A follow-up of infants born following intrauterine growth restriction: Is there a relation between neonatal cerebral tissue oxygenation and developmental outcome at 4 years?

Previous studies have suggested that intrauterine growth restriction (IUGR) may
expose to neurodevelopmental delay. Furthermore, the degree of cerebral
oxygenation monitored with near-infrared-spectroscopy (NIRS) seems to be
related to the range of general movements seen in neonates. This may be related
to the degree of fetal brain-sparing resulting from IUGR in pregnancy. There is
also some evidence that very high cerebral oxygenation levels (possibly related
to extreme brain-sparing) may be related with neurodevelopmental delay just as
very low cerebral oxygenation levels. Similarly, DNA methylation of metabolism
related loci has been shown to partially depend on oxygen and nutrient supply.
On the other hand, the expression of important regulators of oxygen transport
(HIF, EPO, EPO receptor) are controlled by DNA methylation. We hypothesize that
neurodevelopmental delay at preschool age is associated with both cerebral
hypo- and hyperoxia of the newborn with a history of IUGR. We also hypothesize
that cerebral oxygenation levels of IUGR infants are significantly associated
with changes in DNA methylation.

Primarily, to study the relation between neonatal cerebral oxygen saturation
and extraction and intelligence at 4 years of age in infants born following
intrauterine growth restriction. The second aim is to study the relation
between neonatal cerebral oxygen saturation and extraction and behaviour at 4
years of age in infants born following intrauterine growth restriction. Third,
the correlation between early oxygen saturation and later differences in DNA
methylation will be studied.

Prospective follow-up study of an IUGR cohort, who previously participated in a
study performed in the UMCG with cerebral NIRS measurements (METc nummer
2012-055). Parents wil be asked to visit the UMCG with their child for
follow-up and to bring a feces specimen of their child for DNA analysis. During
the visit the child will be doing an intelligencetest (WPPSI) in the presence
of a neuropsychologist or trained medical researcher. We will also perform a
physical exam on the child measuring height, weight, head circumference, skin
crease thickness, and blood pressure. A buccal swab for DNA analysis will also
be taken. While the child will be tested, parents will be asked to fill in
three questionnaires (CBCL, ASQ, BRIEF-P) and give information on their
socioeconomic status and relevant medical history of the child such as hearing-
and visionproblems, psychiatric disorders and neurologic disorders.

Data for this study cannot be obtained in another population, as the intention
is to study relation between the postnatal cerebral tissue oxygenation and late
neurodevelopmental outcome in children born following IUGR. As data on
postnatal cerebral tissue oxygenation have already been collected for this IUGR
cohort in the context of an earlier study (METC number 2012-055), we will only
have to collect data on the neurodevelopment of these children at
preschool/primary school age. Burden and risks associated with the
participation in this study are small to non-existent. Participation will
require only one visit comprised of an intelligence test (WPPSI) performed in
the presence of an experienced paediatric neuropsychologist and three
questionnaires which will simultaneously be filled in by the parents/guardian.
The tasks and instructions given to the children will be appropriate for their
age without overwhelming the child unnecessarily. Children who show resistance
will not be forced to participate. The data collected could provide more
insight on the predicting value of measured cerebral oxygenation after birth on
the neurodevelopmental outcome at preschool/primary school age. DNA
methylation, measured in samples obtained in a non-invasive way, could in
future potentially serve as biomarkers for tissue oxygenation if correlated.
Data also have the potential to make inferences about the actual benefit of
brain-sparing often occurring in foetuses with IUGR.