morbilidad de la hipertensión pulmonar persistente del recién … · 2020. 1. 6. · causa de...
TRANSCRIPT
Morbilidad de la Hipertensión pulmonar persistente del Recién nacido en el
primer año de vida
Martina A. Steurer, Rebecca J. Baer, Scott Oltman, Kelli K. Ryckman, Sky K. Feuer, Elizabeth
Rogers, Roberta L. Keller, and Laura L. Jelliffe-Pawlowski
Objetivo Examinar la morbimortalidad postalta en infantes diagnosticados con diferentes
etiologías y grados de severidad de hipertensión pulmonar persistente del recién nacido
(HPPN), e identificar factores de riesgo para resultados clínicos adversos.
Diseño del estudio Este fue un estudio de base poblacional utilizando un set de datos
administrativos uniendo certificados de nacimiento y de fallecimiento, registros de egreso
hospitalarios y reinternaciones entre 2005 y 2012 en California. Los casos fueron infantes
≥34 semanas de EG con códigos de la Clasificación Internacional de Enfermedades, 9º
Edición consistentes con HPPN. El resultado primario fue definido como mortalidad
postalta o reingreso hospitalario durante el primer año de vida. Se calculó el cociente de
riesgo crudo y ajustado (aRR) con ICs 95% para cuantificar el riesgo para el resultado
primario e identificar factores de riesgo.
Resultados Los infantes con HPPN (n=7847) tuvieron un aRR de 3.5 (IC 95%, 3.3-3.7) para
el resultado primario comparados con infantes sin HPPN (n= 3.974.536), y los infantes con
HPPN leve (n= 2477) tuvieron un aRR de 2.2 (IC 95%, 2.0-2.5). Los infantes en quienes la
causa de HPPN fue hernia diafragmática congénita tuvieron un aRR de 8.6 (IC 95%, 7.0-
10.6) y los infantes con síndrome de aspiración de meconio tuvieron un aRR de 4.0 (IC
95%, 3.6-4.4) comparados con infantes sin HPPN. La etnia hispana, PEG, HPPN severa y la
etiología de la HPPN fueron factores de riesgo para el resultado primario.
Conclusiones La carga de morbilidad postalta de los infantes con HPPN es grande. Estos
hallazgos se extienden a infantes con HPPN leve, y etiologías con cambios vasculares
pulmonares que se creen son de corto plazo y recuperables. Estos datos podrían ser de
información y consejería para padres. (J Pediatr 2019;213:58-65).
El principal marcador de la transición exitosa de la circulación intrauterina a la postnatal es
una disminución en la resistencia vascular pulmonar y aumento en el flujo sanguíneo
pulmonar (1, 2). Cuando falla la caída postnatal de la resistencia vascular pulmonar, se
produce la hipertensión pulmonar persistente del recién nacido (HPPN). Un número de
desórdenes dificultan la transición y pueden causar HPPN. Pese a que pueden
superponerse, la fisiopatología subyacente de HPPN puede caracterizarse en uno de 3
tipos: (1) vasculatura pulmonar anormalmente contraída debido a enfermedades del
parénquima pulmonar como síndrome de aspiración de meconio (SAM), síndrome de
dificultad respiratoria (SDR), o sepsis/infección, (2) vasculatura pulmonar remodelada,
conocida como HPPN idiopática, o (3) vasculatura hipoplásica como se ve en la hernia
diafragmática congénita (HDC) u otras anomalías congénitas del sistema respiratorio (1, 2).
En la era moderna, la mortalidad general de los infantes con HPPN ha sido reportada en
7%-15% (3, 6). Sin embargo, dada su heterogeneidad, la mortalidad y otros resultados
clínicos dependen de la severidad y etiología de la HPPN. Algunas etiologías están
asociadas con cambios vasculares pulmonares que se piensan son de corto plazo y
recuperables, mientras que tras etiologías tales como la hipoplasia pulmonar son
consideradas de largo plazo. Similarmente, las comorbilidades asociadas con algunas
etiologías pueden contribuir a mortalidad temprana (ej., disfunción multiorgánica asociada
a sepsis o encefalopatía neonatal asociada a SAM), donde las anormalidades anatómicas y
fisiológicas asociadas con defectos congénitos pueden tener efectos persistentes en la
salud del niño.
Pese a que la mortalidad neonatal y la evolución hospitalaria de los niños con HPPN
severa ha sido bien descripta (4-6), menos se sabe acerca de la mortalidad postalta y la
carga de morbilidad de esta condición. Unos pocos estudios reportan sobre anormalidades
del neurodesarrollo, uso de broncodilatadores y reingreso hospitalario más allá del
período neonatal en infantes con las formas más severas de HPPN (7-11). Sin embargo, los
resultados más allá del período neonatal no han sido evaluados sobre una base
poblacional, incluyendo los infantes con HPPN menos severa, o con números suficientes
para investigar la variabilidad en los resultados postalta según la etiología de la HPPN.
Entonces, el objetivo de este estudio fue evaluar la mortalidad y morbilidad postalta,
medida según el reingreso al hospital durante el primer año de vida, en infantes de
término (≥37 semanas de gestación) y pretérmino tardío (34-36 semanas de gestación)
diagnosticados con diferentes etiologías y grado de severidad de HPPN. También
buscamos identificar factores de riesgo para estos resultados clínicos adversos.
Métodos
La Oficina de Desarrollo y Planeamiento de Salud Estatal de California (OSHPD) mantiene
una base de datos que incluye información detallada sobre características maternas e
infantiles derivadas de los registros de egreso hospitalario que están conectados a los
certificados de nacimiento y defunción desde el nacimiento hasta el año de edad. Los
códigos de diagnóstico y procedimientos están basados en el ICD-9. También están
disponibles EG, PN, factores demográficos y diagnóstico materno. La base de datos ha sido
empleada en múltiples estudios que examinan los resultados de parto y neonatales (12-
18).
La población en estudio consistió de infantes nacidos vivos desde Enero 2005 a Diciembre
2012. Previamente construimos nuestra cohorte identificada con datos desde 2007-2011
(19). Para el estudio anterior, excluimos 2005-2006 debido al porcentaje relativamente
elevado de variables maternas faltantes necesarias para determinar factores de riesgo para
incidencia de HPPN. Sin embargo, para el estudio actual enfocado en resultados, incluimos
datos de esos 2 años. Adicionalmente, pudimos utilizar una nueva base de datos de
OSHPD que incluyó 2012 y proveyó una mejor conexión de los registros del hospital,
nacimiento y muerte, llevando a un número mayor de casos y controles para 2007-2011.
Usamos la misma metodología para identificar casos con HPPN que en nuestro estudio
anterior (19). Brevemente, identificamos infantes nacidos ≥30 0/7 sem EG con códigos ICD-
9 consistentes con el diagnóstico de HPPN (747.83- circulación fetal persistente, 416.0-
hipertensión pulmonar primaria, o 416.8- otra hipertensión pulmonar secundaria) presente
en la hospitalización al nacer. Hospitalización neonatal fue definida como la internación
desde el nacimiento hasta el egreso al hogar o muerte, lo que ocurra primero.
Hospitalización neonatal incluye el traslado a otro hospital, si existió. Excluimos infantes
con enfermedad cardíaca congénita mayor, pero incluimos aquellos con defectos cardíacos
menores asociados con diagnóstico de HPPN, o diagnosticados en su evaluación (ej.,
defecto septal ventricular, defecto septal auricular, y DAP; ICD-9 745-747.4 excepto 745.4-
6, 747). Las siguientes 6 causas de HPPN fueron identificadas empleando códigos ICD-9 de
una manera jerárquica (19): HDC, otras anomalías congénitas del sistema respiratorio,
SAM, infección/sepsis y SDR, e idiopática. Una lista de todos los códigos ICD-9 y detalles
de la metodología pueden encontrarse en otro sitio (19).
Para determinar los resultados postalta en esta cohorte, excluimos los infantes que
fallecieron durante la hospitalización neonatal. Nuestro resultado primario fue mortalidad
postalta o cualquier reingreso hospitalario dentro del primer año de vida. El método de
certeza de muerte fue certificado de defunción o estado de egreso fallecido para 2007-
2011 y estado de egreso fallecido para 2012. El archivo OSHPD contiene registros
acumulados del nacimiento del infante y otros ingresos o visitas a emergencias durante el
primer año de vida. Los individuos en el registro tienen un número identificador (RN ID)
para los datos de nacimiento, admisiones hospitalarias, y visitas a emergencias. Los
traslados se identificaron en el estado de egreso indicado como egreso a otro hospital. Las
admisiones al hospital después del egreso inicial al hogar o a un servicio domiciliario de
salud fueron identificadas como reingresos. Cundo un infante tenía un registro de visita a
emergencias con la misma fecha del reingreso, sólo se utilizó el ingreso hospitalario para el
análisis. Nuestros resultados secundarios fueron reingreso hospitalario por causa
respiratoria, visita a emergencias, y visita a emergencia por causa respiratoria. Definimos
causa respiratoria como la presencia de alguno de los siguientes códigos ICD-9 en el
registro respectivo de reingreso hospitalario o de visita a emergencia: infección respiratoria
aguda incluyendo bronquiolitis (460-466), neumonía e influenza (480-488), otras
enfermedades del tracto respiratorio superior (470-478), bronquitis (490-491), asma (493),
bronquiectasia (494), alveolitis alérgica extrínseca (495), obstrucción crónica de la vía aérea
(496), condiciones respiratorias debidas a otros agentes externos no especificados (508),
absceso de pulmón y mediastino (513), otra enfermedad del pulmón (518.8), y otra
enfermedad del sistema respiratorio no especificada (519.8 y 519.9).
Definimos HPPN severa como requerimiento de ventilación con presión positiva (VPP)
invasiva o no invasiva (ICD-9 V 46.1, V 46.11-14 y códigos de procedimientos 96.04, 96.70-
72, 93.90-1) en el registro de hospitalización neonatal. Los infantes sin código VPP fueron
clasificados como HPPN leve.
