Systematic Hospital-based Assessment of Rotterdam*s critically Ill children,
their Neurodevelopment and Growth

Over the last decade, the number of children admitted to neonatal intensive
care units has increased significantly worldwide.1,2 Due to medical
improvements, the majority of these children now survive to discharge1,2,
necessitating our focus to broaden from prevention of mortality to long-term
outcome. Knowledge has emerged that even the so-called *good survivors* are at
risk of neuropsychological impairments and school problems, despite having
generally average intelligence.3
Strikingly, the incidence of academic difficulties has been found to be
high across common causes of neonatal critical illness such as preterm birth,
complex congenital cardiac and non-cardiac anomalies and severe respiratory
failure in need of treatment with extracorporeal membrane oxygenation
(ECMO).4-9 As intelligence is generally normal, the school problems are likely
related to specific neuropsychological deficit rather than general intellectual
functioning. Indeed, memory deficits in particular are frequently reported
following neonatal critical illness.7,8,10-16
The hippocampus, a grey matter structure within the brain*s limbic
system, is the critical hub for memory formation and has been found to be
particularly vulnerable to conditions associated with critical illness.17-19
Recently, we have described a common neurodevelopmental pathway across
critically ill neonates, where early hippocampal alterations result in
long-term memory deficits, irrespective of the underlying diagnosis or
gestational age.3 However, the exact pathophysiological mechanisms of these
long-term neurodevelopmental deficits following neonatal critical illness
remain unknown. This is problematic as patients at risk of long-term deficits
are generally not identified until the problems have affected school
functioning and daily life activities. Furthermore, targeted and early
intervention or even prevention is impossible without proper knowledge of what
causes these long-term deficits.

The main objective of this longitudinal study is to gain insight into the
neurodevelopmental trajectories following neonatal critical illness, from the
perinatal period to school-age compared to healthy controls. This insight may
lead to the identification of early biomarkers of long-term memory deficits in
survivors of neonatal critical illness that will improve early identification
and treatment of survivors at risk of school problems later in life.

This study is a single-center prospective, longitudinal study conducted at the
department of IC and Pediatric Surgery, the department of Pediatrics
(subdivisions Neonatology and Pediatric Cardiology), the department of
Radiology, the Department of Obstetrics and Gynecology, the department of
Anesthesiology, and the department of Child- and Adolescent
Psychiatry/Psychology at the Erasmus MC - Sophia Children*s Hospital. The study
will be conducted over a period of 9 years as children will be asked to return
for follow-up visits at five years of age and eight years of age.
To compare the neurodevelopmental trajectory and outcome following neonatal
critical illness to typical neurodevelopment, we will use the Generation R NEXT
cohort as a reference sample. In this pediatric population study children will
undergo neuroimaging during the neonatal period and again around 9 years of
age.32 We will use the Generation R MRI scanner and will synchronize our scan
protocol with the protocol used in the Generation R NEXT study (MEC-2016-589)
to optimize comparison.

We regard the risk for participants in this prospective research project to be
negligible. An MRI exam is non-invasive and can be reliably performed in
infants without sedation.11,20 For the MRI exam at eight years of age, we will
use a mock-scanner before the actual MRI to familiarize children with the
MR-environment.21 Our extensive experience with non-clinical MRI exams in
school-age survivors of neonatal critical illness have shown MRI research to be
highly feasible, not harmful and well tolerated by children.21-23 The MRI exam
and mock-scanner has been previously approved by the METC in children (Protocol
ID NL33603.078.10 and Protocol ID NL47335.078.13). The main burden associated
with participation will be the time spent on extra neuropsychological testing
at five years of age and extra neuropsychological testing as well as an MRI
exam at eight years of age. From previous experience, we have found that
children in general enjoy these assessments.
In terms of direct or short-term benefits, the results from the
neuropsychological assessments will be shared with the patients, as is part of
routine care. As the incidence of academic difficulties and learning problems
following neonatal critical illness is significant but often poorly understood,
these results from the neuropsychological assessments will help patients and
their care takers and teachers to better understand where potential problems
lie. Specifically, from previous experience we know that parents have shared
these results with school in order to help their child perform better in the
classroom. Furthermore, participation in this study increases our insight into
long-term neurodevelopmental outcome in survivors of neonatal critical illness,
which is needed to improve early identification, and eventually intervention,
of patients at risk of learning problems at a later age.