Neuroimaging assessment of Cortical Development and Corpus Callosum as predictive markers of neurodevelopmental outcome in small for gestational age fetuses

Abstract

1. INTRODUCTION

Intrauterine growth restriction (IUGR) is diagnosed at the presence of an estimated fetal weight below the 10th centile and is a frequent condition in perinatal medicine, reaching a prevalence of 5-8% in live newborn babies being a major contributor of perinatal and long term morbidity, such as neurological deficits. We hypothesized that these neurological impairement are related to brain microstructural changes which might be characterized by fetal neuroimaging, either MRI or ultrasonography. Identifying fetuses at risk for abnormal neurodevelopment in fetal medicine lays the basis to perform specific strategies to potentially improve both pre and postnatal management, such as timely delivery, careful support for breastfeeding and a thoughtful use of this window of opportunity to improve their neurocognitive outcome through specific strategies. So the objective of this thesis was to identify brain imaging biomarkers that could predict an adverse neurological outcome in small for gestational age fetuses.

2. METHODS This is a prospective cohort study which included 2 study groups: AGA (adequeate for gestational age fetuses) with an estimated fetal weight >10th centile and, SGA (small for gestational age fetuses) with an estimated fetal weight <10th centile. A fetal ultrasound was performed to establish clinical group membership and Doppler evaluation. Then, either a MRI at 37 weeks was performed or a neurosonography during the 3rd trimester in order to assess cortical development, insular and corpus callosum morphometry. Once these babies were born, they underwent a neurobehavioral assessment during the neonatal period (NBAS) and a neurodevelopmental test at 2 years (Bayley-III).

The analysis was focused on the evaluation of differences among study groups. As secondary analysis, linear regression was used to evaluate the relationship between brain development and postnatal neurological outcome adjusting by potentially confounders. Statistical anlyses were performed using the SPSS for Windows version 17.0 statistical software.

3. RESULTS

The thesis led to five articles which are published in international journals.

Maternal characteristics did not differ between the study groups.

We found that late-onset IUGR fetuses showed a different pattern of brain development assessed by fetal MRI, expressed by deeper fissures, smaller brain volumes and a more pronounced right asymmetry. They also presented thinner cortex with lower fractional anisotropy values wich was significantly associated to worse NBAS test.

Small fetuses presented smaller corpus callosum assessed by MRI and US, particularly in its posterior portion which was associated to worse neurobehavioral outcome.

When we explored the correlation between brain structure and neurodevelopment at 2 years, we found that smaller measurements were associated to worse Bayley-III scores. 7. DISCUSSION

Although previous studies have shown poorer neurodevelopmental outcome in term, none of them have provided information about their brain developmental status before birth. Our findings support a microstructural/functional association. Interestingly, we found that small-born babies had lower cognitive, motor and language competencies. All of these functions are closely related to the insula and callosal functionality. Indeed, Geva et al. proposed that thinner cortex found in severe IUGR born children could be responsible for their lower IQ scores.

The importance of this study relais in the high prevalence of late-onset IUGR, therefore they represent a significant public health problem and its impact on the adverse neurodevelopment outcome of this population cannot be overestimated. Therefore findings applicable imaging biomarkers in fetal medicine can identify those fetuses at risk in this and other clinical scenarios. Finally, our study suggests that brain alterations at term could constitute the first step in the cascade of functional impairments underlying neurodevelopmental pathologies.

“EVALUACIÓN DEL DESARROLLO CORTICAL Y CUERPO CALLOSO COMO MARCADORES PREDICTIVOS DE NEURODESARROLLO EN FETOS PEQUEÑOS PARA LA EDAD GESTACIONAL “

INTRODUCCION: la restricción del crecimiento intrauterino (RCIU) afecta alrededor del 8% de los recién nacidos vivos y se asocia a morbilidad a corto y a largo plazo, dentro de los cuales se encuentran los déficits neurológicos. Nuestra hipótesis es que dichos déficits se asocian a una reprogramación cerebral durante la vida intrauterina gatillada por la RCIU. Por lo que el objetivo de esta tesis fue detectar biomarcadores cerebrales que puedan predecir un resultado neurológico adverso en los fetos con RCIU.

MÉTODOS: incluimos dos grupos de estudio: AGA (fetos adecuados para la edad gestacional) y SGA (fetos pequeños para la edad gestacional definidos por un percentil de crecimiento <p10). Se realizó una ecografía Doppler para establecer el grupo clínico y una MRI a las 37 semanas o una neurosonografía en el 3er trimestre para evaluar el desarrollo cortical y el cuerpo calloso. En el período neonatal, se evaluó en neurocomportamiento con el test de Brazelton y a los 2 años, el neurodesarrollo con el Bayley-III test. Se realizó un primer análisis para evaluar las diferencias entre AGA y SGA y un segundo análisis para evaluar la capacidad predictiva del desarrollo cerebral antenatal de un pobre resultado neurológico.

RESULTADOS: Los fetos con RCIU presentaron fisuras más profundas, volúmenes cerebrales más pequeños, una asimetría derecha más pronunciada, cortezas más delgadas y cuerpos callosos más pequeños. Medidas más pequeñas se asociaron significativamente a un peor resultado en el neurocomportamiento y en el neurodesarrollo a los 2 años.

DISCUSIÓN: Por primera vez se relaciona la microestructura cerebral en fetos SGA a término con el desarrollo neurológico. Los déficits neurológicos presentados se encuentran estrechamente relacionados a la funcionalidad de la corteza insular y el cuerpo calloso. La importancia de este estudio se basa en la alta prevalencia de RCIU a término, por lo tanto representan un importante problema de salud pública y su impacto en el resultado neurológico adverso de esta población no se debe subestimar. Además, al identificar los fetos en riesgo a través de biomarcadores de fácil aplicación, se pueden aplicar estrategias para mejorar los resultados neurológicos.