemoglobin 13.7 g/dL (8.5 mmol/L),
hematocrit 42%, platelet 170 × 103/mL (170 × 109/L)
• Blood culture: Sent

Progression
The infant required increased total fluid volume administra-
tion for high insensible losses and persistent hypernatremia.
Cranial ultrasonography at 1 and 4 days of age did not show
any abnormalities. The blood culture had no growth. At
2 days of age, enteral feedings were initiated and she toler- Figure 1. Infant at 5 days of age demonstrating inflammatory skin
ated advancement, though her feedings were later discontin- changes.
ued due to acute illness. Echocardiography was performed at
4 days of age because of increased work of breathing and low (ARCI) as often being born prematurely and encased in a
blood pressure to rule out a patent ductus arteriosus; the collodion membrane that typically transitions to a scal-
findings were normal except for a small atrial septal defect. ing, erythematous skin within 2 to 4 weeks. Affected in-
Given her worsening skin appearance with standard incuba- fants are at risk for high insensible losses and resulting
tor humidity weaning protocol, she was maintained at high electrolyte abnormalities. (1)
levels of humidity (75%–85%) during the first week after With various forms of congenital ichthyosis and limited
birth. Topical emollients as well as topical and systemic anti- documented cases of ELBW infants, the patient did not fit
fungal medications were used to treat advancing erythema- within a specific ARCI type. Thus, the genetics team was
tous skin changes. Her skin findings at 5 days of age and
15 days of age are shown in Figs 1 and 2.

Differential Diagnosis
• Immature premature skin
• Congenital candidiasis
• Congenital ichthyosis
• Genetic condition

Actual Diagnosis
Given this infant’s presentation, an initial working diagnosis
of congenital ichthyosis was pursued. Dias et al (1) describe
Figure 2. Infant at 15 days of age demonstrating inflammatory skin
infants with autosomal recessive congenital ichthyosis changes.

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 consulted at 7 days of age and a microarray was sent. The
single nucleotide polymorphism microarray results were re-
ported at 18 days of age and demonstrated the absence of
heterozygosity in an area of epidermal growth factor recep-
tor (EGFR) presence. Given the clinical overlap with her
features, autosomal recessive EGFR variant was considered
as a possible diagnosis. The infant underwent rapid trio
exome sequencing.
Trio whole exome sequencing revealed homozygous
pathogenic variants in EGFR, c.1631 1 1 G>A, in intron
13 of the gene, which are novel canonical splice site var-
iants. Results confirmed the diagnosis of autosomal reces-
sive EGFR-related inflammatory skin and bowel disease.
During the rest of her hospitalization, the infant’s skin
underwent various inflammatory changes including scaling,
sloughing, seeping, and pustule development (Fig 3), and
her once prominent eyebrows began to “peel” off (Fig 4).
She underwent multiple courses of systemic antibiotic and
antifungal treatment of presumed and identified infections
(including Serratia marcescens in the blood and tracheal cul-
tures and Enterococcus fecalis from a swab of a chest skin le-
sion). She required increased total fluid volumes (as high as
260 mL/kg per day) for persistent electrolyte derangements
but did not have any gastrointestinal issues. She had persis-
tent and profound hypotension that required inotropic sup-
port and was found to have adrenal insufficiency treated
with hydrocortisone. She had decreased urine output and
developed acute renal failure. At 39 days of age, she de-
veloped significant bradycardic and apneic events and re-
quired intubation. Brain magnetic resonance imaging Figure 4. Inflammatory skin and eyebrow changes at 35 days of age.
showed devastating progressive severe encephalomalacia,
extensive cystic periventricular leukomalacia, and ventri-
What the Experts Say
culomegaly. She ultimately died of multiorgan system
Neonatal inflammatory skin and bowel disease are associ-
failure at 6 weeks of age.
ated with homozygous disease-causing variants of the EGFR
gene. (2)(3)(4)(5) Receptors found along the cellular surface
bind to epidermal growth factor and other factors, inducing
the processes responsible for cell survival, proliferation, and
differentiation. (2)(3) Mutations of this gene are commonly
expressed in neoplastic disease. (2)(3)(4)(5) Neonatal inflam-
matory skin and bowel disease is a rare condition. (2) This
presents the challenge of limited amount of literature on
the neonatal disease course and management, specifically in
the premature ELBW infant.
Lemos et al (2) describe a similar case of a premature fe-
male infant born at 28 weeks’ gestation with intrauterine
growth restriction and subsequent ELBW, failure to thrive,
fragile skin with recurrent infections, and distinctive atypi-
Figure 3. Inflammatory skin changes at 21 days of age. cal craniofacial features. The infant is described as having

