Factores de riesgo para problemas emocionales y del
comportamiento en niños prematuros moderados-tardíos
Pauline J. den Haan, Marlou L. A. de Kroon, Nienke H. van Dokkum, Jorien M. Kerstjens, Sijmen A.
Reijneveld, Arend F. Bos
Objetivo
Determinar qué factores, incluyendo estilo de vida materno, los relacionados con la
gestación y el parto, fetales y neonatales ajustados por estado socioeconómico, se
relacionan con problemas emocionales y del comportamiento en niños nacido
prematuros moderados-tardíos (PMTs; edad gestacional 32.0-35.9 semanas) a los 4 años
de edad. PMTs están en mayor riesgo para problemas emocionales y de conducta que
los bebés nacidos a término. Especialmente para los PMTs, es escaso el conocimiento de
los factores que aumentan o disminuyen el riesgo de problemas emocionales y del
comportamiento.
Diseño y Métodos
Evaluamos problemas emocionales en 809 PMTs en edades entre 41 y 49 meses del
Proyecto Longitudinal de resultados en Pretérmino basado en la comunidad (LOLLIPOP),
empleando la Child Behavior Checklist (CBCL) informada por padres. Recolectamos datos
acerca de potenciales factores de riesgo desde los registros hospitalarios y cuestionarios
parentales. Se aplicaron análisis univariado y logístico de regresión múltiple.
Principales medidas de resultado
Scores (sub)clínicos de CBCL
Resultados
La infección perinatal incrementó el riesgo de presentar scores de problema CBCL total
con un OR 2.22 (p<0.01). La infección perinatal, tabaquismo materno, y sexo masculino
aumentaron el riesgo de scores para problemas de externalización CBCL con ORs entre
1.64 y 2.46 (todos p<0.05). El nacimiento múltiple disminuyó los scores de riesgo de
problema de internalización CBCL con un OR 0.63 (p<0.05).
Conclusiones
Los factores de riesgo para problemas conductuales en PMTs son sexo masculino,
infección perinatal y tabaquismo materno, siendo estos dos últimos potencialmente
modificables. El nacimiento múltiple es un factor protector para problemas emocionales
en PMTs. Estos resultados sugieren potenciales factores en los que focalizar intervención
preventiva en PMTs, que representan la gran mayoría de todos los niños nacidos
pretérmino
Introducción
Los niños nacidos PMTs, (EG 32.0-35.9 semanas, 85% de todos los niños nacidos PT (1))
están en un riesgo 1.5 a 2.5 mayor de problemas emocionales y del comportamiento
comparados con los niños nacidos a término (RNT, EG 38.0-41.9 semanas) (2-4).
Adicionalmente, PMTs nacidos sanos demuestran mayores problemas emocionales y
conductuales que los RNT tratados en UCIN después de nacer (3). Estos problemas
emocionales y del comportamiento frecuentemente persisten a lo largo de la vida (5).
Afectan la calidad de vida del niño (6), pueden llevar a repetición de grado (2),
necesidades educativas especiales (2, 7), y numerosas adversidades a largo plazo tales
como dificultades laborales (8, 9), crimen, y abuso de sustancias en la adultez (10).
En cuanto a PMTs, hat sólo pequeña evidencia de los factores que aumentan el riesgo
de problemas emocionales y de conducta. Los pocos factores que han sido identificados
son ingreso en UCIN (3), bajo nivel socioeconómico (SE) (11), y sexo femenino, todos
aumentando el riesgo de problemas emocionales al año y medio de edad (12). El déficit
de crecimiento longitudinal postnatal no se encontró asociado con problemas
emocionales y de conducta a los siete años de edad (13), y un estudio británico del 2001
(7) encontró varios factores que aumentaban el riesgo de problemas en la escuela en
PMTs, tales como sexo masculino y egreso postnatal desde la unidad de cuidados
especiales más allá de las 36semanas de edad postmenstrual. En contraste, estudios entre
PT tempranos (EG<32 semanas) y RNT reportan varios factores asociados con aumento
del riesgo de problemas emocionales y de conducta (14-19). Los factores identificados
conciernen a varios dominios: parental-emocional (ej., problemas emocionales maternos
y de pareja [14], tabaquismo materno, y pobre bienestar físico y mental materno [15, 20]),
relacionados con el parto (ej., pérdida de sangre durante la gestación [16], y sección
cesárea [14]), y neonatal (ej., sexo masculino [14, 17, 21], y (prolongada) internación en
UCIN [14, 16, 18]). Los factores de riesgo y sus efectos pueden ser definitivamente
diferentes en el grupo de PMTs. Por ejemplo, en un estudio de nuestra propia cohorte,
nivel SE se encontró con un efecto más fuerte sobre problemas emocionales y de
conducta en niños con menor EG (11).
Debido a las importantes consecuencias clínicas y de salud pública de los problemas
emocionales y de conducta, una mirada más profunda hacia los factores de riesgo que
están asociados con estos problemas en el grupo más grande de niños nacidos
prematuros puede ayudar a identificar a los PMTs en riesgo. Dado que la intervención
temprana sobre problemas emocionales y de conducta ha probado ser efectiva tanto
para RNT como niños PT en general (22, 23), nuevo conocimiento acerca de factores de
riesgo potencialmente modificables y la identificación de PMT en mayor riesgo puede
ser utilizado para enfocar intervenciones preventivas. Por lo tanto, nuestro objetivo fue
investigar cuáles factores, incluyendo maternos, estilo de vida, relacionados con la
gestación-parto, y factores fetales neonatales aumentan o disminuyen el riesgo de
problemas emocionales totales, de internalización, externalización y conductuales en
PMTs al ingreso escolar (ej., 4 años).
Métodos
Diseño del estudio y técnica de muestreo
Este estudio forma parte del Proyecto LOLLIPOP (24). En total, 13 Centros de Cuidado
Preventivo de la salud Infantil en Holanda (PCHCs) examinaron las historias clínicas de
45446 niños (25% de una cohorte de un año en Holanda) con edad entre 43 y 49 meses,
que nacieron en 2002 y 2003 en las tres provincias del norte de los Países Bajos. De esos
45446 niños, 1412 nacieron moderadamente- tardíos pretérmino. Los padres de 1145
niños consintieron por escrito, llevando a una tasa de inclusión de 81%. Los criterios de
inclusión fueron malformaciones congénitas o síndromes, infecciones congénitas, y una
EG que no pudiera ser verificada o estuviera por fuera del rango establecido. Los no-
participantes con mayor frecuencia fueron niños hijos de padres con bajo nivel SE y/o
etnicidad no-holandesa (ambos p<0.001), y fueron parte de una gestación múltiple con
menor frecuencia (p<0.05) (25). Para este estudio, para obtener una muestra lo más
homogénea posible incorporamos sólo PMTs que se unieron al seguimiento al ingreso
escolar, con administración de la CBCL entre los 41 y 19 meses de edad, y para los cuales
estaba disponible la información acerca de todos los factores de riesgo (N= 809, ej., 71%
de los padres deseando participar) El estudio LOLLIPOP fue aprobado por el comité de
revisión del Centro Médico de la Universidad de Groningen (ISRCTN número de registro
del estudio 80622320) y se obtuvo consentimiento informado de todos los padres. Un
esquema de flujo completo de nuestro procedimiento muestral ha sido reportado
previamente (24).