Para el plan de análisis estadístico, comparamos las características basales para infantes
con y sin HPPN con test x2. Calculamos los cocientes de riesgo (RR) crudos y ajustados
(aRRs) e IC 95% para cada resultado comparando infantes con y sin HPPN. Ajustamos por
EG, sexo, PN (PEG, AEG, GEG) y raza/etnicidad. Luego calculamos RR crudo y aRR para cada
resultado separadamente en los casos con HPPN severos y leves. Dada la heterogeneidad
de las etiologías subyacentes para HPPN, comparamos resultados primarios y secundarios
en cada grupo etiológico de infantes con HPPN con infantes sin HPPN calculando el RR
crudo y aRR e IC 95%. Se generaron curvas de Kaplan-Meier para comparar el resultado
primario según etiología de HPPN; cocientes de riesgo crudo con IC 95% también fueron
calculados. Finalmente, calculamos RR crudo y aRR con IC 95% para identificar factores de
riesgo asociados con el resultado primario en infantes con HPPN. Todos los factores
significativos en el análisis univariado fueron incluidos en el modelo multivariado. Un valor
de P menor al 0.05 fue considerado significativo en todos los análisis. Todos los análisis
fueron realizados empleando la versión SAS 9.3 (SAS Institute, Inc, Cary, North Carolina). El
protocolo de estudio fue aprobado por el comité de revisión institucional de la Agencia de
Servicios de Salud y Humanos del Estado de California.
Resultados
Entre 3.974.536 infantes, identificamos 7847 con HPPN (incidencia 0.2%). Entre todos los
infantes con HPPN, 68.4% (5370/7847) recibieron VPP invasiva o no invasiva cumpliendo
nuestro criterio para HPPN severa; esto fue muy similar a nuestra cohorte descripta
previamente (67.6%) (19). La distribución de etiologías de HPPN y características del
infante fueron también similares a aquellos previamente descriptos (19) (Tabla I; disponible
en www.jpeds.com). La etiología más común fue infección (33.1%) seguida por SAM
(20.7%), idiopática (20.3%), SDR (8.4%), otras (7.0%), HDC (6.0%), y otras anomalías del
sistema respiratorio (4.5%). Los infantes con HPPN tuvieron más posibilidad de haber
nacido prematuramente (18.1% vs. 7.0%; P<.001), ser PEG (13.5% vs. 9.4%; =<.001), y ser
GEG (17.9% vs. 10.2%; P<.001).
La mortalidad general en infantes con HPPN fue 7.3%, con una mortalidad prealta de 6.5%
y una mortalidad al año postalta de 0.7%. El 28.6% de los infantes con HPPN que
sobrevivieron al alta, fueron reingresados al hospital al menos una vez durante el primer
año de vida (comparado con 9.8% de los RN sin HPPN; P<.001; Tabla II) Cerca de un tercio
de los reingresos hospitalarios fueron por causa respiratoria, tanto en los infantes con y sin
HPPN (tasa de reingreso 10.4% por causa respiratoria en bebés con HPPN y 3.4% en niños
sin HPPN; P<.001; Tabla II).
Nuestro resultado compuesto primario de mortalidad postalta o cualquier reingreso
hospitalario en el primer año de vida ocurrió en 29% de los infantes con HPPN vs. 9.9% en
infantes sin HPPN (RR crudo y aRR de 3.7 [IC 95%, 3.5-3.9] y 3.5 [IC 95%, 3.3-3.7],
respectivamente; Tabla II). El resultado primario ocurrió en 33.4% de infantes con HPPN
severa vs. 9.9% de infantes sin HPPN (RR crudo y aRR de 4.5 [IC 95%, 4.3-4.8] y 4.2 [IC 95%,
4.0-4.5], respectivamente; Tabla III, disponible en www.jpeds.com), y en 20.2% de infantes
con HPPN leve (RR crudo y aRR de 2.3 [IC 95%, 2.1-2.5] y 2.2 [IC 95%, 2.0-2.5],
respectivamente; Tabla IV, disponible en www.jpeds.com). Otros resultados secundarios
(visitas a emergencias y visitas a emergencias por causa respiratoria) se presentan en la
Tabla II para el grupo completo con HPPN, y en las Tablas III y IV para el subgrupo de
infantes con HPPN severa y leve, respectivamente. La Tabla V (disponible en
www.jpeds.com) muestra las tasas anuales de los resultados seleccionados. Nuestro
resultado primario disminuyó de 32.2% en 2005 a 24.4% en 2012 (P<.001).
La Figura 1 muestra los aRR para los resultados seleccionados acorde a la etiología de
HPPN. En cuanto a la mortalidad postalta o reingreso hospitalario (resultado primario;
Figura 1), los infantes con anomalías del sistema respiratorio y HDC tuvieron el más alto
aRR con 14.0 (IC 95%, 10.8-18.1) y 8.2 (IC 95%, 6.7-10.2), respectivamente. Notamos que el
promedio de la hospitalización inicial fue aproximadamente 60 días más prolongado para
estos dos grupos, limitando la oportunidad para el resultado primario al año de edad. Los
RN con SAM, infección, y otras etiologías de HPPN tuvieron hospitalizaciones iniciales que
fueron más prolongadas en 18-20 días que en los infantes sin HPPN. El aRR para el
resultado primario para SAM fue el más alto en 4.2 (IC 95%, 3.7-4.6) y el más bajo fue para
HPPN idiopática (aRR, 1.8; IC 95%, 1.5-2.0) La Tabla VI muestra la edad al resultado
primario para cada causa subyacente de HPPN. Las curvas de sobrevida para las diferentes
etiologías subyacentes de HPPN se muestran en la Figura 2 (disponible en
www.jpeds.com), demostrando que los infantes con HPPN debida a HDC y otras anomalías
congénitas pulmonares tienen nuevos eventos que se extienden hacia la última parte del
primer año de vida.
La Tabla VII muestra los factores de riesgo asociados con nuestro resultado primario. En el
análisis ajustado, que incluía todas las variables significativas en el análisis univariado, los
únicos factores de riesgo significativamente asociados con nuestro resultado primario de
muerte postalta o al menos una reinternación dentro del primer año de vida fueron la
etnicidad hispana (aRR, 1.2; IC 95%, 1.1-1.4), PEG (aRR, 1.2; IC 95%1.1-1.3), severidad de
HPPN (aRR, 1.6; IC 95%, 1.5-1.8, para severa vs. leve), y etiología de HPPN (Tabla VII). La
Tabla VIII muestra la mortalidad, reingreso y visitas a emergencia en el primer año de vida
en casos y controles sin anomalías cromosómicas o enfermedad cardíaca congénita.
Discusión
Este estudio contemporáneo de una gran cohorte poblacional examinó la mortalidad y la
carga de morbilidad postalta medida según reingresos hospitalarios durante el primer año
de vida en prematuros tardíos e infantes de término con diferentes etiologías y grado de
severidad de HPPN nacidos en California. Después de ajustar por EG y otras variables
demográficas, encontramos una tasa >3 veces superior de mortalidad y reingresos postalta
en infantes con HPPN durante el primer año de vida comparados con infantes sin PPHN.
Infantes con HPPN severa, HDC, o anomalías pulmonares tuvieron las frecuencias más altas
de reingreso. Sin embargo, aún los infantes con sólo HPPN leve o etiologías que se
asumen de corto plazo, tales como SAM, sepsis, o SDR, tuvieron una frecuencia de
reingreso hospitalario significativamente superior comparada con infantes sin HPPN.
Finalmente, identificamos severidad y etiología de HPPN, etnia hispana, y PEG como
factores de riesgo independientes significativos para carga de mortalidad y morbilidad
postalta en el primer año de vida, pero no EG.
Hay pocos estudios examinando la morbilidad y mortalidad postalta, y los datos han sido
limitados a infantes con formas severas de HPPN (7-10). Poe ejemplo, estudios que
investigan el efecto del óxido nítrico inhalado sobre la mortalidad neonatal reportaron
tasas desde 20% hasta 39% a la edad de 1-4 años (7-10). Estas figuras son comparables
con nuestra frecuencia de readmisión de 32.9% en infantes con HPPN severa. Encontramos
una tasa de reingreso de 20% en el subgrupo de infantes con HPPN leve, que fue dos
veces más alta que en los infantes sin HPPN.
También examinamos las tasas de rehospitalización por causa respiratoria. El Grupo
Colaborativo ECMO de UK estudió HPPN severa, definida como el índice de oxigenación
>40. Reportaron 57 reingresos respiratorios al hospital en 99 infantes durante el primer
año de vida sin especificar cuántos infantes eran ingresados múltiples veces (11). En el
presente estudio, sólo cerca de 30% de todos los ingresos estuvieron relacionados a causa
respiratoria, que fue observada para la cohorte entera con HPPN y para los subgrupos
severo y leve. Es posible que esto se deba a codificación incompleta del ICD-9 y que la
verdadera frecuencia de reingreso por causa respiratoria es algo superior. Sin embargo,
nuestros hallazgos demuestran que HPPN está asociada con otros problemas de salud, y
que hacer un foco estrecho exclusivamente sobre el estado respiratorio de estos infantes
podría omitir la extensión completa de la carga de morbilidad.
Además del grado de severidad, la causa subyacente de HPPN es un importante
determinante del curso clínico y resultados (19). Generalmente, condiciones que están
asociadas con vasculatura hipoplásica son severas y con frecuencia llevan a HP persistente.