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 had “persistently erythematous and friable skin” with elec- inflammatory changes found on this infant’s examination.
trolyte derangements requiring high total fluid volumes Candida was also unlikely because the skin did not show
and frequent replacement therapy. This infant had signifi- improvement with antifungal treatments. Congenital ich-
cant congenital heart defects (ventricular disproportion with thyosis was also determined to be inconsistent with this in-
hypoplastic left ventricle, severe aortic arch hypoplasia, fant’s findings as it describes thick, scaly plates of skin that
complete atrioventricular septal defect, and a patent ductus shed over time.
arteriosus), as well as nephromegaly and severe brain injury
(bilateral ventricular hemorrhage with severe periventricular Lessons for the Clinician
and subcortical white matter lesion, cerebellum atrophy, • Neonatal inflammatory skin and bowel disease due to
and a mega cisterna magna). Genetic testing resulted in a disease-causing variants in EGFR should be included in
homozygous variant of the EGFR gene. The infant ulti- the differential diagnosis when encountering unusual
mately died of related cardiac failure at 3 months of age. dermatologic findings in the ELBW infant.
In another report, Alruwaithi and Sherlock (4) describe • Early involvement of genetics consultants with rapid
a 5-year-old female patient born at 27 weeks’ gestation whole exome sequencing should be considered in pre-
with ELBW, similarly fragile skin, recurrent infections, mature infants with obscure inflammatory skin changes.
failure to thrive, cardiac defects (large ventriculoseptal de-
fect and mitral valve regurgitation), renal enlargement,
and multiple phenotype abnormalities (thick eyebrows, al-
opecia, arachnodactyly). This child is believed to be the
American Board of Pediatrics
longest living of the few known ELBW patients with this Neonatal-Perinatal Content
EGFR disease–causing variant with a course notable for Specification
failure to thrive and recurrent hospitalizations for skin • Know the indications, limitations, and techniques for
and gastrointestinal infections at the time her case was newborn screening for genetic disorders.
documented. (4)
Most recently, Labbouz et al (3) described a 685 g male
infant born at 26 4/7 weeks’ gestation with a homozygous
EGFR gene mutation, further delineated as a missense mu- References
tation resulting in loss of function. (3) The infant’s clinical
1. Dias JV, Cardoso K, Prado SN, Cavaco H. Congenital ichthyosis: a
presentation was similar to the other published cases, how- multidisciplinary approach in a neonatal care unit. BMJ Case Rep.
ever, with necrotizing enterocolitis and rectal perforation as 2023;16(2):e250077
well. This infant developed acute renal failure and subse- 2. Lemos M, Gonçalves JS, Correia CR, Maria AT. Neonatal
inflammatory skin and bowel disease type 2: a very rare disease
quent metabolic acidosis, and died at 11 months of age. (3)
associated with EGFR mutation. JPNIM. 2021;10(1):e100123
In their report, Labbouz et al also provide a detailed de-
3. Labbouz S, Keegan G, King T. Neonatal cutaneous inflammatory
scription of clinical findings in the literature on patients syndrome associated with homozygous epidermal growth factor
with EGFR gene variants for comparison. Only 3 of the 8 receptor mutation. Pediatr Dermatol. 2023;40(1):171–175
clinical cases reviewed were of infants born at less than or 4. Alruwaithi M, Sherlock M. A210 neonatal inflammatory skin and
bowel disease caused by a homozygous egfr mutation: a case report
equal to 28 weeks’ gestation, and all had the same homozy-
and review of the medical literature. J Can Assoc Gastroenterol. 2018;
gous EGFR gene mutation of c. 1283G>A (p. Gly428Asp). 1(suppl_1):367–368
The differential diagnoses of immature premature skin 5. Scaltriti M, Baselga J. The epidermal growth factor receptor pathway:
and congenital candidiasis were inconsistent with persistent a model for targeted therapy. Clin Cancer Res. 2006;12(18):5268–5272