Datos y recolección de datos
Un mes de antes de la última visita programada a la edad de 43-49 meses los padres
recibieron una invitación para permitir la participación de su hijo en el estudio. Junto a
la invitación había información acerca del estudio LOLLIPOP, el consentimiento
informado, un cuestionario CBCL, y un cuestionario general sobre las características
familiares y perinatales, todos los cuales fueron devueltos por los padres en la visita.
Evaluamos los problemas emocionales y conductuales a los 4 años, empleando el CBCL
válido para las edades 1.5-5 años. El CBCL es un cuestionario parental conteniendo 99
ítems de problemas con valuaciones FALSO/ Con frecuencia/ VERDADERO. Fue
completado por la madre en aproximadamente el 81% de los PMTs incluídos en este
estudio. Estas preguntas fueron todas incluídas en la escala total de problemas, y fueron
computadas dos escalas amplias, problemas de internalización (“emocional”) y
externalización (“conductual”) (26). Los datos CBCL fueron dicotomizados conforme al
manual, con scores de corte establecidos en <83% (normal), y ≥84% ((sub) clínico). El
CBCL tiene buenas propiedades psicométricas y una versión holandés validad (26-28).
Basados en la literatura, examinamos qué factores analizaríamos como potenciales
factores de riesgo para problemas emocionales y conductuales en PMTs: (1) factores de
riesgo conocidos para problemas emocionales y conductuales en RNTs, EPTs (14-16, 18,
19, 21), y PMTs (3, 11, 12). Los datos sobre estos factores maternos y de estilo de vida,
factores relacionados con la gestación y el parto, y factores fetales y neonatales fueron
obtenidos de un cuestionario general, registros del nacimiento, y registros médicos de
madre y niño. Esto hizo posible cruzar información de diferentes fuentes.
Table 1. Factores de riesgo potencial para trastornos emocionales y de conducta en RNPT Moderadamente tardío dentro de la cohort e LOLLIPOP.
Factores de riesgo potencial Prevalencia Definición de la variable
n/Ntotal %
Factores Maternos y de estilo de vida
Etnia no holandesa 42/809 (5.2 Madre no nacida en los Países Bajos.
Multiparidad 284/809
(35.1) Madre con más de 1 embarazo
Obesidad previa al embarazo 88/767 (11.5) Indice de Masa Corporal IMC > 30kg/m2
Fumar durante el embarazo 185/807 (22.9) Fumar durante el embarazo
Enfermedad mental materna 13/809 (1.6) Enfermedad mental crónica (depresión, psicosis, otras)
Relacionado al embarazo y parto
HELLP/pre-eclampsia Hemólisis, enzimas hepáticas elevadas y recuento bajo de plaquetas
157/809 (19.4) Tipo severo de preeclampsia debido al mal funcionamiento de la placenta
Esteroides Antenatales 156/809 (19.3) Tratamiento completo con esteroides antenatales
Parto inducido por causa fetal 121/809 (15.0) Indicación fetal / combinada fetal + materna de parto inducido
pRPM 187/809 (23.1) Ruptura prematura prolongada de membranas (> 24 horas antes del parto)
Cesárea 293/809 (36.2) Cesárea primaria o secundaria
Infección Perinatal 119/809 (14.7) Signos clínicos de infección bacteriana, de madre y / o niño, o corioamnionitis comprobada.
Fetal y Neonatal
Género 459/809 (56.7) Sexo Masculino
Nacimiento múltiple 233/809 (28.8) Ser parte de un parto múltiple (gemelo, trillizo)
PEG 72/809 (8.9) Pequeño para la edad gestacional por debajo de P10 según las tablas de crecimiento holandesas
Baja EG 259/809 (32.0) EG 32-33 semanas
Asfixia 17/807 (2.1) Diagnóstico de asfixia en informe médico de egreso
Insuficiencia Circulatoria 24/807 (3.0) Administración de medicación inotrópica 1 vez o más.
Insuficiencia Respiratoria 144/807 (17.8) Uso de CPAP y / o ventilación asistida en la sala de partos por más tiempo que la estabilización inicial
Tratamiento con cafeína 89/802 (11.1) Uso de cafeína para el tratamiento de Apnea
Hiperbilirrubinemia 351/805 (43.6) Valor pico de bilirrubina: y / o fototerapia. EG 32-33 semanas:> 255 μmol / L, EG 34-35 semanas:> 340 μmol / L
Hipoglicemia 65/798 (8.1) En las primeras 72 horas, al menos un valor de glucosa plasmática registrado <1.7 mmol en / L (30 mg / dL)
Septicemia 30/806 (3.7) Síntomas clínicos y 1 o más hemocultivos positivos
Duración de la estancia hospitalaria por encima del p10
75/799 (9.4) Duración de la estancia hospitalaria en un 10% más, en comparación con los pares de la misma semana de EG
Sociodemografico
ESE Estado socioeconómico
Basado en cinco mediciones que incluyen educación de la madre, educación del padre, ingreso de los padres, ocupación de la madre y ocupación de el padre.
Bajo 212/808 (26.2) Mayor o igual 1DE por debajo de la media
Intermedio 408/808 (50.5) Media +/- 1 DE
Alto 188/808 (23.3) Mayor o igual 1DE por encima de la media
EG fue confirmada con mediciones de ultrasonido temprano en >95% de los casos. En
otros casos, la EG fue cruzada y chequeada con las estimaciones clínicas al nacer. Los
datos se codificaron siguiendo prácticas estándar.
Análisis estadístico
Primero, empleando Chi cuadrado determinamos las características de base de la
muestra en relación a la presencia de los problemas totales en CBCL dicotomizados.
Segundo, utilizando el análisis de regresión logística univariado determinamos los
riesgos de aumento total en CBCL, problemas de internalización, y externalización para
varios factores maternos y de estilo de vida, factores de la gestación y el nacimiento, y
factores fetales y neonatales. Finalmente, incluímos en el análisis de regresión logístico
multivariado final todos los factores de riesgo que tuvieron un valor de p<0.2 en el
análisis de regresión logística univariado (18), y ajustamos por nivel SE basados en la
combinación de educación de la madre, educación del padre, ocupación de la madre,
ocupación del padre e ingreso parental (11). En este análisis de regresión logística
multivariado desarrollamos una selección por regresión gradual, aplicando eliminación
basado en el nivel estadístico de significación de p<0.05. Todos los análisis se hicieron
utilizando SPSS, versión 23 (SPSS Inc., Chicago, Illinois, USA).
Resultados
Características basales
Las tasas de prevalencia de los factores de riesgo potencial incluídos en nuestro estudio
se muestran en la Tabla 1. En nuestra población de PMTs, la mayoría fueron varones (n=
459; 56.7%), y un tercio nacieron con EG de 32-33 semanas (n= 259; 32.0%).