Por ejemplo, la mortalidad al alta hospitalaria para infantes con HDC en la era moderna es
30-50% en estudios de base poblacional (20, 21). Burgos y otros reportan una mortalidad
postalta de 5% en 250 infantes con HDC ≤2 años de edad, con las muertes más tempranas
obedeciendo a insuficiencia respiratoria y las tardías relacionadas a morbilidad
gastrointestinal (22). En un estudio prospectivo multicéntrico, Wynn y otros encontraron
que los niños con HDC tenían score significativamente debajo de la media normal en la
escala Bayley III en los dominios motor, cognitivo y lenguaje a los 2 años de edad (23). En
nuestro estudio, confirmamos la elevada carga de mortalidad y morbilidad en este
subgrupo de infantes. Encontramos una mortalidad postalta de 1.7% en infantes con HDC
y 3.7% en infantes con otras anomalías del sistema respiratorio; estos grupos también
tuvieron el más alto porcentaje de reingresos hospitalarios (47.7% y 60.9%,
respectivamente).
La literatura sobre la carga de mortalidad y morbilidad en infantes con HPPN debida a
SALAM, SDR, o infección es escasa, posiblemente debido a que la enfermedad vascular
pulmonar es considerada de corto plazo y recuperable. Encontramos que los niños con
SAM, infección, y SDR tienen un riesgo significativamente más alto de reingreso durante el
primer año de vida vs. aquellos sin HPPN (Tabla VI). Un porcentaje mayor de estos
reingresos fue debido a causas no respiratorias, resaltando las potenciales secuelas de
compromiso multiorgánico.
Nuestros hallazgos tienen implicancias importantes para el seguimiento del paciente
ambulatorio, consejería a los padres, y medidas preventivas tales como vacunas. Estudios
posteriores debieran investigar estos resultados clínicos prospectivamente en infantes con
HPPN severa y etiologías tales como SAM, SDR, o sepsis.
Además de la severidad y etiología de HPPN, identificamos como factor de riesgo para la
mortalidad o reingreso postalta a la etnia hispana. Pese a que reportamos previamente
que los niños de etnia hispana eran menos propensos a sufrir de HPPN, nuestros hallazgos
actuales muestran que después del diagnóstico de HPPN, ellos tienen mayor riesgo de
resultados adversos (19). Este hallazgo permaneció cierto después de ajustar por factores
de riesgo sociodemogáfico tales como educación materna y seguro de salud, señalando
hacia potenciales variaciones biológicas subyacentes. También identificamos PEG, un
marcador de crecimiento fetal, como un factor de riesgo independiente para el resultado
primario de este estudio. Previamente identificamos PEG como factor de riesgo para la
incidencia de HPPN, y especulamos que esta asociación está potencialmente relacionada al
crecimiento disminuido alveolar y vascular o a disfunción de las células endoteliales de la
arteria pulmonar (19, 24). Este mismo mecanismo podría explicar la carga aumentada de
mortalidad y morbilidad postalta a lo largo del primer año de vida.
Las limitaciones de nuestro estudio están mayormente con la naturaleza administrativa del
set de datos. Utilizar los códigos ICD-9 para identificar HPPN y la etiología subyacente
lleva un riesgo de mala clasificación para estas variables. Sin embargo, esta limitación es
por lo menos parcialmente desarmada por el gran número de casos identificados en esta
base de datos poblacional. No podemos excluir que haya casos perdidos basados en los
códigos usados del ICD-9 o que el uso inapropiado de códigos ICD-9 para HPPN puede
haber registrado niños sin HPPN como casos de HPPN. Sin embargo, el uso de los códigos
ICD-9 para HPPN ha sido validado por un valor predictivo positivo de 68.3%-89.6% al
compararlo con la revisión del registro médico primario (25, 26).
Tampoco pudimos determinar el momento de la codificación ICD-9. Por ejemplo, es
posible que la sepsis o la infección ocurrieran más tarde en el curso hospitalario después
del diagnóstico de HPPN en ciertos infantes, entonces, asignándole falsamente ser la causa
subyacente de la enfermedad. Adicionalmente, tuvimos detalles relativamente limitados
acerca del curso clínico de los casos con HPPN. Por ejemplo, fue imposible confirmar el
diagnóstico de HPPN con datos ecocardiográficos. Tampoco pudimos incorporar
predictores clínicos potencialmente importantes tales como requerimiento de oxígeno,
duración de ventilación mecánica, uso de iNO, o ECMO en nuestro análisis.
No es inesperado que infantes con HPPN severa, o con etiologías de alto riesgo para
hipertensión pulmonar permanente como HDC, tengan una carga de mortalidad y
morbilidad más alta a través del primer año de vida que los infantes sin HPPN. Sin
embargo, es sorprendente que infantes con HPPN leve y etiologías de más corto plazo
como SAM, infección o SDR mantienen una elevada carga de mortalidad y morbilidad más
allá del período neonatal, comparados con infantes sin HPPN. Esta información debería
utilizarse para medidas preventivas y consejería a los padres.
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6. Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term
infants with hypoxic respiratory failure. N Engl J Med 1997;336:597-604.
7. Konduri GG, Vohr B, Robertson C, Sokol GM, Solimano A, Singer J, et al. Early inhaled nitric oxide
therapy for term and near-term newborn infants with hypoxic respiratory failure:
neurodevelopmental follow-up.
J Pediatr 2007;150:235-40. 240.e1.
8. Clark RH, Huckaby JL, Kueser TJ, Walker MW, Southgate WM, Perez JA, et al. Low-dose nitric oxide
therapy for persistent pulmonary hypertension: 1-year follow-up. J Perinatol 2003;23:300-3.
9. Group TNINOS. Inhaled nitric oxide in term and near-term infants: neurodevelopmental follow-up
of the neonatal inhaled nitric oxide study group (NINOS). J Pediatr 2000;136:611-7.
10. Ellington M, O’Reilly D, Allred EN, McCormick MC, Wessel DL, Kourembanas S. Child health
status, neurodevelopmental outcome, and parental satisfaction in a randomized, controlled trial of
nitric oxide
for persistent pulmonary hypertension of the newborn. Pediatrics 2001;107:1351-6.
11. Group UCE. The collaborative UK ECMO (Extracorporeal Membrane Oxygenation) trial: follow-up
to 1 year of age. Pediatrics 1998;101:E1.
12. Baer RJ, Chambers CD, Jones KL, Shew SB, MacKenzie TC, Shaw GM, et al. Maternal factors
associated with the occurrence of gastroschisis. Am J Med Genet A 2015;167:1534-41.
13. Baer RJ, Lyell DJ, Norton ME, Currier RJ, Jelliffe-Pawlowski LL. First trimester pregnancy-
associated plasma protein-A and birth weight. Eur J Obstet Gynecol Reprod Biol 2016;198:1-6.
14. Jelliffe-Pawlowski LL, Norton ME, Baer RJ, Santos N, Rutherford GW. Gestational dating by
metabolic profile at birth: a California cohort study. Am J Obstet Gynecol 2016;214:511.e1-13.
15. Stey A, Barnert ES, Tseng CH, Keeler E, Needleman J, Leng M, et al. Outcomes and costs of
surgical treatments of necrotizing enterocolitis. Pediatrics 2015;135:e1190-7.
16. Gage S, Kan P, Lee HC, Gould JB, Stevenson DK, Shaw GM, et al. Maternal asthma, preterm birth,
and risk of bronchopulmonary dysplasia. J Pediatr 2015;167:875-80.e1.
17. Jelliffe-Pawlowski LL, Norton ME, Shaw GM, Baer RJ, Flessel MC, Goldman S, et al. Risk of critical
congenital heart defects by nuchal translucency norms. Am J Obstet Gynecol 2015;212:518.e1-10.
18. Crisham Janik MD, Newman TB, Cheng YW, Xing G, Gilbert WM, Wu YW. Maternal diagnosis of
obesity and risk of cerebral palsy in the child. J Pediatr 2013;163:1307-12.
19. Steurer MA, Jelliffe-Pawlowski LL, Baer RJ, Partridge JC, Rogers EE, Keller RL. Persistent
pulmonary hypertension of the newborn in late preterm and term infants in California. Pediatrics
20161-15.
20. Stege G, Fenton A, Jaffray B. Nihilism in the 1990s: the true mortality of congenital
diaphragmatic hernia. Pediatrics 2003;112:532-5.
21. Colvin J, Bower C, Dickinson JE, Sokol J. Outcomes of congenital diaphragmatic hernia: a
population-based study in Western Australia. Pediatrics 2005;116:e356-63.
22. Burgos CM, Mod_ee A, € Ost E, Frenckner B. Addressing the causes of late mortality in infants
with congenital diaphragmatic hernia. J Pediatr Surg 2017;52:526-9.
23. Wynn J, Aspelund G, Zygmunt A, Stolar CJH, Mychaliska G, Butcher J, et al. Developmental
outcomes of children with congenital diaphragmatic hernia: a multicenter prospective study. J
Pediatr Surg 2013;48:1995-2004.
24. Rozance PJ, Seedorf GJ, Brown A, Roe G, O’Meara MC, Gien J, et al. Intrauterine growth
restriction decreases pulmonary alveolar and vessel growth and causes pulmonary artery endothelial
cell dysfunction in vitro in fetal sheep. Am J Physiol Lung Cell Mol Physiol 2011;301:L860-71.
25. Huybrechts KF, Bateman BT, Palmsten K, Desai RJ, Patorno E, Gopalakrishnan C, et al.
Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn.
JAMA 2015;313:2142-51.
26. Palmsten K, Huybrechts KF, Kowal MK, Mogun H, Hern_andez-D_ıaz S. Validity of maternal and
infant outcomes within nationwide Medicaid data. Pharmacoepidem Drug Safe 2014;23:646-55.