ANSWER KEY FOR NOVEMBER 2024 NEOREVIEWS

Disorders of Coagulation in the Newborn:
1. B; 2. E; 3. A; 4. C; 5. D
Thrombotic Disorders in the Newborn:
1. A; 2. E; 3. D; 4. C; 5. D

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 COMPLEX FETAL CARE

COMPLEX
FETAL CARE

Pallister-Killian Syndrome
Ritu Chitkara, MD,*† Valerie Chock, MD, MS Epi,*† Richard Barth, MD,*‡ Hisham Dahmoush, MBChB,*‡
Carly Smith, MGC, LCGC,*§ Dena R. Matalon, MD,*§ Melissa Herring, MBBS,¶ Susan Hintz, MD, MS Epi*†
*Fetal and Pregnancy Health Program, Lucile Packard Children’s Hospital, Stanford Medicine Children’s Health, Palo Alto, CA
†
Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA
‡
Department of Radiology, Stanford University School of Medicine, Palo Alto, CA
§
Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA
¶
Department of Pathology, Stanford University School of Medicine, Palo Alto, CA

CASE PRESENTATION
AUTHOR DISCLOSURES Dr Chock works
A 27-year-old gravida 6, para 2 woman was referred to our fetal care center at under grants from Stanford University
26 3/7 weeks’ gestation because of the presence of multiple fetal anomalies. Global Health, The Cerebral Palsy Alliance
Research Foundation and the Harman
The maternal and pregnancy histories were notable for substance use (tetra-
Faculty Scholars award, The NICHD
hydrocannabinol, alcohol, methamphetamines), depression, herpes labialis (on Neonatal Research Network, and
suppressive therapy), exercise-induced asthma, and normocytic anemia. She es- Nationwide Children’s Hospital. She has
attended meetings with the support of the
tablished late prenatal care at 25 1/7 weeks’ gestational age (GA) at which time,
University of California Los Angeles and
anatomic ultrasonography showed sonographic age of 23 3/7 weeks’ gestation the Newborn Brain Society, and is a board
(estimated fetal weight [EFW], 2nd percentile), polyhydramnios (amniotic fluid member of the Newborn Brain Society.
Dr Dahmoush has attended meetings with
index [AFI], 28.6 cm), omphalocele, shortened femurs (measuring 17 2/7 weeks’ ges-
the support of Stanford University.
tation), concave chest, and stomach positioned above the diaphragm. These findings Dr Matalon works under grants from the
prompted referral to our fetal care center for further evaluation and multidisciplinary NIH Genomics Research to Elucidate the
Genetics of Rare Disease Consortium and
consultation.
Stanford MCHRI and Department of
Anatomic ultrasonography at our institution at 26 3/7 weeks’ gestation revealed Pediatrics. They have delivered paid expert
multiple congenital anomalies including left-sided congenital diaphragmatic hernia testimony for Dinsmore & Shohl, LLP, and
Sutton Pierce, LLC. Ms Smith works under
(CDH) containing liver, bowel, and stomach (lung-to-head circumference ratio [LHR],
a grant from, and has attended meetings
0.95); small omphalocele containing liver and bowel; severe shortening of the long with the support of, Stanford Medicine
bones especially the femurs (9 weeks behind dates); right hand deformity; severe pol- Children’s Health. Drs Chitkara, Barth,
Matalon, Herring, and Hintz have disclosed
yhydramnios (maximum vertical pocket, 11 cm); small chest cavity; generalized skin
no financial relationships relevant to this
thickening; flattened facial profile; interocular distance suggesting hypertelorism; fetal article. This article does not contain a
growth restriction (EFW <2nd percentile); and elevated umbilical artery Dopplers discussion of an unapproved/investigative
use of a commercial product/device.
(4.7–6.3). Fetal magnetic resonance imaging (MRI) performed the same day showed
a large left-sided CDH containing the left hepatic lobe and stomach associated with
rightward displacement of the heart and severely diminished fetal lung predictors ABBREVIATIONS