Factores de riesgo potencial con scores de problemas en CBCL
Las tasas de prevalencia de problemas CBCL en PMTs se muestran en la Tabla 2. En
general, 118 (14.6%) de los PMTs tuvieron problemas en el CBCL total, 135 (16.7%) PMTs
tuvieron problemas de externalización, y 137 (16.9%) PMTs tuvieron problemas de
internalización en el CBCL.
En el análisis multivariado, la infección perinatal aumentó el riesgo (OR 2.22 (IC 95% 1.38-
3.58)) de los problemas totales CBCL, mostrado en Tabla 3. La infección perinatal,
tabaquismo materno durante la gestación, y sexo masculino aumentaron
significativamente el riesgo (OR 2.46 (IC95% 1.55-3.93), 1.64 (1.07- 2.52), y 1.77 (1.19-
2.65), respectivamente) de los problemas de externalización CBCL. Finalmente, sólo ser
parte de un nacimiento múltiple disminuyó el riesgo (OR 0.63 (IC95% 0.40-0.98)) de
problemas de internalización en CBCL.
Discusión
Nuestro estudio demostró que en PMTs la infección perinatal aumentó el riesgo de
problemas totales, y particularmente de externalización en CBCL, al ingreso escolar. El
riesgo de problemas de externalización en CBCL fue también más elevado si la madre
fumó durante el embarazo, y para los varones. Ser parte de un parto múltiple disminuyó
el riesgo de problemas de internalización en CBCL. Encontramos en particular la
asociación de infecciones perinatales con más de doble riesgo para problemas de
conducta. En nuestro estudio, infección perinatal se refiere a infección bacteriana
sospechada de la madre y/o del niño basado en signos clínicos, o corioamnionitis
comprobada. En este sentido, Lee et al. (2015) (31) encontraron asociación de infección
bacteriana durante la gestación con trastornos del espectro autista en el recién nacido.
Sin embargo, los hallazgos de otros estudios contradijeron los nuestros en cuanto a la
asociación entre corioamnionitis y problemas emocionales y de conducta (32). Esta
discrepancia puede ser explicada por los signos clínicos de infección en la madre y/o el
niño que nosotros incluímos en la definición de nuestro factor de riesgo “infección
perinatal”. Las infecciones perinatales y neonatales diagnosticadas clínicamente durante
el parto son el resultado de respuestas inflamatorias sistémicas (citokinas, radicales
libres) (33) y hemodinámica alterada fetoplacentaria y neonatal. Nuestra hipótesis es que
estas respuestas sistémicas inflamatorias y hemodinámica llevan a injuria estructural del
cerebro (34), lo que a su vez puede ser responsable del funcionamiento conductual
deficitario en edades posteriores en PMTs. Esta hipótesis patogénica es apoyada por
nuestro hallazgo de que la ruptura prematura de membranas, que con frecuencia sucede
sin respuesta inflamatoria sistémica, no estuvo asociada con aumento del riesgo.
Encontramos que el tabaquismo materno durante la gestación aumentó el riesgo de
problemas conductuales en 1.5 veces en PMTs, similar a lo que ha sido reportado para
RNTs (35, 36), EPTs (15, 20, 37), y en el único estudio posterior disponible que investigó
este factor específicamente para PMTs, aunque focalizando en problemas escolares (7).
Una explicación posible es que el tabaquismo materno durante la gestación lleva a
menor activación de dopamina, reduciendo la respuesta de inhibición en el niño (38).
Otra explicación es que el tabaquismo materno está asociado con deterioro de la función
placentaria (39), aumentando el riesgo de hipoxia crónica fetal (40), causando a su vez
cambios estructurales del cerebro asociados tanto con problemas de internalización (41)
y externalización (42). Sin embargo, nuestros hallazgos contrastan con algunos hallazgos
en RNTs, para quienes no se ha encontrado esta asociación (14, 16). Esto puede ser
porque en niños RNT de madres fumadoras la placenta funcionó adecuadamente, al
revés que en los niños PT.
Además encontramos que el sexo masculino y el nacimiento múltiple estuvieron
asociados con problemas emocionales y conductuales, estos dos factores son no
modificables, en contraste con los dos factores discutidos más arriba. Para sexo
masculino encontramos casi el doble de riesgo de problemas conductuales, que está en
la misma línea que otros estudios en EPTs y RNTs (14, 16, 18), mientras que para PMTs
los hallazgos previos no fueron consistentes (7, 12). Este comportamiento género-
específico puede estar causado por concentraciones de andrógenos pre- y post-natales,
que son más elevadas en varones que en niñas (43). En nuestro estudio, el nacimiento
múltiple, en contraste con tener hermanos mayores, disminuyó el riesgo de problemas
de internalización. Este hallazgo es nuevo. La mayoría de otros estudios que incluyen
tener hermanos al nacer en sus análisis no focalizan específicamente en ser parte de
mellizos o trillizos. Huddy et al. (2001) (7) encontraron que la multiparidad, en contraste
con el nacimiento múltiple, estuvo asociada con riesgo aumentado de pobre desempeño
escolar. Una explicación podría ser que los múltiples tienen más posibilidades de
interactuar intensamente entre ellos que otros niños de diferentes edades en la familia,
como demuestran otros estudios reportando más comportamientos positivos durante el
juego en PT múltiples comparados con PT únicos (44). Una segunda explicación podría
ser que el paternaje para múltiples es más desafiante, como muestran estudios que
reportan mayores niveles de stress parental (44, 45) y menor interacción padre- hijo (46).
También debería tenerse en cuenta que el comportamiento del niño podría influenciar
indirectamente el comportamiento parental.
Remarcablemente, en nuestro estudio encontramos sólo cuatro de 23 factores de riesgo
con asociación significativa con problemas emocionales y conductuales. En cuanto a
problemas de conducta, otros factores esperables basados en la literatura previa incluyen
PEG (16) y ser el primer hijo (17). En cuanto a toda la gama de problemas de
internalización para PMTs, ninguno de los estudios previos enfocó en la relación con
factores perinatales. Entre, RNTs, sin embargo, varios factores se ha mostrado que
aumentan el riesgo de problemas de internalización: problemas emocionales maternos
y paternos, operación cesárea, ser varón (14), tabaquismo materno, y ascendencia no-
caucásica de la madre (17). Nuestro estudio basado en la comunidad en la población
holandesa incluyó un número sustancial de PMTs, permitiéndonos concluir que en los
PMTs sólo pocos factores están asociados con problemas emocionales y conductuales.
Dado el escaso número de factores asociados con estos problemas en EPTs, los PMTs
pueden tener una capacidad sustancial de mejora con respecto al desarrollo de
problemas emocionales y conductuales.
Nuestro estudio tiene varias fortalezas. Lo más importante, que es una cohorte amplia,
basada en la comunidad con una alta tasa de inclusión, y por lo tanto representativa de
la población promedio de PMTs en los Países Bajos, subraya su relevancia clínica.
Adicionalmente, pudimos analizar los efectos de un gran número de factores sociales y
perinatales y evaluar el rango completo de problemas emocionales y conductuales.
