NEURODEVELOPMENTAL OUTCOME AFTER NEONATAL HYPOGLYCEMIA: A MULTI-CENTER RANDOMIZED CONTROLLED TRIAL COMPARING INTENSIVE TREATMENT VERSUS EXPECTANT GLUCOSE MONITORING IN 'HIGH RISK' NEWBORNS.

Hypoglycemia is the most common metabolic problem in neonatology: around 25% of
all newborns are at risk for neonatal hypoglycemia. Because hypoglycemia can
lead to permanent brain damage, 'high risk' infants for hypoglycemia are
admitted, screened and, if necessary, treated. However, there is still much
controversy about the definition of a 'safe' plasma glucose concentration.
Currently used limits for hypoglycemia vary between 2.0 and 2.6 mmol/l. As a
result, current clinical practice varies widely, especially for infants with
'moderate' hypoglycemia (glucose 2.0-2.5 mmol/l). This leads to both over- and
under-treatment of hypoglycemic infants.

This study-protocol is directed at the comparison of two accepted management
strategies at both ends of the current treatment-spectrum of moderate
hypoglycemia in 'high risk' newborns: an intensive treatment versus an
expectant monitoring strategy.
The main research questions are: How does intensive treatment in 'high risk'
newborn infants with moderate hypoglycemia compare with expectant glucose
monitoring in terms of 1. neurodevelopmental outcome at the age of 18 months;
2. costs for diagnostic tests and treatment of the infant, and hospitalization
costs for both the infant and mother; and 3. costs for medical consumption
related to neurodevelopmental impairment until the age of 18 months.

Multi-center randomized controlled trial.

Intervention: In the intensive treatment arm the aim is to increase the glucose
concentration above 2.5 mmol/l within 3 hours by increasing the carbohydrate
intake by oral nutrition and/or intravenous glucose administration.

Control: In the expectant arm the aim is to maintain the glucose concentration
above 2.0 mmol/l by the usual oral nutrition protocol.

Burden:
1. Amount and number of blood samples: a minimum of 8 blood samples (7 blood
drops and once 0.25 ml) will be taken by heelstick, depending on the course of
the glucose concentration in the infant. Only *high risk* newborns will be
included, in whom the glucose concentration is routinely checked in current
clinical practice.
2. Number of site visits: current clinical practice dictates that these *high
risk* infants are admitted to a maternity or neonatal ward for routine glucose
monitoring and treatment. Therefore, the hospital admission in the neonatal
period is not considered a burden due to the study protocol. Determination of
the neurodevelopmental outcome requires one hospital visit (1 hour) at the age
of 18 months.
3. For determination of medical costs the parents of the participating infants
are asked to fill out a questionnaire at the age of 3-6-9-12-15-18 months.

Benefit and risks: Both treatment strategies have possible (reciprocal) benefit
and risks for the participating infants: an intensive treatment strategy can
lead to better neurodevelopmental outcome and prevent cases of brain damage
(which leads to substantial lifelong morbidity, health care consumption,
decreased quality of life, and associated financial cost), whereas an expectant
strategy most likely requires less blood sampling, less invasive treatment,
shorter hospital stay (of both the infant and the mother) in the neonatal
period.

Group relatedness: Neonatal hypoglycemia is a transient problem, occurring in
the first postnatal days. In addition, the neonatal period is a unique period
from a metabolic and nutritional point of view and for brain development.
Therefore, studies on the effects of different treatment strategies on
neurodevelopmental outcome will have to be performed in *high risk* newborn
infants, thereby involving minors.