(LHR 0.76 and observed/expected [O/E] LHR 29.5%). Although severe fetal growth AFI amniotic fluid index
restriction makes predictive interpretation more challenging, calculated total fetal CDH congenital diaphragmatic hernia
EFW estimated fetal weight
lung volume (TFLV) was 4.3 mL (normal TFLV at this GA is 34.8 mL [range GA gestational age
22.5–44.2 mL]), O/E TFLV was 12%, and no significant left fetal lung tissue was iden- LHR lung-to-head circumference ratio
tified. Additional fetal MRI findings included a small omphalocele containing liver; MRI magnetic resonance imaging
O/E observed/expected
deformity of the right hand; generalized prominence of the extra-axial spaces; and PKS Pallister-Killian syndrome
widely spaced eye globes and thick coarseness of the facial soft tissues (Fig 1). Fetal TFLV total fetal lung volume

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 Figure 1. A. Fetal ultrasonography at 26 3/7 weeks’ gestation showing a small abdominal omphalocele (arrow). Fetal magnetic resonance imaging scan
at 26 3/7 weeks’ gestation showing congenital diaphragmatic hernia with liver (black arrows) herniated into left chest and heart displaced into right
chest (white arrow) (B); deformed hand (arrows) (C); widely spaced eye globes (D); coarse facial features and prominence of extra-axial spaces (E).

echocardiography at 26 3/7 weeks’ gestation showed normal input of our colleagues from maternal-fetal medicine, neo-
cardiac structure and function with mild hypertrophy of both natology, genetics, and pediatric surgery. From fetal lung
ventricles. Cell-free DNA screening showed low risk (<1/ predictors for CDH alone, mortality and/or need for extra-
10,000) for trisomies 21, 18, and 13 and monosomy X as well corporeal membrane oxygenation were estimated to be
as low risk for triploidy; a female fetus was predicted. The high. The additional anomalies also predicted a low likeli-
couple received urgent genetic counseling given the imaging hood of survival. If the infant’s respiratory function could
findings and were offered late amniocentesis but declined. be supported, surgical management would remain chal-
lenging given both the CDH and omphalocele. The initial fo-
EXPERT OPINION cus would be to approach the CDH from the chest because
Given the multiple anomalies, the case was presented at the omphalocele prevented an abdominal approach. There
our multidisciplinary fetal care conference to solicit the was high suspicion for an underlying genetic etiology. Medical