Nuestro estudio tiene también algunas limitaciones. Primero, dado que el CBCL es un
cuestionario para padres confiamos en las opiniones de uno de los padres acerca del
comportamiento de su niño. No encontramos asociación entre el llenado del
cuestionario por el padre y la ocurrencia de problemas emocionales y de conducta (datos
no mostrados). Pese a que una entrevista psiquiátrica podría haber sido más exacta, el
CBCL ha sido demostrado como muy válido en diversos países, incluyendo los Países
Bajos (26-28). Otra limitación fue que las familias de bajo nivel SE estuvieron poco
representadas en el análisis. Dado que el bajo nivel SE ha sido previamente asociado con
mayores problemas emocionales y de conducta (11) esto puede haber llevado a alguna
subestimación de las asociaciones reales. Más aún, incluímos varios factores maternos,
sin embargo los factores paternos incluidos en nuestro estudio fueron escasos. Dado que
ya hemos evaluado una amplia variedad de factores en nuestro estudio, y no hay más
factores disponibles en nuestra cohorte de estudio, no podemos presentar más
información de factores parentales. Más aún, los niños fueron incluídos sólo si los datos
sobre todos los factores de riesgo estaban disponibles. Esto puede haber llevado a cierto
sesgo de selección porque los padres de los niños que están menos enfermos
participarán con más frecuencia. Si ocurrió, esto puede haber debilitado las asociaciones
encontradas.
Nuestros hallazgos contribuyen a la creciente evidencia sobre factores de riesgo para
problemas emocionales y de conducta en PMTs. Este nuevo conocimiento permite a
PCHCs identificar mejor los PMTs con riesgo aumentado de problemas emocionales y de
conducta, e indicar destinatarios potenciales para intervención preventiva en este grupo
más grande de niños nacidos PT. Es mandatorio dar mayor atención para la prevención
y/o tratamiento de dos factores importantes de riesgo modificables, principalmente el
tabaquismo materno durante la gestación y las infecciones perinatales. Finalmente,
nuestros hallazgos requieren futuros estudios destinados a desentrañar los pasos
causales (biológicos) entre estos específicos factores perinatales y los problemas
emocionales y conductuales estratificados por EG.
Conclusión
La infección perinatal aumentó el riesgo de problemas emocionales y conductuales en
PMTs al ingreso escolar. En lo referente a los problemas conductuales, la infección
perinatal, tabaquismo materno durante el embarazo, así como el sexo masculino
aumentaron el riesgo. El nacimiento múltiple, en contraste, disminuyó los problemas
emocionales en PMTs. La prevención del tabaquismo materno durante el embarazo es
entonces de suma importancia. Concluímos que nacer PMTs con una infección clínica
perinatal, nacer de madres fumadores, o varón debería garantizar monitoreo más
cercano durante el seguimiento que en los PMTs en general.
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RESEARCH ARTICLE
Risk factors for emotional and behavioral
problems in moderately-late preterms
Pauline J. den HaanID1*, Marlou L. A. de Kroon2, Nienke H. van Dokkum1,2, Jorien
M. Kerstjens1, Sijmen A. ReijneveldID2, Arend F. Bos1
1 Department of Pediatrics, Division of Neonatology, Beatrix Children’s Hospital, University Medical Center
Groningen, University of Groningen, Groningen, The Netherlands, 2 Department of Health Sciences,
University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Abstract
Objective
To assess which factors, including maternal, lifestyle, pregnancy- and delivery-related, fetal
and neonatal factors adjusted for socio-economic status, are related to emotional and
behavioral problems in moderately-late preterm born children (MLPs; gestational age 32.0–
35.9 weeks) at 4 years of age. MLPs are at greater risk of emotional and behavioral prob-
lems than full-term born children. Especially for MLPs, knowledge about factors that
increase or decrease the risk of emotional and behavioral problems is scarce.
Design and setting
We assessed emotional and behavioral problems in 809 MLPs between ages 41 and 49
months from the prospective community-based Longitudinal Preterm Outcome Project
(LOLLIPOP), using the parent-reported Child Behavior Checklist (CBCL). We collected
potential risk factors from hospital records and parental questionnaires. Univariable and
multiple logistic regression analyses were applied.
Main outcome measures
(Sub)clinical CBCL scores.
Results
Perinatal infection increased the risk of CBCL total problem scores with an OR 2.22
(p<0.01). Perinatal infection, maternal smoking, and male gender increased the risk of
CBCL externalizing problem scores with ORs between 1.64 and 2.46 (all p<0.05). Multiple
birth decreased the risk of CBCL internalizing problem scores with an OR 0.63 (p<0.05).
Conclusions
Risk factors for behavioral problems in MLPs are male gender, perinatal infection and
maternal smoking, the latter two being potentially modifiable. Multiple birth is a protective
PLOS ONE | https://doi.org/10.1371/journal.pone.0216468 May 2, 2019 1 / 11
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OPEN ACCESS
Citation: den Haan PJ, de Kroon MLA, van
Dokkum NH, Kerstjens JM, Reijneveld SA, Bos AF
(2019) Risk factors for emotional and behavioral
problems in moderately-late preterms. PLoS ONE
14(5): e0216468. https://doi.org/10.1371/journal.
pone.0216468
Editor: Luca Cerniglia, International Telematic
University Uninettuno, ITALY
Received: February 16, 2019
Accepted: April 23, 2019
Published: May 2, 2019
Copyright: © 2019 den Haan et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: The participant
consent for the collection of data did not explicitly
or implicitly include details of sharing their
anonymized data. Due to the sensitivity of the data
and the restrictions from the informed consent, the
data will not be stored at a public repository. The
data and meta-data will be stored at a repository at
the UMCG, which ensures security of the data and
back-up. The UMCG pursues a FAIR data policy for
the research conducted in the UMCG. To make
the data findable for others, we will include a
description of the data in the data catalogue of the
factor for emotional problems in MLPs. These results suggest potential factors for targeting
preventive intervention in MLPs, comprising the large majority of all preterm born children.
Introduction
Moderately-late preterm born children (MLPs, gestational age (GA) 32.0–35.9 weeks, 85% of
all preterm born children [1]) are at a 1.5 to 2.5-fold increased risk of emotional and behavioral
problems compared to full-term born children (FTs, GA 38.0–41.9 weeks) [2–4]. Additionally,
MLPs born healthy at birth demonstrate more emotional and behavioral problems than FTs
treated at the neonatal intensive care unit (NICU) after birth [3]. These emotional and behav-
ioral problems frequently persist in later life [5]. They affect the child’s quality of life [6], and
may lead to grade retention [2], special educational needs [2,7], and numerous long-term
adversities such as employment difficulties [8,9], crime, and substance abuse in adulthood
[10].