ORIGINALARTICLES
Morbidity of Persistent Pulmonary Hypertension of the Newborn in theFirst Year of Life
Martina A. Steurer, MD1,2,3, Rebecca J. Baer, MPH3,4, Scott Oltman, MS2,3, Kelli K. Ryckman, PhD5, Sky K. Feuer, PhD3,
Elizabeth Rogers, MD1,3, Roberta L. Keller, MD1, and Laura L. Jelliffe-Pawlowski, PhD2,3
Objective To assess postdischarge mortality and morbidity in infants diagnosed with different etiologies andseverities of persistent pulmonary hypertension of the newborn (PPHN), and to identify risk factors for these adverseclinical outcomes.Study design This was a population-based study using an administrative dataset linking birth and deathcertificates, hospital discharge and readmissions records from 2005 to 2012 in California. Cases were infants³34 weeks’ gestational age with International Classification of Diseases, 9th edition, codes consistent withPPHN. The primary outcome was defined as postdischarge mortality or hospital readmission during the first yearof life. Crude and adjusted risk ratio (aRR) with 95%CIs were calculated to quantify the risk for the primary outcomeand to identify risk factors.Results Infants with PPHN (n = 7847) had an aRR of 3.5 (95%CI, 3.3-3.7) for the primary outcome compared withinfants without PPHN (n = 3974 536), and infants with onlymild PPHN (n = 2477) had an aRR of 2.2 (95%CI, 2.0-2.5).Infants with congenital diaphragmatic hernia as etiology for PPHN had an aRR of 8.6 (95% CI, 7.0-10.6) and infantswith meconium aspiration syndrome had an aRR of 4.0 (95% CI, 3.6-4.4) compared with infants without PPHN.Hispanic ethnicity, small for gestational age, severe PPHN, and etiology of PPHN were risk factors for the primaryoutcome.Conclusions The postdischarge morbidity burden of infants with PPHN is large. These findings extend to infantswith mild PPHN and etiologies with pulmonary vascular changes that are thought to be short term and recoverable.These data could inform counseling of parents. (J Pediatr 2019;213:58-65).
The hallmark of successful transition from the intrauterine to the postnatal circulation is a decrease in pulmonary vascularresistance and an increase in pulmonary blood flow.1,2 When the pulmonary vascular resistance fails to fall postnatally,persistent pulmonary hypertension of the newborn (PPHN) results. A number of disorders impair this transition and
can cause PPHN. Although there may be overlap, the underlying pathophysiology of PPHN can be characterized as 1 of 3 types:(1) abnormally constricted pulmonary vasculature owing to lung parenchymal diseases such as meconium aspiration syndrome(MAS), respiratory distress syndrome (RDS), or sepsis/infection, (2) remodeled pulmonary vasculature, known as idiopathicPPHN, or (3) hypoplastic vasculature as seen in congenital diaphragmatic hernia (CDH) or other congenital anomalies of therespiratory system.1,2
In the modern era, the overall mortality of infants with PPHN has been reported to be 7%-15%.3-6 However, given itsheterogeneity, mortality and other clinical outcomes depend on the severity and etiology of PPHN. Some etiologies areassociated with pulmonary vascular changes that are thought to be short term and recoverable, whereas other etiologiessuch as lung hypoplasia are considered to be long term. Similarly, comorbidities associated with some etiologies can contributeto early mortality (eg, multiorgan dysfunction associated with sepsis or neonatal encephalopathy associated with MAS),whereas anatomic and physiologic abnormalities associated with birth defects might have persistent effects on child health.
Although neonatal mortality and hospital course of infants with severe PPHN have been well-described,4-6 less is knownabout the postdischarge mortality and morbidity burden of this condition. A few studies report on neurodevelopmentalabnormalities, bronchodilator use and hospital readmissions beyond the neonatal period in infants with the most severe formsof PPHN.7-11 However, outcomes beyond the neonatal period have not been evaluated on a population basis, included infants
From the 1Department of Pediatrics, 2Department ofEpidemiology and Biostatistics, and 3California PretermBirth Initiative, University of California San Francisco, SanFrancisco; the 4Department of Pediatrics, University ofCalifornia San Diego, La Jolla, CA; and the 5Departmentof Epidemiology, College of Public Health, University ofIowa, Iowa City, IA
Funded by the California Preterm Birth Initiative. Theauthors declare no conflicts of interest.
0022-3476/$ - see frontmatter.ª2019Elsevier Inc.All rights reserved.
https://doi.org/10.1016/j.jpeds.2019.06.053
aRR Adjusted risk ratio
CDH Congenital diaphragmatic hernia
ED Emergency department
ICD-9 International Classification of Diseases, 9th Revision, Clinical Modification
MAS Meconium aspiration syndrome
OSHPD California Office of Statewide Health Planning and Development
PPHN Persistent pulmonary hypertension of the newborn
RDS Respiratory distress syndrome
RR Risk ratio
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Volume 213 � October 2019
with less severe PPHN, or have numbers large enough toinvestigate variability in postdischarge outcomes accordingto the etiology of PPHN. Thus, the aim of this study was toassess postdischarge mortality and morbidity, measured byreadmission to the hospital during the first year of life, interm (³37 weeks of gestation) and late preterm (34-36 weeksof gestation) infants diagnosed with different etiologies andseverities of PPHN. We further sought to identify risk factorsfor these adverse clinical outcomes.
Methods
The California Office of Statewide Health Planning andDevelopment (OSHPD) maintains a database that includesdetailed information on maternal and infant characteristicsderived from hospital discharge records that are linked tobirth and death certificates from birth to one year of age.Diagnosis and procedure codes are based on the InternationalClassification of Diseases, 9th Revision, Clinical Modification(ICD-9). Gestational age, birth weight, demographic factors,and maternal diagnoses are also available. The database hasbeen used in multiple studies examining birth and neonataloutcomes.12-18
The study population consisted of live born infants fromJanuary 2005 to December 2012. We built on our previouslyidentified cohort assembled with data from 2007-2011.19 Forthe prior study, we excluded 2005-2006 owing to the relativelyhigh percentage ofmissingmaternal variables needed to assessrisk factors for incidence of PPHN. However, for the currentstudy focusing on outcomes, we included data from those2 years. Additionally, we were able to use a newer OSHPDdataset that included 2012 and provided better linkage ofhospital, birth, and death records, leading to a higher numberof cases and controls for 2007-2011.
We used the same methodology to identify cases withPPHN as in our prior study.19 Briefly, we identified infantsborn at ³340/7 weeks of gestation with ICD-9 codes consistentwith the diagnosis of PPHN (747.83 [persistent fetalcirculation], 416.0 [primary pulmonary hypertension], or416.8 [other secondary pulmonary hypertension]) presentin the birth hospitalization. Birth hospitalization was definedas the hospitalization from birth to death or initial dischargehome, whichever comes first. The birth hospitalizationincludes any transfer to another hospital, if present. Weexcluded infants with major congenital heart disease, butincluded infants with minor cardiac defects associated withthe diagnosis of PPHN, or diagnosed in its evaluation(eg, ventricular septal defect, atrial septal defect, and patentductus arteriosus; ICD-9 codes 745-747.4, except 7.45.4-.6,747). The following 6 underlying causes of PPHN wereidentified using ICD-9 codes in a hierarchical manner19:CDH, other congenital anomalies of the respiratory system,MAS, infection/sepsis and RDS, and idiopathic. A list of allICD-9 codes and details about the methodology can be foundelsewhere.19
To assess postdischarge outcomes in this expandedcohort, we excluded infants who died during the birth
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hospitalization. Our primary outcome was postdischargemortality or any hospital readmission within the first yearof life. The method of death ascertainment was deathcertificate or hospital discharge status of death for2007-2011 and hospital discharge status of death for 2012.The OSHPD file contains stacked infant birth records andany other admissions or emergency department (ED) visitsduring their first year of life. Individuals in the file have arecord identifier (birth ID) for birth records, hospitaladmissions, and ED visits. Infant transfers were identifiedwhen the discharge status of the infant indicated a dischargeto another hospital. The subsequent row with an identicaldate of discharge and date of admission was presumed tobe transfer record. Hospital admissions after initial dischargehome or to a home health service were identified asreadmissions. When an infant had an ED record with thesame date as a hospital admission, only the hospitaladmission was used for the analyses. Our secondaryoutcomes were hospital readmission for respiratory cause,ED visit, and ED visit for respiratory cause. Wedefined respiratory cause as the presence of one of thefollowing ICD-9 codes in the respective hospitalreadmission or ED visit record: acute respiratory infectionsincluding bronchiolitis (460-466), pneumonia and influenza(480-488), other diseases of upper respiratory tract(470-478), bronchitis (490-491), asthma (493), bronchiec-tasis (494), extrinsic allergic alveolitis (495), chronic airwayobstruction (496), respiratory conditions owing to otherand unspecified external agents (508), abscess of lung andmediastinum (513), other disease of lung (518.8), and otheror unspecified disease of respiratory system (519.8 and519.9).We defined severe PPHN as the requirement for invasive
or noninvasive positive pressure ventilation (ICD-9diagnostic codes V46.1, V46.11, V46.12, V46.13, V46.14and procedure codes 96.04, 96.70, 96.71, 96.72, 93.90,93.91) in the birth hospitalization record. Infants without acode for positive pressure ventilation were classified as mildPPHN.For the statistical analysis plan, we compared baseline
characteristics for infants with and without PPHN by thec2 test. We calculated crude risk ratios (RR) and adjustedRRs (aRR) and 95% CI for each outcome comparing infantswith PPHN with infants without PPHN. We adjusted forgestational age, sex, birth weight (small for gestational age,adequate for gestational age, and large for gestational age)and race/ethnicity. We then calculated crude and aRR foreach outcome separately in cases with severe and mildPPHN. Given the heterogeneity of underlying etiologies forPPHN, we compared primary and secondary outcomes ineach etiology group of infants with PPHN with infantswithout PPHN calculating crude and aRR and 95% CI.Kaplan-Meier curves were generated to compare the primaryoutcome by underlying etiology of PPHN; crude hazardratios with 95% CI were calculated. Finally, we calculatedcrude and aRR with 95% CI to identify risk factors associatedwith the primary outcome in infants with PPHN. All factors
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THE JOURNAL OF PEDIATRICS � www.jpeds.com Volume 213
significant in the univariate analysis were included in themultivariable model. A P value of less than .05 wasconsidered significant for all analyses. All analyses wereperformed by using SAS version 9.3 (SAS Institute, Inc,Cary, North Carolina). The study protocol was approvedby the institutional review board of the Health and HumanServices Agency of the State of California.
