Brain development after prenatal growth retardation; effects of growth hormone treatment

Fetal malnutrition during the last trimester will lead to fetal growth failure,
whereby the brain is spared (disproportional growth failure). Recently it has
been described that infants born with a low birth weight, referred as small for
gestational age (SGA) due to last trimester growth failure, display slightly
reduced cognitive capacity at young adult age compared with controls born with
appropriate weight. Only a small percentage of about 5-10 % remains short after
the age of 4 years. Since GH treatment is considered to have a favorable effect
on final height, the treatment protocol in children with SGA has been accepted
and recently been operationalised. Children should be carefully monitored
because they are associated with an increased risk of development of
cardiovascular diseases and type 2 diabetes. Recently a Dutch research group
reported that the intelligence quotients (IQ*s) of SGA- children increased on
GH treatment. There are, however, methodolocical shortcomings in this study in
which no controlgroup was added.These data need to be replicated in a healthy
and otherwise controlled study that also starts at pre-treatment baseline.
In the present study we expect to increase understanding what the effect is of
GH treatment on brain developing and functioning in SGA-children, and whether
the brain is still plastic during childhood, so that GH is capable to stimulate
cell proliferation neuronal outgrowth and more specific will GH influence the
maturation and outgrowth of connections between the different brain areas

Whether cognitive functions in SGA children are impaired due to inappropriate
developmental outgrowth in children born with a low birth weight is unknown.
This is also the case for the fact whether GH treatment from the age of 4 years
is still capable to stimulate neuronal outgrowth and to increase IQ's. We
expect the presented study design in which functional imaging techniques and
neuropsychological assessment are combined, to increase understanding on the
impact of GH therapy on higher brain functioning in children with SGA.
Therefore the 3 research questions of the study are:
1. Will growth hormone treatment in children born with a low birth
weight/length with incomplete catch up growth improve brain functioning?
2. Is there a difference in brain functioning in children born with a low birth
weight/length between those without and with complete catch up growth?
3. Will intra-uterine growth failure affect brain development/functioning?

The study is an open prospective controlled study in which SGA children without
complete catch up growth treated with growth hormone are compared with SGA
children without complete catch up growth without growth hormone treatment and
with children with complete catch up growth. Also SGA children with complete
catch up will be compared with children with normal prenatal growth.

structural (only at baseline) and functional MRI*s, MEG and extensive
neuropsychologic testing as described below will be performed at baseline,
after one year and three years in both groups A and B.
SGA patients older than 6 years of age, with incomplete catch-up growth with
the indication of GH treatment, will be followed on neuropsychologic
functioning. Structural and functional MRI*s, MEG and extensive
neuropsychological testing will be performed only at start of the study in
groups C and D

International literature reports on fMR-imaging and MEG-recording from the age
of 5 years and older. Appropriate preparation, training, supervising and
extended instruction on procedures before real testing are requisite. For these
purposes we intend to train children using colored plastic tubes to mimic the
small and close situation of the scan apparatus. During practising, the
children will be exposed to the noise of the fMRI/MEG as well. Furthermore, an
experienced pediatrician as well as a well-trained psychologist will supervise
and evaluate the situation. When the child is not able to perform the
investigations, the study procedure will be discontinued. When the first
investigation of the study fails in a patient/control, the patient is
considered as drop out and a new patient/control will be recruited.