For MLPs, there is only little evidence on factors that increase the risk of emotional and
behavioral problems. The few factors that have been identified are admission to a NICU [3],
low socioeconomic status (SES) [11], and female gender, all increasing the risk of emotional
problems at 1.5 years of age [12]. Poorer longitudinal postnatal growth was not found to be
associated with emotional and behavioral problems at seven years of age [13], and a British
study from 2001 [7] found several factors increasing the risk of school problems in MLPs, such
as male sex and postnatal discharge from the special baby care unit beyond 36 weeks post-
menstrual age. In contrast, studies among both early preterm born children (EPs, GA <32
weeks) and FTs report several factors to be associated with increased risk of emotional and
behavioral problems [14–19]. The factors as identified regard several domains: parental-emo-
tional (e.g. emotional maternal and couple problems [14], maternal smoking, and poor mater-
nal physical and mental well-being [15,20]), delivery-related (e.g. blood loss during pregnancy
[16], and caesarian section [14]), and neonatal (e.g. male gender [14,17,21], and (prolonged)
NICU admission [14,16,18]). Next risk factors and their effects may definitely be different for
the group of MLPs. For example, in a study based on our own cohort, SES was found to have a
stronger effect on the development of emotional and behavioral problems in children with a
lower GA [11].
Because of the large clinical and public health consequences of emotional and behavioral
problems, more insight into risk factors that are associated with these problems in this largest
group of preterm born children may expedite the identification of MLPs at risk. Since early
intervention on emotional and behavioral problems has proven to be effective for both FTs
and preterm born children in general [22,23], new knowledge on potentially modifiable risk
factors and on identification of MLPs at increased risk may be used for targeted preventive
interventions. Therefore, we aimed to investigate which factors, including maternal, lifestyle,
pregnancy- and delivery-related, fetal and neonatal factors increase or decrease the risk of
total, externalizing, and internalizing emotional and behavioral problems in MLPs at school
entry (i.e. 4 years).
Methods
Study design and sampling procedure
This study is part of the Longitudinal Preterm Outcome Project (LOLLIPOP) [24]. In total,
thirteen Dutch Preventive Child Healthcare Centers (PCHCs) examined charts of 45,446
Moderately-late preterms at risk of emotional and behavioral problems
PLOS ONE | https://doi.org/10.1371/journal.pone.0216468 May 2, 2019 2 / 11
UMCG that is currently under development. Via the
catalogue the meta-data of the data will be made
available for researchers inside and outside the
institute. This catalogue is in sync with relevant
(inter)national catalogues. The LOLLIPOP-study
data access committee, consisting of the principal
investigators of the project, will review requests, to
assure accessibility of the data. This access
committee can be reached via [email protected],
manager of the data repository of Health Sciences
and secretary of the access committee.
Funding: The LOLLIPOP study has been supported
by grants from the research foundation of the
Beatrix Children’s Hospital, the Cornelia Foundation
for the Handicapped Child, the A. Bulk-Child
Preventive Child Health Care research fund, the
Dutch Brain Foundation, and unrestricted
investigator initiated research grants from
FrieslandCampina, Friso Infant Nutrition, and Pfizer
Europe. The funders had no role at any stage of the
project including the decision to submit the
manuscript.
Competing interests: Unrestricted investigator
initiated research grants from the following
companies: FrieslandCampina, Friso Infant
Nutrition, and Pfizer Europe. There are no patents,
products in development or marketed products to
declare. The sources of funding do not alter our
adherence to PLOS ONE policies on sharing data
and materials.
children (25% of a Dutch year cohort) aged 43 to 49 months, who were born in 2002 and 2003
in the three northern provinces of the Netherlands. Of those 45,446 children, 1,412 were born
moderately-late preterm. Parents of 1,145 children gave written informed consent, leading to
an inclusion rate of 81%. Exclusion criteria were congenital malformations or syndromes, con-
genital infections, and a GA that could not be verified or was outside the set range. Non-partic-
ipating children more often had parents with low SES and/or non-Dutch ethnicity (both
P<0.001), and were part of a multiple pregnancy less often (P<0.05) [25]. For this study, to
obtain as homogeneous as possible a study sample we sampled only MLPs that joined the fol-
low-up at school entry, had the Child Behavior Checklist (CBCL) administered between 41
and 49 months of age, and for which information on all risk factors was available (N = 809, i.e.
71% of parents willing to participate). The LOLLIPOP-study was approved by the University
Medical Center Groningen review board (ISRCTN register trial number 80622320) and writ-
ten informed consent was obtained from all parents. A complete flowchart of our sampling
procedure has been previously reported [24].
Data and data collection
A month prior to the last scheduled PCHC visit at age 43–49 months parents received an invi-
tation to let their child participate in the study. Included in the invitation were information
about the LOLLIPOP-study, an informed consent form, an emotional and behavioral problem
questionnaire (CBCL), and a general questionnaire on familial and perinatal characteristics, all
of which parents returned during their visit.
We assessed emotional and behavioral problems at age 4, using the CBCL suitable for ages
1.5–5 years. The CBCL is a parental questionnaire containing 99 problem items with ratings
between not true and often/very true. It was filled out by the mother in approximately 81% of
MLPs included in this study. These questions were all included in the total problems scale, and
two broadband scales, internalizing (i.e. ‘emotional’) and externalizing (i.e. ‘behavioral’) prob-
lems, were computed [26]. CBCL data were dichotomized conform the manual, with cut-off
scores set at�83% (normal), and�84% ((sub)clinical). The CBCL has good psychometric
properties and a validated Dutch version [26–28].
Based on the literature, we assessed which factors we would analyze as potential risk factors
for emotional and behavioral problems in MLPs: (1) known risk factors for emotional and
behavioral problems in FTs, EPs [14–16,18,19,21], and MLPs [3,11,12], and (2) known risk fac-
tors for general developmental problems in MLPs (Table 1) [7,29,30]. Data on these maternal
and lifestyle factors, pregnancy- and delivery-related factors, and fetal and neonatal factors
were collected from a general questionnaire, birth registers, and medical records of both
mother and child. This made it possible to cross-check information from different sources.
GA was confirmed by early ultrasound measurements in >95% of cases. In other cases, GA
was cross-checked against clinical estimates after birth. Data were coded following standard
practices.
Statistical analyses
First, using Chi-Square Tests we assessed background characteristics of the sample in relation
to the presence of dichotomized CBCL total problems. Second, using univariable logistic regres-
sion analyses we assessed the risks of increased CBCL total, internalizing, and externalizing
problems for various maternal and lifestyle factors, pregnancy- and delivery-related factors, and
fetal and neonatal factors. Finally, we included in the final multivariable logistic regression anal-
ysis all risk factors that had a p-value<0.2 in the univariable logistic regression analyses [18],
and adjusted for SES based on the combination of education of the mother, education of the
Moderately-late preterms at risk of emotional and behavioral problems
PLOS ONE | https://doi.org/10.1371/journal.pone.0216468 May 2, 2019 3 / 11
father, occupation of the mother, occupation of the father and parental income [11]. In this
multivariable logistic regression analysis we performed a backward stepwise selection, applying
backward elimination based on a statistical significance level of p<0.05. All analyses were per-
formed using SPSS, version 23 (SPSS Inc., Chicago, Illinois, USA).
Results
Background characteristics
Prevalence rates of the potential risk factors included in our study are shown in Table 1. In our
sample of MLPs, more children were male (n = 459; 56.7%), and one third were born with a
GA of 32–33 weeks (n = 259, 32.0%).
Table 1. Potential risk factors among MLP for emotional and behavioral problems within the LOLLIPOP cohort.