Results
Out of 3 974 536 infants, we identified 7847 infants withPPHN (incidence of 0.2%). Of all infants with PPHN,68.4% (5370/7847) received invasive or noninvasive positivepressure ventilation meeting our criteria for severe PPHN;this was very similar to our previously described cohort(67.6%).19 The distribution of etiologies of PPHN and infantcharacteristics were also similar to those we previouslydescribed19 (Table I; available at www.jpeds.com). Themost common etiology was infection (33.1%) followed byMAS (20.7%), idiopathic (20.3%), RDS (8.4%), other(7.0%), CDH (6.0%), and other anomalies of therespiratory system (4.5%). Infants with PPHN were morelikely to be born prematurely (18.1% vs 7.0%; P < .001), tobe small for gestational age (13.5% vs 9.4%; P < .001), andto be large for gestational age (17.9% vs 10.2%; P < .001).
The overall mortality in infants with PPHNwas 7.3%, witha predischarge mortality of 6.5% and a 1-year postdischargemortality of 0.7%. Of all infants with PPHN who survived todischarge, 28.6%were readmitted to the hospital at least onceduring their first year of life (compared with 9.8% of infantswithout PPHN; P < .001; Table II). About one-third of thehospital readmissions were for a respiratory cause in both
Table II. Mortality, readmissions, or ED visits in first year o
Characteristics PPHN, n (%)
Entire sample 7847MortalityNo 7276 (92.7)Yes 571 (7.3)Predischarge mortality 513 (6.5)Postdischarge mortality 58 (0.7)
Sample who survived to discharge 7334ReadmissionNone 5238 (71.4)Any 2096 (28.6)>1 readmission 426 (5.8)
Readmission for respiratory causeNone 6568 (89.6)Any 766 (10.4)>1 readmission for respiratory cause 151 (2.1)
ED visitsNone 4688 (63.9)Any 2646 (36.1)>1 ED visit 1248 (17.0)
ED visits for respiratory causeNone 5940 (81.0)Any 1394 (19.0)>1 ED visit for respiratory cause 458 (6.2)
Postdischarge mortality or hospital readmissionNo 5210 (71.0)Yes 2124 (29.0)
*Adjusted for gestational age, sex, fetal growth, and race/ethnicity.
60
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infants with and without PPHN (10.4% readmission ratefor respiratory cause in infants with PPHN and 3.4% ininfants without; P < .001; Table II).Our primary composite outcome of postdischarge
mortality or any hospital readmission in the first year oflife occurred in 29% of infants with PPHN vs 9.9% in infantswithout PPHN (crude RR and aRR of 3.7 [95% CI, 3.5-3.9]and 3.5 [95% CI, 3.3-3.7], respectively; Table II). Theprimary outcome occurred in 33.4% of infants with severePPHN vs 9.9% of infants without PPHN (crude RR andaRR of 4.5 [95% CI, 4.3-4.8] and 4.2 [95% CI, 4.0-4.5],respectively; Table III, available at www.jpeds.com), and in20.2% of infants with mild PPHN (crude RR and aRR of2.3 [95% CI, 2.1-2.5] and 2.2 [95% CI, 2.0-2.5],respectively; Table IV, available at www.jpeds.com). Othersecondary outcomes (ED visits and ED visits for respiratorycause) are presented in Table II for the entire group withPPHN, and in Tables III and IV for the subgroupof infants with severe and mild PPHN, respectively.Table V (available at www.jpeds.com) shows yearly rates ofselected outcomes. Our primary outcome decreased from32.2% in 2005 to 24.4% in 2012 (P < .001).Figure 1 shows the aRRs for selected outcomes according
to PPHN etiology. For postdischarge mortality or hospitalreadmission (primary outcome; Figure 1), infants withanomalies of the respiratory system and CDH had thehighest aRR with 14.0 (95% CI, 10.8-18.1) and 8.2 (95%CI, 6.7-10.2), respectively. We noted that the average initialhospitalization was approximately 60 days longer for these2 groups, limiting the opportunity for primary outcome by1 year of age. Infants with MAS, infection, and otheretiologies of PPHN had initial hospitalizations that were
f life in cases and controls
No PPHN, n (%) Crude RR (95% CI) aRR* (95% CI)
3 966 689
3 960 260 (99.8) Reference Reference6429 (0.2) 44.5 (40.8-48.4) 39.5 (36.2-43.1)2366 (0.1) 97.2 (88.8-106.3) 82.9 (75.5-91.1)4063 (0.1) 7.7 (5.9-9.9) 7.2 (5.5-9.3)
3 964 241
3 574 165 (90.2) Reference Reference390 158 (9.8) 3.7 (3.5-3.8) 3.5 (3.3-3.6)46 190 (1.2) 6.2 (5.7-6.9) 5.7 (5.2-6.3)
3 827 826 (96.6) Reference Reference136 497 (3.4) 3.3 (3.0-3.5) 3.1 (2.9-3.3)11 971 (0.3) 7.3 (6.2-8.5) 6.7 (5.7-7.9)
2 589 817 (65.3) Reference Reference1 374 506 (34.7) 1.1 (1.1-1.1) 1.0 (1.0-1.1)595 024 (15.0) 1.2 (1.1-1.2) 1.1 (1.1-1.2)
3 289 313 (83.0) Reference Reference675 010 (17.0) 1.1 (1.1-1.2) 1.1 (1.1-1.2)186 850 (4.7) 1.4 (1.2-1.5) 1.3 (1.2-1.4)
3 571 569 (90.1) Reference Reference392 754 (9.9) 3.7 (3.5-3.9) 3.5 (3.3-3.7)
Steurer et al
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Figure 1. Forest plot for selected outcomes by etiology of PPHNcompared to infants without PPHN. A, Post dischargemortality;B, Other selected outcomes in the first year of life. Adjusted Risk ratio: adjusted for gestational age, sex, birth weight and race/ethnicity. For post-discharge mortality, adjusted risk ratio not available for MAS, RDS or other due to the small number ofpostdischarge deaths in these groups. CDH = congenital diaphragmatic hernia (n = 470) , MAS =meconium aspiration syndrome(n = 1628), pulmonary anomaly (n = 352), infection (n = 2598), RDS = respiratory distress syndrome (n = 660), other = birthasphyxia, cystic kidney disease, hydrops fetalis, interstitial emphysema, leukemia, polycythemia, renal agenesis and dysgen-esis, trisomy 21 (n = 547) and idiopathic (n = 1592).
October 2019 ORIGINAL ARTICLES
Morbidity of Persistent Pulmonary Hypertension of the Newborn in the First Year of Life 61
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Table VI. Timing of mortality and readmissions in first year of life
Variables All PPHN CDH Pulmonary anomaly MAS Infection RDS Other Idiopathic
Entire sample 7847 470 352 1628 2598 660 547 1592Mortality, n (%) 571 (7.3) 130 (27.7) 112 (31.8) 59 (3.6) 149 (5.7) 30 (4.6) 39 (7.1) 52 (3.3)Age at death in days, median (IQR) 8 (29) 19 (39) 4 (30.5) 5 (24) 7.5 (32) 6 (27) 5 (11) 9.5 (51)Any readmission, n (%) 2096 (28.6) 166 (47.7) 154 (60.9) 476 (30.3) 740 (30.0) 158 (25.0) 148 (29.0) 254 (16.4)Age at first readmission in days, median (IQR) 38 (122.5) 59 (130) 68.5 (168) 14 (50) 27 (97) 39 (116) 103.5 (151) 80.5 (161)Any readmission for respiratory cause, n (%) 766 (10.4) 96 (27.6) 93 (36.8) 117 (7.4) 297 (12.0) 56 (8.9) 40 (7.8) 67 (4.3)Age at first readmission for respiratory cause in days,median (IQR)
96 (156) 106 (152) 96 (142) 71 (159) 93.5 (166) 86 (135.5) 112.5 (150) 93 (151.5)
THE JOURNAL OF PEDIATRICS � www.jpeds.com Volume 213
prolonged by 18-20 days compared with infants withoutPPHN. The aRR for the primary outcome for MAS washighest at 4.2 (95% CI, 3.7-4.6) and lowest for idiopathicPPHN (aRR, 1.8; 95% CI, 1.5-2.0). Table VI shows age atthe primary outcome for each underlying cause of PPHN.Survival curves for the different underlying etiologies ofPPHN are shown in Figure 2 (available at www.jpeds.com), demonstrating that infants with PPHN owing toCDH and other congenital pulmonary anomalies have newevents extending into the latter part of their first year of life.
Table VII shows risk factors associated with our primaryoutcome. In the adjusted analysis, which included allvariables significant in the univariate analysis, the only riskfactors significantly associated with our primary outcomeof postnatal discharge or at least one hospital readmissionwithin the first year of life were Hispanic ethnicity (aRR,1.2; 95% CI, 1.1-1.4), small for gestational age (aRR, 1.2;95% CI, 1.1-1.3), severity of PPHN (aRR, 1.6; 95% CI,1.5-1.8 for severe vs mild PPHN), and etiology of PPHN(Table VII). Table VIII shows mortality, readmission andED visits infirst year of life in cases and controls withoutchromosomal anomalies or any congenital heart disease.
Discussion
This contemporary, large, population-based cohort studyassessed postdischarge mortality and morbidity burdenmeasured by hospital readmissions during the first year oflife in late preterm and term infants with different etiologiesand severities of PPHN born in California. After adjustingfor gestational age and other demographic variables, we founda >3-fold higher rate of postdischarge mortality or hospitalreadmission in infants with PPHN during the first year oflife compared with infants without PPHN. Infants with severePPHN, CDH, or pulmonary anomalies had the highestreadmission rates. However, even infants with only mildPPHN or etiologies that are assumed to be short term, suchas MAS, sepsis, or RDS, had a significantly increased hospitalreadmission rates compared with infants without PPHN.Finally, we identified severity and etiology of PPHN, Hispanicethnicity, and small for gestational age as independent signi-ficant risk factors for postdischarge mortality and morbidityburden in the first year of life, but not gestational age.