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 genetics would be consulted postnatally with a plan to send a clamped and cut. The infant was moved to the warmer,
microarray and reflex to exome sequencing if necessary. placed in a bowel bag to cover the omphalocele, and under-
The expectant parents were extensively counseled by went intubation. A Replogle tube was inserted to aid with
specialists in neonatology, pediatric surgery, and medical gastrointestinal decompression. Auscultation of the heart
genetics. Social work involvement was vital during counseling rate was difficult given the CDH, and the infant briefly re-
and throughout the prenatal course. In-depth discussions fo- ceived chest compressions in the delivery room. Electrical
cused on delivery room management of the CDH and om- activity was noted on the cardiac monitors and, while aus-
phalocele as well as escalation of resuscitative efforts to cultation continued to pose a challenge, a brachial pulse
possibly include chest compressions and intravenous medica- was palpable.
tions should their daughter not respond to initial interven- Upon arrival to the NICU, attempts at establishing ac-
tions. The option of solely comfort care was also explained in cess proved difficult given the limitations posed by the
detail. The couple opted for a trial of intensive care with full omphalocele. Both peripheral intravenous access and pe-
attempts at resuscitation. ripheral arterial access were unsuccessful. Intraosseous ac-
cess obtained in the right tibia initially functioned but
PRENATAL COURSE then infiltrated. An emergent umbilical venous catheter
The pregnant patient presented several times over the next was placed through the omphalocele while pediatric sur-
few weeks with abdominal pain due to worsening polyhy- gery attempted femoral access that was unsuccessful.
dramnios (AFI 35 cm and then 44 cm). Amnioreduction The infant was placed on high-frequency oscillatory
was offered but the patient declined. She received betame- ventilation with a fraction of inspired oxygen of 1.0 and in-
thasone and tocolysis. At 30 5/7 weeks’ gestation, she haled nitric oxide of 20 parts per million. She was given 1
again presented with abdominal pain and contractions dose of intratracheal surfactant. Her chest radiograph
(AFI 47 cm), and this time consented to amnioreduction showed near total opacification of the thorax [Fig 2]. The en-
given the severity of her pain. Approximately 2 L of fluid dotracheal tube was noted to be high and subsequently ad-
was removed with notable symptomatic relief; an addi- vanced. Pre- and postductal oxygen saturations demonstrated
tional 30 mL of amniotic fluid was sent for cytogenetic a 60-point difference. The infant’s heart rate slowly
studies including a karyotype. She was followed closely as
an outpatient with serial ultrasonography. Her last ultrasono-
graphic scan performed at 32 2/7 weeks’ gestation before ul-
timately delivering at 32 5/7 weeks’ gestation showed an AFI
of 44.7 cm. At that time, the EFW was 1,149 g (<2nd per-
centile) mainly due to severely shortened long bones fol-
lowing a rhizomelic pattern (femur length measuring 20
6/7 weeks’ gestation and humeral length measuring 21
2/7 weeks’ gestation whereas biparietal diameter and head
circumference measured at 34 and 35 4/7 weeks’ gesta-
tion, respectively). Umbilical artery Dopplers were elevated
with systolic/diastolic ratio of 3.9 to 5.4 (95th percentile
systolic/diastolic ratio at 32 weeks’ GA is 3.79) and the
LHR was 0.87 (O/E LHR 26%–28%). The left-sided CDH
was again seen with right mediastinal shift as was the om-
phalocele. There was mild skin edema but no other evi-
dence of hydrops.

OUTCOME AND POSTNATAL COURSE

The pregnant patient presented in active labor at 32 5/7 weeks’ Figure 2. Chest radiograph at approximately 30 minutes of age. Endotra-
cheal tube is in the cervical trachea (subsequently advanced 1 cm). Naso-
gestation. She underwent urgent cesarean delivery in the gastric/orogastric tube with tip and side-port projecting over the left
context of multiple fetal anomalies and a desire for full re- lower thorax. There is complete opacification of the thorax with air bron-
chograms and the cardiomediastinal silhouette is completely obscured by
suscitation and intensive care support. The infant emerged the opacified lungs. Subcutaneous edema is noted as well as 11 ribs
hypotonic and apneic. The umbilical cord was immediately bilaterally.

