Long-term effects of neonatal glucocorticoid treatment on health in later life (follow-up study)

Neonatal glucocorticoid (GC) treatment, in particular dexamethasone (DEX), is
used worldwide to prevent prematurely born babies from developing chronic lung
disease (CLD). Despite the inevitability for clinicians to use GCs and the
effectiveness of DEX to prevent CLD, recent evidence showed long-term adverse
effects of neonatal DEX treatment. From our previous study we had to conclude
that long-term effects of neonatal DEX treatment in children at school-age (age
7-10 years) were in line with earlier findings in animals. We observed
hyporeactivity of the cardio-vascular system, autonomous nervous system, and
hypothalamic-pituitary-adrenal (HPA-) axis in response to stress and an altered
immune balance. DEX-treated children had deviant neuromotor development, more
often needed special education, and had a higher tendency towards aggressive
and delinquent behavior, more social and emotional problems, and attention
deficits than non-treated children. Interestingly, negative long-term effects
were absent in children at school-age who had been treated with the equally
effective hydrocortisone (HC). It is unknown what the consequences of neonatal
GC treatment in humans are later in life. The gloomy picture of life-long
deleterious effects of DEX, as was observed in rats embodies a strong
indication for careful follow up of GC-treated children.

The first objective is to determine the effects of neonatal GC treatment on
basal behavioral and neuropsychological measures, emotion and motor development
during adolescence. The second objective is to study basal physiological
parameters in ex-prematures treated with glucocorticoids. HPA-axis, and immune,
cardio-vascular and central nervous system function will be evaluated and
diagnostic markers for cardio-vascular, renal and metabolic diseases will be
screened. The effects of neonatal glucocorticoid treatment on development of
increased pain sensitivity will be determined as well. The third objective will
be to study whether the impaired stress-induced HPA-axis, cardiovascular and
central nervous system responses in glucocorticoid-treated individuals at
school-age further decrease during adolescence. For all three objectives it
will be evaluated whether long term effects of neonatal DEX differ from the use
of and neonatal HC treatment and whether deviations during adolescence increase
compared to measurement at earlier school-age.

The proposed study is a retrospective cohort study in which cross-sectional
group comparisons will be carried out. Furthermore, it is a long-term follow up
study investigating the longitudinal development or possible aggravation of
functional deviances due to neonatal use of glucocorticoids in prematurely born
babies at risk to CLD.

All participants will be visited at home for neuropsychological testing and for
filling out psychological questionnaires (2* hours). Participants will be asked
to collect saliva on two consecutive mornings for the determination of the
cortisol awakening response, and to perform a DEX suppression test (intake of
0.25mg DEX), for the evaluation of the negative feedback function of the
HPA-axis. After 2 weeks a test day will be planned at the Wilhelmina Children*s
Hospital (duration: 7 hours), which will include a: anamnesis + physical
examination, pain sensitivity measured by algometer, motor development testing,
questionnaires on health, emotion, and behaviour, and a standardized social
stress test. Before the stress test an i.v. line will be inserted to draw 6
blood samples, a total volume of 76 ml, and cardio-vascular functions will be
measured non-invasively by an ambulatory device (Nexfin-HD). To minimize burden
during the insertion of the i.v. line, lidocaine spray will be used. If
requested by the participant, the parent / caretaker will be present in the
same room during testing. Based on the age of the participants, the nature of
the tests, and the requested time we consider the burden as acceptable and the
risks associated with participation as negligible. More than half of the group
already participated in the previous study on glucocorticoid treatment at
school-age and the burden of the current study has hardly increased. Screening
for the possibility of cardio-vascular, renal, and metabolic alterations makes
participation for both the individual participants and the study group as a
whole profitable. Moreover, this study may lead to early intervention and
prevention of disease.