There are few studies to date addressing morbidity andpostdischarge mortality, and the data have been limited toinfants with severe forms of PPHN.7-10 For example, studies
62
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investigating the effect of inhaled nitric oxide on neonatalmortality reported hospital readmission rates from 20% to39% at 1-4 years of age.7-10 These figures are comparablewith our hospital readmission rate of 32.9% in infants withsevere PPHN. We found a readmission rate of 20% in thesubgroup of infants with mild PPHN, which was twice ashigh as in infants without PPHN.We also assessed rehospitalization rates for respiratory
causes. The UK Collaborative ECMO Group studied severePPHN, defined as an oxygenation index of >40. Theyreported 57 respiratory readmissions to the hospital in 99infants during the first year of life without specifying howmany infants were admitted multiple times.11 In the presentstudy, only about 30% of all readmissions were related to arespiratory cause, which was observed for the entire PPHNcohort with PPHN and for the severe and mild subgroups.It is possible that this was due to incomplete ICD-9 codingand that the true readmission rate for respiratory cause issomewhat higher. However, our findings demonstrate thatPPHN is associated with other healthcare problems, andthat a narrow focus exclusively on the respiratory status ofthese infants might omit the full extent of the morbidityburden.In addition to the degree of severity, the underlying
etiology of PPHN is an important determinant of clinicalcourse and outcomes.19 Generally, conditions that areassociated with hypoplastic vasculature are severe and oftenlead to persistent PH. For example, the hospital dischargemortality for infants with CDH in the modern era is30%-50% in population-based studies.20,21 Burgos et alreport a postdischarge mortality of 5% in 250 infants withCDH £2 years of age, with earlier deaths mainly owing torespiratory insufficiency and later deaths related togastrointestinal morbidity.22 In a prospective multicenterstudy, Wynn et al found that children with CDH scoredsignificantly below the normal mean on the Bayley Scale ofInfant Development-III motor, cognitive, and languagedomains at 2 years of age.23 In our study, we confirm thehigh mortality and morbidity burden in this subgroup ofinfants. We found a postdischarge mortality of 1.7% ininfants with CDH and 3.7% in infants with other anomaliesof the respiratory system; these groups also had the highestpercentage of hospital readmissions (47.7% and 60.9%,respectively).The literature on mortality and morbidity burden in
infants with PPHN owing to MAS, RDS, or infection is
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Table VII. Risk factors associated with postdischarge mortality or hospital readmissions in infants with PPHN
Variables No mortality or hospital readmissionsPostdischarge mortality or hospital
readmissions Crude RR (95% CI) aRR* (95% CI)
Sample 5210 2124Gestational age (weeks)34-36 890 (17.1) 381 (17.9) 1.1 (0.9-1.2) 1.1 (0.9-1.2)37-38 1524 (29.3) 676 (31.8) 1.1 (1.0-1.2) 1.1 (1.0-1.2)39-40 1189 (22.8) 471 (22.2) Reference Reference³41 601 (11.5) 220 (10.4) 0.9 (0.8-1.1) 0.9 (0.8-1.1)
SexMale 3011 (57.8) 1284 (60.4) Reference ReferenceFemale 2199 (42.2) 840 (39.6) 0.9 (0.8-1.0) 0.9 (0.9-1.0)
RaceWhite not Hispanic 1621 (31.1) 582 (27.4) Reference ReferenceHispanic 2095 (40.2) 989 (46.6) 1.2 (1.1-1.3) 1.2 (1.1-1.4)Black 462 (8.9) 197 (9.3) 1.1 (1.0-1.3) 1.1 (1.0-1.3)Asian 611 (11.7) 213 (10.0) 1.0 (0.8-1.1) 1.0 (0.8-1.1)Other 421 (8.1) 143 (6.7) 1.0 (0.8-1.2) 1.0 (0.8-1.2)
Birth weight†
Adequate for gestational age 3588 (68.9) 1471 (69.2) Reference ReferenceSmall for gestational age 575 (11.0) 305 (14.4) 1.2 (1.1-1.3) 1.2 (1.1-1.3)Large for gestational age 1028 (19.7) 341 (16.1) 0.9 (0.8-1.0) 0.9 (0.8-1.0)
Maternal asthmaNo 4926 (94.6) 1999 (94.1) Reference ReferenceYes 284 (5.5) 125 (5.9) 1.1 (0.9-1.3) 1.1 (0.9-1.3)
Smoking during pregnancyNo 4911 (94.3) 2011 (94.7) Reference ReferenceYes 299 (5.7) 113 (5.3) 0.9 (0.8-1.1) 0.9 (0.8-1.1)
Maternal age (years)<18 90 (1.7) 52 (2.5) 1.3 (1.0-1.7) 1.3 (1.0-1.7)18-34 3997 (76.7) 1572 (74.0) Reference Reference>34 1123 (21.6) 500 (23.5) 1.1 (1.0-1.2) 1.1 (1.0-1.2)
Maternal BMI‡
Underweight 104 (2.0) 52 (2.5) 1.2 (0.9-1.6) 1.2 (0.9-1.6)Normal weight 1482 (28.5) 554 (26.1) Reference ReferenceOverweight 916 (17.6) 369 (17.4) 1.1 (0.9-1.2) 1.1 (0.9-1.2)Obese 1055 (20.3) 403 (19.0) 1.0 (0.9-1.2) 1.0 (0.9-1.2)
Maternal diabetesNone 4367 (83.8) 1806 (85.0) Reference ReferencePreexisting 175 (3.4) 49 (2.3) 0.7 (0.6-1.0)‡ 0.8 (0.6-1.0)Gestational 668 (12.8) 269 (12.7) 1.0 (0.9-1.1) 1.0 (0.9-1.2)
Mental illnessNo 4899 (94.0) 2006 (94.4) Reference ReferenceYes 311 (6.0) 118 (5.6) 0.9 (0.8-1.1) 0.9 (0.8-1.1)
Illicit drug useNo 5029 (96.5) 2060 (97.0) Reference ReferenceYes 181 (3.5) 64 (3.0) 0.9 (0.7-1.2) 0.9 (0.7-1.2)
HypertensionNone 4584 (88.0) 1879 (88.5) Reference ReferencePreexisting 114 (2.2) 37 (1.7) 0.8 (0.6-1.2) 0.9 (0.6-1.2)Gestational 129 (2.5) 59 (2.8) 1.1 (0.8-1.4) 1.1 (0.8-1.4)
PreeclampsiaNo 4889 (93.8) 1997 (94.0) Reference ReferenceYes 321 (6.2) 127 (6.0) 1.0 (0.8-1.2) 1.0 (0.8-1.1)
ParityNulliparous 2161 (41.5) 827 (38.9) 0.9 (0.9-1.0) 0.9 (0.8-1.0)Multiparous 3046 (58.5) 1296 (61.0) Reference Reference
GestationSingleton 5080 (97.5) 2087 (98.3) Reference ReferenceMultiple 130 (2.5) 37 (1.7) 0.8 (0.5-1.1) 0.7 (0.5-0.9)
Maternal education (years)<12 1218 (23.4) 588 (27.7) 1.1 (1.0-1.2) 1.1 (1.0-1.2)12 1350 (25.9) 585 (27.5) Reference Reference>12 2433 (46.7) 863 (40.6) 0.9 (0.8-1.0) 0.9 (0.8-1.0)
InsurancePrivate 2243 (46.9) 923 (43.5) Reference ReferencePublic 2472 (47.5) 1089 (51.3) 1.1 (1.0-1.2) 1.1 (1.0-1.2)Self-pay 107 (2.1) 37 (1.7) 0.9 (0.7-1.3) 0.9 (0.7-1.3)Other 170 (3.3) 69 (3.3) 1.1 (0.8-1.3) 1.0 (0.8-1.3)
(continued )
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Table VII. Continued
Variables No mortality or hospital readmissionsPostdischarge mortality or hospital
readmissions Crude RR (95% CI) aRR* (95% CI)
FIPS code1-2 (urban) 2693 (51.7) 1137 (53.5) Reference Reference3-4 (moderately rural) 770 (14.8) 314 (14.8) 1.0 (0.9-1.1) 1.0 (0.9-1.1)5-6 (rural) 57 (1.1) 20 (0.9) 0.9 (0.6-1.4) 0.9 (0.5-1.3)
Type PPHNMild 1961 (37.6) 497 (23.4) Reference ReferenceSevere 3249 (62.4) 1627 (76.6) 1.7 (1.5-1.8) 1.6 (1.5-1.8)
Etiology of PPHNIdiopathic 1289 (24.7) 260 (12.2) Reference ReferenceCDH 179 (3.4) 169 (8.0) 2.9 (2.4-3.5) 2.8 (2.3-3.4)Congenital pulmonary anomaly 95 (1.8) 158 (7.4) 3.7 (3.1-4.5) 3.6 (2.9-4.4)MAS 1094 (21.0) 478 (22.5) 1.8 (1.6-2.1) 1.9 (1.6-2.2)Infection 1720 (33.0) 749 (35.3) 1.8 (1.6-2.1) 1.8 (1.5-2.0)RDS 473 (9.1) 160 (7.5) 1.5 (1.2-1.8) 1.4 (1.1-1.7)
Other 473 (9.1) 160 (7.5) 1.8 (1.4-2.1) 1.7 (1.4-2.1)
BMI, body mass index; FIPS, Federal Information Processing Standards.*Adjusted for all significant predictors the univariate analysis.†Definition according to Talge NM, Mudd LM, Sikorskii A, Basso O. United States birth weight reference corrected for implausible gestational age estimates. Pediatrics. 2014;133:844-853.‡Underweight: BMI < 18.5 kg/m2; normal weight: BMI 18.5-24.9 kg/m2; overweight: BMI 25.0-29.9 kg/m2; obese: BMI ³ 30.0 kg/m2.