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 downtrended to less than 60 beats/min. Chest compressions hexasomic for the short arm of chromosome 12. Mosaicism
were provided, and she was given a dose of intravenous epi- for an isochromosome of the short arm of chromosome 12
nephrine. She received 1 dose of sodium bicarbonate for pro- is clinically associated with Pallister-Killian syndrome (PKS).
found metabolic acidosis and 60 mL of packed red blood cells While most cases of PKS are the result of tetrasomy 12p,
for a hematocrit value of 21%. She was given fentanyl boluses rare cases of hexasomy 12p have been reported. (1)(2)
for pain and sedation. The mother was brought to the bedside The parents consented to have an autopsy. Notable find-
and counseled on the infant’s condition. In discussion with ings on autopsy (Fig 3) included abnormal facies (promi-
the team and given the infant’s poor prognosis, the family nent forehead, hypertelorism, sparse eyebrows, flattened
elected to stop resuscitative efforts. The infant underwent com- nasal bridge, short nose, long philtrum, peaked upper lip,
passionate extubation and was placed in her mother’s arms. patchy cranial hair, short neck) and skeletal anomalies
She died approximately 30 minutes later at 2 hours of age. (short limbs with humerus and radius length fourth per-
Results of the karyotype from the amniocentesis were centile for GA; femur, tibia, and fibula length <1st percen-
48,XX,1i(12)(p10)x2[2]/46,XX[17]. Identification of the presence tile for GA; fused right duplicated first toe; 11 ribs). The
of 2 i(12p) chromosomes indicated that the fetus was omphalocele included intestinal malrotation containing a

Figure 3. Gross autopsy photographs. A. Skeletal radiograph demonstrating rhizomelic limb shortening. B. Omphalocele. C. Intestinal malrotation con-
taining 10 cm dilated loop of bowel. D. Lung hypoplasia. E. Congenital diaphragmatic hernia containing portion of stomach and liver.

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 10-cm segment of dilated bowel. The CDH included hernia- diagnosis after the neonatal period as euploid cells in the
tion of the spleen, a portion of the stomach, and a portion blood replace tetrasomic cells. (13)
of the liver. The infant’s hypoplastic lungs measured less Postnatally, multiple systems are affected in PKS. Com-
than the 1st percentile for GA, and the cardiac atria were mon findings include atypical facial features, differences
compressed. A tissue culture was performed, and chromo- in pigmentation, intellectual disability, epilepsy, CDH,
somes were analyzed. Chromosome analysis identified 2 congenital heart disease, and limb differences. Character-
copies of isochromosome 12 in 12 of 20 cells examined, re- istic facial features include prominent forehead, frontopar-
sulting in mosaic hexasomy for chromosome 12p. The pres- ietal sparse hair with sparse eyebrows, hypertelorism or
ence of this i(12p) was confirmed with fluorescence in situ telecanthus, long philtrum, depressed nasal bridge, promi-
hybridization and substantiated the abnormal amniocente- nent cheeks, low-set and posteriorly rotated ears with ear
sis result, consistent with a diagnosis of PKS. pits and/or thickened helices, palate differences, accessory
nipples, and short neck. (7) “Pallister lip,” described as ex-
DISCUSSION tension of the philtral skin into the vermilion border of
the upper lip, is a classic feature. Facial features coarsen
PKS is a rare genetic syndrome caused by extra copies of
over time and the typical pattern of alopecia tends to re-
the short arm of chromosome 12 (12p) with an estimated
solve, making diagnosis more difficult with age.
incidence of 5.1 per million live births; however, it is likely
Multiple organ systems may be affected in patients with
underdiagnosed. (3) PKS is due to a spontaneous mosaic
PKS. Neurologic manifestations of PKS include severe intel-
duplication event most often resulting in tetrasomy 12p
lectual disability, epilepsy, and abnormal muscle tone (7) with
from the formation of an additional 12p isochromosome,
hypotonia often noted in infancy and variable spasticity and
(4) however, PKS may also be due to cases of trisomy and
hypertonia in older individuals. (10) Common abnormal MRI
hexasomy 12p (as in our case). First described by Dr Pallis-
findings in patients with PKS include cerebral volume loss,
ter in 1977 (5) and subsequently by Drs Teschler-Nicola
malformations of cortical development, dysgenesis of the cor-
and Killian in 1981, (6) PKS is a multisystem developmen-
pus callosum, white matter disease, and craniofacial malforma-
tal disorder with significant variability in phenotype owing
tions (abnormally shaped skull, hypertelorism, and maxillary
to the mosaic distribution of the disease. While the mech-
hypoplasia). (4) Congenital heart disease, most commonly
anism leading to formation of the isochromosome 12p cell atrial or ventricular septal defects, can be seen in individuals
lines is still to be determined, most studies suggest mater- with PKS. Other cardiac manifestations include bicuspid aortic
nal meiosis II nondisjunction as the likely mechanism of valve, aortic dilation, patent ductus arteriosus, and patent fora-
mosaic tetrasomy 12p. (7) More rarely, paternal nondis- men ovale. Later onset cardiomyopathy is rare but potentially
junction has been reported as well. (8)(9) Similar to other life-threatening. (14)
autosomal aneuploidy syndromes such as trisomy 21, a Ophthalmologic findings in patients with PKS can include
maternal age effect is seen in PKS. (10) Reported cases of strabismus, nystagmus, and/or myopia, with 20% having sig-
PKS have all been sporadic; recurrence risk is therefore nificant visual impairment and diagnosed as legally blind. (15)
close to that of the general population. Hearing loss of all forms is also common in PKS and is often
Prenatal diagnosis of PKS can be challenging because bilateral. (10) Gastrointestinal involvement ranges from ana-
of the variability of associated features and difficulty de- tomic to functional. Intestinal malrotation, CDH, umbilical
tecting the isochromosome 12p. (11) The 3 most frequent hernias, and displacement of the anus are common anatomic
prenatal ultrasonographic indicators in PKS, all of which findings whereas functional manifestations can include feed-
were noted in our case, are polyhydramnios, CDH, and ing difficulties, dysphagia, constipation, and gastroesophageal
rhizomelic shortening. (12) A flat facial profile and thick- reflux disease. (7) The most common genitourinary finding in
ened nuchal fold can also be seen on ultrasonography. (11) PKS is cryptorchidism. (7) Musculoskeletal manifestations can
Additional common prenatal findings may include cere- include polydactyly, broad thumbs and first toes, joint contrac-
bral ventriculomegaly, and congenital heart disease. (13) tures, and hip dislocations. (7)
Tissue-limited mosaicism for isochromosome 12p is Individuals with PKS often show a pattern of prenatal
the hallmark of PKS, making diagnosis challenging. The overgrowth followed by growth deceleration over the first
percentage of mosaicism is higher in skin fibroblasts, am- few years of age. (7) Developmental delay is common and
niocytes, or chorionic villi cells as opposed to lymphocytes. ranges from mild to profound, most often severe to pro-
(13) Often, a buccal smear or skin biopsy is needed for found. (7) Behavioral manifestations can include repetitive