Potential risk factors Prevalence Definition of the variable
n/Ntotal %
Maternal and lifestyle
Non-Dutch ethnicity 42/809 (5.2) Mother not born within the Netherlands
Multiparity 284/809 (35.1) Mother who has gone through�1 pregnancies
Pre-pregnancy obesity 88/767 (11.5) BMI > 30kg/m2
Smoking during pregnancy 185/807 (22.9) Any smoking during pregnancy
Maternal mental illness 13/809 (1.6) Chronic mental illness (depression, psychosis, other)
Pregnancy- and delivery-related
HELLP/pre-eclampsia 157/809 (19.4) (Severe type of) pre-eclampsia due to placenta malfunction
Antenatal steroids 156/809 (19.3) Completed treatment with antenatal steroids
Induced birth; fetal reasons 121/809 (15.0) Fetal/combined fetal + maternal indication of induced delivery
pPROM 187/809 (23.1) Prolonged premature rupture of membranes (>24 hours before delivery)
C-section 293/809 (36.2) Primary or secondary caesarian section
Perinatal infection 119/809 (14.7) Clinical signs of bacterial infection, of mother and/or child, or proven chorioamnionitis
Fetal and neonatal
Gender 459/809 (56.7) Male sex
Multiple birth 233/809 (28.8) Being part of a multiple birth (twin, triplet)
SGA 72/809 (8.9) Small for gestational age below P10 according to Dutch growth charts
Lower GA 259/809 (32.0) Gestational age 32–33 weeks (opposed to GA 34–35 weeks)
Asphyxia 17/807 (2.1) Asphyxia in conclusion in discharge letter
Circulatory insufficiency 24/807 (3.0) �1 time inotropic medication administration
Respiratory insufficiency 144/807 (17.8) CPAP and/or assisted ventilation in delivery room for longer than initial stabilization
Caffeine treatment 89/802 (11.1) Caffeine treatment for apnea
Hyperbilirubinemia 351/805 (43.6) Peak bilirubin value: and/or phototherapy. GA 32-33wk: >255 μmol/L, GA 34-35wk: >340 μmol/L
Hypoglycemia 65/798 (8.1) In first 72 hours at least one recorded plasma glucose value < 1.7 mmol/L (30 mg/dL)
Septicemia 30/806 (3.7) Clinical symptoms and�1 positive blood culture test
Highest P10 length of hospital stay 75/799 (9.4) In upper 10% of duration of hospital admission compared to peers of the same GA week
Sociodemographic
SES Socio-economic status
Low 212/808 (26.2) �1SD below mean
Intermediate 408/808 (50.5) mean +/- 1SD
High 188/808 (23.3) �1SD above mean
Abbreviations: BMI: Body Mass Index; HELLP: Hemolysis Elevated Liver Enzymes, and Low Platelet Count; CPAP: continuous positive airway pressure; SES: Socio-
economic status; based on five measurements including education of the mother, education of the father, parental income, occupation of the mother and occupation of
the father.
https://doi.org/10.1371/journal.pone.0216468.t001
Moderately-late preterms at risk of emotional and behavioral problems
PLOS ONE | https://doi.org/10.1371/journal.pone.0216468 May 2, 2019 4 / 11
Potential risk factors with increased CBCL problem scores
Prevalence rates of CBCL problems in MLPs are shown in Table 2. Overall, 118 (14.6%) of the
MLPs had CBCL total problems, 135 (16.7%) MLPs had CBCL externalizing problems, and
137 (16.9%) MLPs had CBCL internalizing problems.
In the multivariable analyses, perinatal infection increased the risk (OR 2.22 (95% CI 1.38–
3.58)) of CBCL total problems, shown in Table 3. Perinatal infection, maternal smoking during
pregnancy, and male gender significantly increased the risk (OR 2.46 (95% CI 1.55–3.93), 1.64
(1.07–2.52), and 1.77 (1.19–2.65), respectively of CBCL externalizing problems. Lastly, only
Table 2. Risk of increased CBCL total, externalizing, and internalizing problem scores for potential risk factors at age 4: Results of univariable logistic regression
analyses.
Potential risk factors N Total problems Externalizing problems Internalizing problems
Prevalence P-value§ Prevalence P-value§ Prevalence P-value§
n % n % n %
Total: 809 118 14.6 135 16.7 137 16.9
Maternal and lifestyle
Non-Dutch ethnicity 42 8 (19.0) 0.40 8 (19.0) 0.67 9 (21.4) 0.43
Multiparity 284 47 (16.5) 0.25 55 (19.4) 0.13# 51 (18.0) 0.57
Pre-pregnancy obesity 88 12 (13.6) 0.84 15 (17.0) 0.81 16 (18.2) 0.74
Smoking during pregnancy 185 35 (18.9) 0.053# 43 (23.2) 0.006�� 38 (20.5) 0.12#
Maternal mental illness 13 3 (23.1) 0.39 5 (38.5) 0.04� 3 (23.1) 0.55
Pregnancy- and delivery-related
HELLP /pre-eclampsia 157 24 (15.3) 0.78 30 (19.1) 0.37 28 (17.8) 0.74
Antenatal steroids 156 28 (17.9) 0.19# 31 (19.9) 0.24 30 (19.2) 0.40
Induced birth; fetal reasons 121 20 (16.5) 0.51 22 (18.2) 0.63 23 (19.0) 0.51
pPROM 187 29 (15.5) 0.68 31 (16.6) 0.96 39 (20.9) 0.10#
C-section 293 38 (13.0) 0.33 49 (16.7) 0.98 44 (15.0) 0.27
Perinatal infection 119 29 (24.4) 0.001�� 33 (27.7) 0.001�� 26 (21.8) 0.12#
Fetal and neonatal
Gender 459 73 (15.9) 0.23 91 (19.8) 0.007�� 73 (15.9) 0.37
Multiple birth 233 30 (12.9) 0.38 29 (12.4) 0.04� 31 (13.3) 0.08#
SGA 72 15 (20.8) 0.12# 16 (22.2) 0.19# 15 (20.8) 0.36
Lower GA 259 38 (14.7) 0.96 49 (18.9) 0.24 39 (15.1) 0.33
Asphyxia 17 3 (17.6) 0.72 3 (17.6) 0.92 5 (29.4) 0.18#
Circulatory insufficiency 24 4 (16.7) 0.77 5 (20.8) 0.59 3 (12.5) 0.56
Respiratory insufficiency 144 23 (16.0) 0.61 25 (17.4) 0.82 22 (15.3) 0.55
Caffeine treatment 89 9 (10.1) 0.197# 13 (14.6) 0.55 10 (11.2) 0.12#
Hyperbilirubinemia 351 55 (15.7) 0.42 63 (17.9) 0.38 55 (15.7) 0.37
Hypoglycemia 65 9 (13.8) 0.85 16 (24.6) 0.08# 11 (16.9) 0.98
Septicemia 30 7 (23.3) 1.18 6 (20.0) 0.63 5 (16.7) 0.96
Highest P10 length of hospital stay 75 10 (13.3) 0.74 9 (12.0) 0.26 12 (16.0) 0.83
# P<0.2,
� P< 0.05,
�� P<0.01.§ Odds ratios (OR) and 95% confidence intervals (CI) are given in Table 3.