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scarce, possibly because pulmonary vascular disease isregarded as short term and recoverable. We found thatinfants with MAS, infection, and RDS had a significantlyhigher risk for readmission during the first year of life vsthose without PPHN (Table VI). A greater percentageof these readmissions was due to nonrespiratory causes,underscoring the potential sequelae of multiorganinvolvement.
Our findings have important implications for outpatientfollow-up, counseling of parents, and preventive measuressuch as vaccinations. Further studies should investigate theseclinical outcomes prospectively in infants with mild PPHNand etiologies such as MAS, RDS, or sepsis.
Aside from the severity and etiology of PPHN, weidentified Hispanic ethnicity as a risk factor for postdischargemortality or readmission. Although we previously reportedthat infants of Hispanic ethnicity were less likely tosuffer from PPHN, our current findings show that after adiagnosis of PPHN, they are at higher risk for later adverseoutcomes.19 This finding was true after adjusting forsociodemographic risk factors such as maternal educationor insurance status, pointing toward potential underlyingbiological variations. We also identified small for gestationalage, a surrogate marker of fetal growth, as an independentrisk factor for the primary outcome in this study. Wepreviously identified small for gestational age as a risk factorfor the incidence of PPHN, and we speculated that thisassociation is potentially related to decreased pulmonaryalveolar and vessel growth or pulmonary artery endothelialcell dysfunction.19,24 This same mechanism could explainthe increased mortality and morbidity burden throughoutthe first year of life.
Limitations of our study are mostly related to theadministrative nature of the dataset. Using ICD-9 codes toidentify PPHN and underlying etiology carries a risk of
64
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misclassification for those variables. However, this limitationis at least partly offset by the large number of cases identifiedin this large population-based dataset. We cannot excludethat cases have been missed based on ICD-9 codes used orthat inappropriate use of ICD-9 codes for PPHN couldhave labeled some infants without PPHN as PPHN cases.However, the usage of the ICD-9 codes for PPHN has beenvalidated by a positive predictive value of 68.3%-89.6%when compared with primary medical record review.25,26
We were also unable to assess timing of the ICD-9 codes.For example, it is possible that the sepsis or infectiondiagnosis occurred late in the hospital course after diagnosisof PPHN in certain infants, thus, falsely assigning it as theunderlying cause. Additionally, we had relatively limiteddetails about the clinical course of the cases with PPHN.For example, it was impossible to confirm the diagnosis ofPPHN with echocardiographic data. We were alsounable to incorporate potentially important clinicalpredictors such as oxygen requirement, length of mechanicalventilation, use of inhaled nitric oxide, or extracorporealmembrane oxygenation into our analysis.It is not unexpected that infants with severe PPHN, or
with etiologies at high risk for permanent pulmonaryhypertension such as CDH, have a higher mortality andmorbidity burden throughout the first year of life thaninfants without PPHN. However, it is surprising thatinfants with mild PPHN and more short-term etiologiessuch as MAS, infection, or RDS still have a significantmortality and morbidity burden beyond the neonatalperiod compared with infants without PPHN. Thisinformation should inform preventive measures andcounseling of parents. n
Submitted for publication Apr 3, 2019; last revision received Jun 4, 2019;
accepted Jun 21, 2019.
Steurer et al
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Reprint requests: Martina A. Steurer, MD, UCSF Department of Pediatrics, 550
16th St, 5th Floor, San Francisco, CA 94143. E-mail: martina.steurermuller@
ucsf.edu
Data statement
Data sharing statement available at www.jpeds.com.
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in the First Year of Life 65
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Figure 2. Kaplan-Meyer curve for mortality or readmission by PPHN etiology. With no PPHN as the reference group, thefollowing are the HRs and 95% CI associated with the above curves: CDH 6.06 (5.21-7.05), other anomaly of the respiratorysystem 8.68 (7.43-10.13), MAS 3.61 (3.30-3.96), infection 3.54 (3.29-3.80), RDS 2.83 (2.43-3.31), other 3.24 (2.76-3.80), andidiopathic 1.74 (1.54-1.96).
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Table I. Baseline characteristics of cases and controls
Characteristics All PPHN Mild PPHN Severe PPHN No PPHN P value*
n 7847 2477 5370 3 966 689Gestational age (weeks)<37 1423 (18.1) 304 (12.3) 1119 (20.8) 276 243 (7.0) <.000137-40 5567 (70.9) 1904 (76.9) 3663 (68.2) 3 306 715 (83.4)³41 857 (10.9) 269 (10.9) 588 (11.0) 383 731 (9.7)
Birth weightSmall for gestational age 1056 (13.5) 258 (10.4) 798 (14.9) 372 248 (9.4) <.0001Adequate for gestational age 5383 (68.6) 1652 (66.7) 3731 (69.5) 3 188 112 (80.4)Large for gestational age 1408 (17.9) 567 (22.9) 841 (15.7) 406 329 (10.2)
Mode of delivery <.0001Vaginal 3237 (41.3) 1215 (49.1) 2022 (37.7) 2 700 323 (68.1)Cesarean 4610 (58.8) 1262 (51.0) 3348 (62.4) 1 266 366 (31.9)
Race <.0001White not Hispanic 2325 (29.6) 750 (30.3) 1575 (29.3) 1 062 318 (26.8)Hispanic 3326 (42.4) 1051 (42.4) 2275 (42.4) 1 945 596 (49.1)Black 705 (9.0) 209 (8.4) 496 (9.2) 208 297 (5.3)Asian 890 (11.3) 285 (11.5) 605 (11.3) 484 385 (12.2)Other 601 (7.7) 182 (7.4) 419 (7.8) 266 093 (6.7)
Sex <.0001Female 3256 (41.5) 1098 (44.3) 2158 (40.2) 1 939 602 (48.9)Male 4591 (58.5) 1379 (55.7) 3212 (59.8) 2 027 075 (51.1)Missing 0 (0.0) 0 (0.0) 0 (0.0) 12 (0.0)
Gestation .3599Singleton 7664 (97.6) 2429 (98.1) 5235 (97.5) 3 865 748 (97.5)Twin 178 (2.3) 46 (1.9) 132 (2.5) 99 020 (2.5)Multiple 5 (0.1) 2 (0.1) 3 (0.1) 1921 (0.1)
Maternal education (years) <.0001<12 1932 (24.6) 618 (25.0) 1314 (24.5) 1 020 294 (25.7)12 2081 (26.5) 660 (26.7) 1421 (26.5) 974 817 (24.6)>12 3513 (44.8) 1117 (45.1) 2396 (44.6) 1 834 515 (46.3)Missing 321 (4.1) 82 (3.3) 239 (4.5) 137 063 (3.5)
Payment for delivery .0461Private insurance 3590 (45.8) 1136 (45.9) 2454 (45.7) 1 871 448 (47.2)Public insurance 3830 (48.8) 1224 (49.4) 2606 (48.5) 1 884 634 (47.5)Self-pay 149 (1.9) 43 (1.7) 106 (2.0) 79 624 (2.0)Other 278 (3.5) 74 (3.0) 204 (3.8) 130 983 (3.3)
Parity .0017Nulliparous 3214 (41.0) 998 (40.3) 2216 (41.3) 1 555 393 (39.2)Multiparous 4633 (59.0) 1477 (59.6) 3152 (58.7) 2 410 750 (60.8)Maternal age (years) <.0001<18 156 (2.0) 43 (1.7) 113 (2.1) 115 004 (2.9)18-34 5970 (76.1) 1823 (73.6) 4147 (77.2) 3 142 608 (79.2)>34 1721 (21.9) 611 (24.7) 1110 (20.7) 708 888 (17.9)
Maternal BMI <.0001Underweight 165 (2.1) 49 (2.0) 116 (2.6) 111 646 (2.8)Normal weight 2190 (27.9) 705 (28.5) 1485 (27.7) 1 351 199 (34.2)Overweight 1382 (17.6) 470 (19.0) 912 (17.0) 705 877 (17.8)Obese 1538 (19.6) 506 (20.4) 1032 (19.2) 562 462 (14.2)Missing 2572 (30.9) 747 (30.2) 1825 (34.0) 1 225 505 (32.8)
Maternal diabetes <.0001None 6615 (84.3) 2040 (82.4) 4575 (85.2) 3 619 136 (91.2)Preexisting 235 (3.0) 88 (3.6) 147 (2.7) 32 714 (0.8)Gestational 997 (12.7) 349 (14.1) 648 (12.1) 314 839 (7.9)
Mental illness 456 (5.8) 128 (5.2) 328 (6.1) 121 695 (3.1) <.0001Smoking during pregnancy 439 (5.6) 125 (5.1) 314 (5.9) 134 219 (3.4) <.0001Illicit drug use 261 (3.3) 72 (2.9) 189 (3.5) 62 252 (1.6) <.0001Maternal asthma 445 (5.7) 123 (5.0) 322 (6.0) 148 057 (3.7) <.0001Hypertension <.0001None 6929 (88.3) 2195 (88.6) 4734 (88.2) 3 690 836 (93.1)Preexisting 223 (2.8) 72 (2.9) 151 (2.8) 54 039 (1.4)Gestational 606 (7.7) 182 (7.4) 424 (7.9) 203 327 (5.1)Unspecified 89 (1.1) 28 (1.1) 61 (1.1) 18 487 (0.4)Preeclampsia 470 (6.0) 139 (5.6) 331 (6.2) 131 518 (3.3) <.0001
Ventilation <.0001Positive pressure 4830 (61.6) 0 (0.0) 4830 (89.9) 41 591 (1.1)CPAP 540 (6.9) 0 (0.0) 540 (10.1) 34 073 (0.9)Neither 2477 (31.6) 2477 (100.0) 0 (0.0) 3 891 025 (98.1)
Days to discharge home (mean, SD) 23 (35.7) 14.1 (29.0) 27.6 (38.0) 2.8 (7.9) <.0001
BMI, body mass index; CPAP, continuous positive airway pressure.Values are number (%) unless otherwise indicated.*P value refers to all PPHN vs controls.