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 hand and body movements as well as self-injurious behav-
• Plan appropriate therapy for an infant with extrapul-
iors. (10) Life expectancy has never been formally evalu- monary causes of respiratory distress.
ated. One report cites individuals with PKS surviving into • Recognize the clinical features of extrapulmonary causes
their 40s and 50s. (7) However, given the diagnostic chal- of respiratory distress.
lenges, more mild presentations, and individuals who may • Recognize the imaging features of extrapulmonary causes
not have undergone genetics assessment, it is likely that of respiratory distress.
there may be undiagnosed older individuals with PKS. (7) • Know how mosaicism modifies clinical presentation.
• Recognize the diagnostic implications of single vs. multi-
ple anomalies.
Summary
This case of PKS fittingly demonstrates this rare,
multisystem, sporadic disorder. PKS is due to
References
mosaic supernumerary isochromosome 12p
1. Toydemir RM, Panza E, Longhurst MC, South ST, Rope AF. Seizures
leading to a wide spectrum of possible clinical
and cardiomyopathy in a patient with Pallister-Killian Syndrome due
manifestations. Most often these manifestations to hexasomy 12p mosaicism. Mol Syndromol. 2020;11(3):125–129
include craniofacial, neurologic, cardiac, 2. Vogel I, Lyngbye T, Nielsen A, Pedersen S, Hertz JM. Pallister-Killian
ophthalmologic, musculoskeletal, dermatologic, syndrome in a girl with mild developmental delay and mosaicism for
and growth and developmental anomalies. hexasomy 12p. Am J Med Genet A. 2009;149A(3):510–514