Abbreviations: HELLP: Hemolysis Elevated Liver Enzymes, and Low Platelet Count; C-section: caesarian section; pPROM: prolonged premature rupture of membranes;
SGA: Small for Gestational Age; Lower GA: lower gestational age.
https://doi.org/10.1371/journal.pone.0216468.t002
Moderately-late preterms at risk of emotional and behavioral problems
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being part of a multiple birth significantly decreased the risk (OR 0.63 (95% CI 0.40–0.98)) of
CBCL internalizing problems.
Discussion
Our study demonstrated that in MLPs perinatal infection increased the risk of CBCL total
problems, and particularly the risk of CBCL externalizing problems, at school entry. The
risk of CBCL externalizing problems was also higher when the mother smoked during preg-
nancy, and for males. Being part of a multiple birth decreased the risk of CBCL internalizing
problems.
Table 3. Odds ratios (OR) and 95% confidence intervals (CI) of the risk of increased CBCL total, externalizing, and internalizing problem scores for potential risk
factors at age 4, adjusted for socio-economic status (SES) in multivariable analyses.
Potential risk factors Total problems Externalizing problems Internalizing problems
Univariable§ Multivariable¥ Univariable§ Multivariable¥ Univariable§ Multivariable¥
OR 95% CI OR 95% CI OR 95% CI OR 95% CI OR 95% CI OR 95% CI
Maternal and lifestyle
Non-Dutch ethnicity 1.41 (0.63–3.12) 1.19 (0.54–2.62) 1.36 (0.64–2.91)
Multiparity 1.27 (0.85–1.89) 1.34 (0.92–1.95)# - - - 1.12 (0.76–1.64)
Pre-pregnancy obesity 0.94 (0.49–1.79) 1.08 (0.59–1.94) 1.10 (0.62–1.96)
Smoking during pregnancy 1.54 (0.99–2.37)# - - - 1.77 (1.18–2.66)�� 1.64 (1.07–2.52)� 1.40 (0.92–2.12)# - - -
Maternal mental illness 1.78 (0.48–6.55) 3.20 (1.03–9.94)� - - - 1.48 (0.40–5.46)
Pregnancy- and delivery-related
HELLP/pre-eclampsia 1.07 (0.66–1.74) 1.23 (0.79–1.93) 1.08 (0.68–1.71)
Antenatal steroids 1.37 (0.86–2.18)# - - - 1.31 (0.84–2.04) 1.22 (0.78–1.90)
Induced birth; fetal reasons 1.19 (0.71–2.02) 1.13 (0.68–1.87) 1.18 (0.72–1.94)
pPROM 1.01 (0.70–1.73) 0.99 (0.64–1.54) 1.41 (0.93–2.13)# - - -
C-section 0.81 (0.54–1.23) 1.00 (0.68–1.48) 0.80 (0.54–1.19)
Perinatal infection 2.18 (1.35–3.50)�� 2.22 (1.38–3.58)�� 2.21 (1.41–3.48)�� 2.46 (1.55–3.93)�� 1.46 (0.90–2.36)# - - -
Fetal and neonatal
Gender 1.28 (0.86–1.91) 1.72 (1.16–2.54)�� 1.77 (1.19–2.65)�� 0.85 (0.58–1.22)
Multiple birth 0.82 (0.53–1.28) 0.63 (0.41–0.98)� - - - 0.68 (0.44–1.05)# 0.63 (0.40–0.98)�
SGA 1.62 (0.88–2.97)# - - - 1.48 (0.82–2.68)# - - - 1.33 (0.73–2.42)
Lower GA 1.01 (0.67–1.53) 1.26 (0.86–1.85) 0.82 (0.55–1.23)
Asphyxia 1.26 (0.36–4.45) 1.07 (0.30–3.77) 2.08 (0.72–5.99)# - - -
Circulatory insufficiency 1.17 (0.39–3.50) 1.32 (0.49–3.60) 0.69 (0.20–2.35)
Respiratory insufficiency 1.14 (0.69–1.87) 1.06 (0.66–1.70) 0.86 (0.52–1.41)
Caffeine treatment 0.62 (0.30–1.28)# - - - 0.83 (0.45–1.54) 0.58 (0.29–1.16)# - - -
Hyperbilirubinemia 1.18 (0.79–1.74) 1.18 (0.81–1.71) 0.84 (0.58–1.23)
Hypoglycemia 0.93 (0.45–1.94) 1.70 (0.94–3.09)# - - - 0.99 (0.50–1.95)
Septicemia 1.82 (0.76–4.35) 1.25 (0.50–3.13) 0.98 (0.37–2.60)
Highest P10 length of hospital stay 0.89 (0.44–1.78) 0.66 (0.32–1.36) 0.93 (0.49–1.78)
# P<0.2;
� P< 0.05;
�� P<0.01;
- - -signifies: ‘did not remain in the model with p<0.05 after backward selection’.§ Only one potential risk factor included in the model.¥ All variables with P<0.2 in univariable analyses were included in the multivariable model, adjusted for socio-economic status.
Abbreviations: HELLP: Hemolysis Elevated Liver Enzymes, and Low Platelet Count; C-section: caesarian section; pPROM: prolonged premature rupture of membranes;
SGA: Small for Gestational Age; Lower GA: lower gestational age.
https://doi.org/10.1371/journal.pone.0216468.t003
Moderately-late preterms at risk of emotional and behavioral problems
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We found perinatal infections in particular to be associated with a more than twofold
increased risk of behavioral problems. In our study, perinatal infection refers to a suspected
bacterial infection of the mother and/or child based on clinical signs, or proven chorioamnio-
nitis. Likewise, Lee et al. (2015) [31] found bacterial infection during pregnancy to be associ-
ated with autism spectrum disorders in the newborn child. However, the findings of other
studies contradicted ours regarding the association between chorioamnionitis and emotional
and behavioral problems [32]. This discrepancy may be explained by the clinical signs of infec-
tion in the mother and/or child which we included in the definition of our risk factor ‘perinatal
infection’. Clinically diagnosed perinatal and neonatal infections during delivery are the result
of systemic inflammatory responses (cytokines, free radicals) [33] and altered feto-placental
and neonatal hemodynamics. We hypothesize that these systemic inflammatory and hemody-
namic responses lead to structural brain injury [34], which may in turn be responsible for
impaired behavioral functioning at later ages in MLPs. This hypothesized pathogenetic path-
way is supported by our finding that prolonged premature rupture of the membranes, which
often goes without a systemic inflammatory response, was not associated with increased risk.
We found that maternal smoking during pregnancy increased the risk of behavioral prob-
lems 1.5-fold in MLPs, similar to what has been reported for FTs [35,36], EPs [15,20,37], and
in the only further available study that investigated this factor specifically for MLPs, though
focusing on school problems [7]. A possible explanation is that maternal smoking during preg-
nancy leads to lower dopamine signaling, reducing response inhibition in the child [38].