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Table III. Mortality, readmissions, or ED visits in first year of life in cases with severe PPHN* vs controls
Characteristics Severe PPHN, n (%) No PPHN, n (%) Crude RR (95% CI) aRR† (95% CI)
Entire sample 5370 3 966 689MortalityNo 4826 (89.9) 3 960 260 (99.8) Reference ReferenceYes 544 (10.1) 6429 (0.2) 64.1 (58.7-70.0) 53.6 (48.9-58.7)Predischarge mortality 494 (9.2) 2366 (0.1) 141.9 (129.4-155.7) 112.2 (101.7-123.8)Postdischarge mortality 50 (0.9) 4063 (0.1) 10.0 (7.6-13.2) 8.9 (6.8-11.8)
Sample who survived to discharge 4876 3 964 323ReadmissionNone 3272 (67.1) 3 574 165 (90.2) Reference ReferenceAny 1604 (32.9) 390 158 (9.8) 4.5 (4.2-4.8) 4.2 (3.9-4.4)>1 readmission 321 (6.6) 46 190 (1.2) 7.5 (6.7-8.5) 6.7 (6.0-7.6)
Readmission for respiratory causeNone 4281 (87.8) 3 827 826 (96.6) Reference ReferenceAny 595 (12.2) 136 497 (3.4) 3.9 (3.6-4.2) 3.6 (3.3-4.0)>1 readmission for respiratory cause 119 (2.4) 11 971 (0.3) 8.8 (7.3-10.6) 7.9 (6.6-9.5)
ED visitsNone 3123 (64.1) 2 589 817 (65.3) Reference ReferenceAny 1753 (36.0) 1 374 506 (34.7) 1.1 (1.0-1.1) 1.0 (1.0-1.1)>1 ED visit 846 (17.3) 595 024 (15.0) 1.2 (1.1-1.3) 1.1 (1.1-1.2)
ED visits for respiratory causeNone 3903 (80.1) 3 289 313 (83.0) Reference ReferenceAny 973 (20.0) 675 010 (17.0) 1.2 (1.1-1.3) 1.2 (1.1-1.3)>1 ED visit for respiratory cause 321 (6.6) 186 850 (4.7) 1.4 (1.3-1.6) 1.4 (1.2-1.5)
Postdischarge mortality or hospitalreadmission
No 3249 (66.6) 3 571 569 (90.1) Reference ReferenceYes 1627 (33.4) 392 754 (9.9) 4.5 (4.3-4.8) 4.2 (4.0-4.5)
*Severe PPHN is defined as infants receiving positive pressure ventilation or CPAP.†Adjusted for gestational age, sex, fetal growth, and race/ethnicity.
Table IV. Mortality, readmissions, or ED visits in first year of life in cases with mild PPHN* vs controls
Characteristics Mild PPHN, n (%) No PPHN, n (%) Crude RR (95% CI) aRR† (95% CI)
Entire sample 2477 3 966 689MortalityNo 2450 (98.9) 3 960 260 (99.8) Reference ReferenceYes 27 (1.1) 6429 (0.2) 6.8 (4.6-9.9) 6.9 (4.7-10.0)Predischarge mortality 19 (0.8) 2366 (0.1) 12.9 (8.2-20.2) 13.1 (8.3-20.6)Postdischarge mortality 8 (0.3) 4063 (0.1) 3.2 (1.6-6.4) 3.2 (1.6-6.5)
Sample who survived to discharge 2458 3 964 241ReadmissionNone 1966 (80.0) 3 574 165 (90.2) Reference ReferenceAny 492 (20.0) 390 158 (9.8) 2.3 (2.1-2.5) 2.2 (2.0-2.5)>1 readmission 105 (4.3) 46 190 (1.2) 4.1 (3.4-5.0) 4.0 (3.3-4.8)
Readmission for respiratory causeNone 2287 (93.0) 3 827 826 (96.6) Reference ReferenceAny 171 (7.0) 136 497 (3.4) 2.1 (1.8-2.4) 2.0 (1.7-2.4)>1 readmission for respiratory cause 32 (1.3) 11 971 (0.3) 4.5 (3.1-6.3) 4.3 (3.0-6.1)
ED visitsNone 1565 (63.7) 2 589 817 (65.3) Reference ReferenceAny 893 (36.3) 1 374 506 (34.7) 1.1 (1.0-1.2) 1.1 (1.0-1.2)>1 ED visit 402 (16.4) 595 024 (15.0) 1.1 (1.0-1.2)‡ 1.1 (1.0-1.2)
ED visits for respiratory causeNone 2037 (82.9) 3 289 313 (83.0) Reference ReferenceAny 421 (17.1) 675 010 (17.0) 1.0 (0.9-1.1) 1.0 (0.9-1.1)>1 ED visit for respiratory cause 137 (5.6) 186 850 (4.7) 1.2 (1.0-1.4) 1.2 (1.0-1.4)
Postdischarge mortality or hospitalreadmission
No 1961 (79.8) 3 571 569 (90.1) Reference ReferenceYes 497 (20.2) 392 754 (9.9) 2.3 (2.1-2.5) 2.2 (2.0-2.5)
*Mild PPHN defined as infants receiving neither positive pressure ventilation nor CPAP.†Adjusted for gestational age, sex, fetal growth, and race/ethnicity.
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65.e3 Steurer et al
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Table V. Incidence, mortality, and readmission for infants with PPHN by year
Variables 2005 2006 2007 2008 2009 2010 2011 2012 P value*
All infants in OSHPD dataset, n 490 926 505 380 533 176 520 776 496 860 481 237 473 671 472 500Infants with PPHN, n 968 1062 1055 991 930 1019 918 904 .0451Incidence of PPHN, % 0.20 0.21 0.20 0.19 0.19 0.21 0.19 0.19Mortality of PPHN, % 77 (8.0) 68 (6.4) 84 (8.0) 70 (7.1) 73 (7.9) 76 (7.5) 70 (7.6) 53 (5.9) .5389Postdischarge mortality of PPHN, % 10 (1.0) 9 (0.9) 13 (1.2) 6 (0.6) 5 (0.5) 8 (0.8) 4 (0.4) 3 (0.3) .2683Sample of infants who survived todischarge, n
901 1003 984 927 862 951 852 854
ReadmissionAny, % 284 (31.5) 292 (29.1) 331 (33.6) 277 (29.9) 233 (27.0) 246 (25.9) 225 (26.4) 208 (24.4) <.0001>1 readmission, % 53 (5.9) 51 (5.1) 62 (6.3) 63 (6.8) 42 (4.9) 53 (5.6) 57 (6.7) 45 (5.3) .5167
Readmission for respiratory causeAny, % 99 (11.0) 105 (10.5) 127 (12.9) 105 (11.2) 77 (8.9) 91 (9.6) 83 (9.7) 80 (9.4) .1127>1 readmission for respiratory
cause, %12 (1.3) 16 (1.6) 18 (1.8) 24 (2.6) 12 (1.4) 19 (2.0) 25 (2.9) 25 (2.9) .0645
Postdischarge mortality or hospitalreadmission, %
290 (32.2) 298 (29.7) 338 (34.4) 279 (30.1) 235 (27.3) 250 (26.3) 226 (26.5) 208 (24.4) <.0001
*c2 test.
Table VIII. Mortality, readmissions, or ED visits in first year of life in cases and controls without chromosomalanomalies or any congenital heart disease
Variables PPHN, n (%) No PPHN, n (%) Crude RR (95% CI) aRR* (95% CI)
Entire sample 5198 3 931 139MortalityNo 4822 (93.0) 3 925 311 (99.9) Reference ReferenceYes 365 (7.0) 5828 (0.2) 47.9 (43.1-53.3) 44.3 (39.8-49.4)Predischarge mortality 326 (6.3) 2046 (0.1) 111.8 (99.9-125.0) 101.7 (90.5-114.3)Postdischarge mortality 39 (0.8) 3782 (0.1) 8.3 (6.1-11.4) 7.9 (5.8-10.9)
Sample who survived to discharge 4872 3 929 093ReadmissionNone 3670 (75.3) 3 551 821 (90.4) Reference ReferenceAny 1202 (24.7) 377 272 (9.6) 3.1 (2.9-3.3) 2.9 (2.7-3.1)>1 readmission 195 (4.0) 42 620 (1.1) 4.4 (3.8-5.1) 4.1 (3.5-4.7)
Readmission for respiratory causeNone 4462 (91.6) 3 797 938 (96.7) Reference ReferenceAny 410 (8.4) 131 155 (3.3) 2.7 (2.4-2.9) 2.5 (2.3-2.8)>1 readmission for respiratory cause 71 (1.5) 10 889 (0.3) 5.5 (4.4-7.0) 5.1 (4.0-6.5)
ED visitsNone 3149 (64.6) 2 569 669 (65.4) Reference ReferenceAny 1723 (35.4) 1 359 424 (34.6) 1.0 (1.0-1.1) 1.0 (1.0-1.1)>1 ED visit 812 (16.7) 587 533 (15.0) 1.1 (1.0-1.2) 1.1 (1.0-1.2)
ED visits for respiratory causeNone 3979 (81.7) 3 261 961 (83.0) Reference ReferenceAny 893 (18.3) 667 132 (17.0) 1.1 (1.0-1.2) 1.1 (1.0-1.2)>1 ED visit for respiratory cause 301 (6.2) 184 320 (4.7) 1.3 (1.2-1.5) 1.3 (1.1-1.5)
Postdischarge mortality or hospitalreadmission
No 3649 (74.9) 3 549 325 (90.3) Reference ReferenceYes 1223 (25.1) 379 768 (9.7) 3.1 (2.9-3.3) 3.0 (2.8-3.2)
ICD-9 codes for chromosomal anomalies are 759.0-759.9.*Adjusted for gestational age, sex, fetal growth and race/ethnicity.
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