Suspicion for PKS should be raised if polyhydramnios, 3. Blyth M, Maloney V, Beal S, et al. Pallister-Killian syndrome: a study
of 22 British patients. J Med Genet. 2015;52(7):454–464
CDH, and/or rhizomelic shortening are seen on
4. Barkovich EJ, Lateef TM, Whitehead MT. Neuroimaging findings in
prenatal ultrasonography. Cytogenetic diagnosis is
Pallister-Killian syndrome. Neuroradiol J. 2018;31(4):403–411
challenging with higher diagnostic rates using
5. Pallister PD, Meisner LF, Elejalde BR, et al. The pallister mosaic
amniotic fluid or skin fibroblasts. As demonstrated syndrome. Birth Defects Orig Artic Ser. 1977;13(3B):103–110
in our case of PKS, coordination of complex care 6. Teschler-Nicola M, Killian W. Case report 72: Mental retardation,
is imperative for fetuses with multiple anomalies unusual facial appearance, abnormal hair. Synd Ident. 1981;7:6–7
of possible genetic etiology, so as to bridge 7. Izumi K, Krantz ID. Pallister-Killian syndrome. Am J Med Genet C
uncertainties in both the prenatal and postnatal Semin Med Genet. 2014;166C(4):406–413

periods. 8. Conlin LK, Kaur M, Izumi K, et al. Utility of SNP arrays in

detecting, quantifying, and determining meiotic origin of tetrasomy
12p in blood from individuals with Pallister-Killian syndrome. Am J
Med Genet A. 2012;158A(12):3046–3053
9. Turleau C, Simon-Bouy B, Austruy E, et al. Parental origin and
mechanisms of formation of three cases of 12p tetrasomy. Clin
American Board of Pediatrics Genet. 1996;50(1):41–46
10. Wilkens A, Liu H, Park K, et al. Novel clinical manifestations in
Neonatal-Perinatal Content Pallister-Killian syndrome: comprehensive evaluation of 59 affected
Specifications individuals and review of previously reported cases. Am J Med Genet
A. 2012;158A(12):3002–3017
• Know the role and risks of magnetic resonance imaging,
11. Doray B, Girard-Lemaire F, Gasser B, et al. Pallister-Killian
as well as other non-ultrasonographic imaging techniques
syndrome: difficulties of prenatal diagnosis. Prenat Diagn.
in assessing fetal anatomy.
2002;22(6):470–477
• Know the importance and limitations of ultrasonographic
12. Thakur S, Gupta R, Tiwari B, Singh N, Saxena KK. Pallister-Killian
findings of common fetal anomalies including congenital syndrome: review of fetal phenotype. Clin Genet. 2019;95(1):79–84
heart disease.
13. Salzano E, Raible SE, Kaur M, et al. Prenatal profile of Pallister-Killian
• Know the significance of polyhydramnios and the syndrome: Retrospective analysis of 114 pregnancies, literature review
management of pregnancy when it is diagnosed. and approach to prenatal diagnosis. Am J Med Genet A. 2018;176(12):
• Know how specific fetal diagnoses, such as airway ab- 2575–2586
normalities, abdominal wall defects, myelomeningocele, 14. Tilton RK, Wilkens A, Krantz ID, Izumi K. Cardiac manifestations of
or severe hydrocephalus might alter prenatal care and Pallister-Killian syndrome. Am J Med Genet A. 2014;164A(5):1130–1135
intrapartum management (eg fetal intervention “Exit” 15. Kostanecka A, Close LB, Izumi K, Krantz ID, Pipan M. Developmental
strategy). and behavioral characteristics of individuals with Pallister-Killian
syndrome. Am J Med Genet A. 2012;158A(12):3018–3025

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