Another explanation is that maternal smoking is associated with deterioration of placental
function [39], increasing the risk of chronic fetal hypoxia [40], in turn causing structural brain
changes associated with both internalizing [41] and externalizing [42] problems. However, our
findings contrast with some findings on FTs, for whom this association has not been found
[14,16]. This may be because in FT children of smoking mothers the placenta still functioned
adequately, unlike in preterm born children.
We further found male gender and multiple birth to be associated with emotional and
behavioral problems, both of these factors are non-modifiable, in contrast to the two factors
discussed previously. For male gender we found a nearly twofold increased risk of behavioral
problems, which is in line with other studies in both EPs and FTs [14,16,18], whereas for
MLPs previous findings were not consistent [7,12]. This gender-specific behavior may be
caused by concentrations of pre- and postnatal androgen, which are higher in males than
females [43]. In our study, multiple birth, in contrast to having older siblings, decreased the
risk of internalizing problems. This is a new finding. Most other studies that include having
siblings at birth in their analyses do not specifically focus on being part of a twin or triplet.
Huddy et al (2001) [7] have found multiparity, in contrast to multiple birth, to be associated
with an increased risk of poor school performance. One explanation could be that multiples
are more likely to interact intensively with each other than other children of different ages in
the family, as illustrated by studies reporting more positive behaviors during play in preterm
multiples compared with preterm singletons [44]. A second explanation could be that parent-
ing for multiples is more challenging, as illustrated by studies reporting higher levels of parent-
ing stress [44,45] and decreased parent-infant interactions [46]. It should also be kept in mind
that child behavior might indirectly influence parenting behavior in accordance.
Remarkably, in our study we found only four of the 23 risk factors studied to have a signifi-
cant association with emotional and behavioral problems. Regarding behavioral problems,
other expected factors based on previous literature include SGA [16] and being the first-born
child [17]. Regarding the full range of internalizing problems for MLPs, none of the previous
studies focused on the relationship with perinatal factors. Among FTs, however, several factors
have been shown to augment the risk of internalizing problems: maternal and paternal
Moderately-late preterms at risk of emotional and behavioral problems
PLOS ONE | https://doi.org/10.1371/journal.pone.0216468 May 2, 2019 7 / 11
emotional problems, caesarian section, being male [14], maternal smoking, and non-Cauca-
sian background of the mother [17]. Our community-based study in the Dutch population
included a substantial number of MLPs, allowing us to conclude that for MLPs only few factors
are associated with emotional and behavioral problems. Given the low number of factors asso-
ciated with these problems for EPs, MLPs may have a substantial capacity for improvement
with respect to the development of emotional and behavioral problems.
Our study has several strengths. Most importantly, that it is a large, community-based
cohort of MLPs with a high inclusion rate, and therefore representative of the average popula-
tion of MLPs in the Netherlands, underlines its clinical relevance. Additionally, we were able
to analyze the effects of a large number of perinatal and social factors and assess the full range
of emotional and behavioral problems.
Our study also had some limitations. First, as the CBCL is a parent-report questionnaire we
relied on one of both parents’ opinions about their child’s behavior. We did not find an associ-
ation between the parent completing the questionnaire and the occurrence of emotional and
behavioral problems (data not shown). Although a psychiatric interview might have been
more accurate, the CBCL has been shown to be highly valid in various countries, including the
Netherlands [26–28]. Another limitation was that families of low SES were underrepresented
in the analyses. As low SES has previously been associated with greater emotional and behav-
ioral problems [11] this may have led to some underestimation of the actual associations. Fur-
thermore, we included several maternal factors, however paternal factors included in our
study are scarce. Since we have already evaluated a broad variety of factors in our study, and
more factors are not available within our cohort study, we are unable to present more informa-
tion on parental factors. Moreover, children were only included if data on all risk factors were
available. This might have led to some selection bias because parents of children that are less ill
will participate more often. If occurring, this may have weakened the associations as found.
Our findings contribute to the growing evidence on risk factors for emotional and behav-
ioral problems in MLPs. This new knowledge enables PCHCs to better identify MLPs at
increased risk of emotional and behavioral problems, and indicate potential targets for preven-
tive intervention in this largest group of preterm born children. More attention is warranted
for the prevention and/or treatment of two important modifiable risk factors, namely maternal
smoking during pregnancy and perinatal infections. Finally, our findings warrant future stud-
ies aimed at unravelling the causal (biological) pathways between these specific perinatal fac-
tors and emotional and behavioral problems stratified for GA.
Conclusion
Perinatal infection increased the risk of emotional and behavioral problems in MLPs at school
entry. Concerning behavioral problems, perinatal infection, maternal smoking during preg-
nancy, as well as male gender increased the risk. Multiple birth, in contrast, decreased the risk
of emotional problems in MLPs. Prevention of maternal smoking during pregnancy is thus of
utmost importance. We conclude that MLPs born with a clinical perinatal infection, born
from a smoking mothers, or born male should have closer monitoring during follow-up than
MLPs in general.
Acknowledgments
This study is part of the LOLLIPOP study (controlled-trials.com, identifier: ISRCTN
80622320), a large cohort study on the development, growth, and health of preterm born chil-
dren. We would therefore like to thank all participating PCHC physicians for their contribu-
tion to the field work, with special gratitude to PCHC physicians E.M.J. ten Vergert, B. van der
Moderately-late preterms at risk of emotional and behavioral problems
PLOS ONE | https://doi.org/10.1371/journal.pone.0216468 May 2, 2019 8 / 11
Hulst, and M. Broer van Dijk. In addition, we acknowledge the help of J. van Seventer for
reviewing this manuscript for its use of the English language.
Author Contributions
Conceptualization: Jorien M. Kerstjens, Sijmen A. Reijneveld, Arend F. Bos.
Data curation: Sijmen A. Reijneveld, Arend F. Bos.
Formal analysis: Pauline J. den Haan, Marlou L. A. de Kroon, Nienke H. van Dokkum, Jorien
M. Kerstjens.
Funding acquisition: Sijmen A. Reijneveld, Arend F. Bos.
Investigation: Pauline J. den Haan, Jorien M. Kerstjens, Arend F. Bos.
Methodology: Pauline J. den Haan, Marlou L. A. de Kroon, Jorien M. Kerstjens.
Project administration: Marlou L. A. de Kroon, Nienke H. van Dokkum, Jorien M. Kerstjens,
Sijmen A. Reijneveld, Arend F. Bos.
Resources: Jorien M. Kerstjens, Sijmen A. Reijneveld, Arend F. Bos.
Supervision: Marlou L. A. de Kroon, Jorien M. Kerstjens, Sijmen A. Reijneveld, Arend F. Bos.
Validation: Marlou L. A. de Kroon, Jorien M. Kerstjens.
Visualization: Pauline J. den Haan.
Writing – original draft: Pauline J. den Haan.
Writing – review & editing: Marlou L. A. de Kroon, Nienke H. van Dokkum, Jorien M. Ker-
stjens, Sijmen A. Reijneveld, Arend F. Bos.
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Moderately-late preterms at risk of emotional and behavioral problems
PLOS ONE | https://doi.org/10.1371/journal.pone.0216468 May 2, 2019 11 / 11
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