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Hypoexit


Neurodevelopmental outcome after neonatal hypoglycemia.

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Problem:
Hypoglycemia is the most common metabolic problem in neonatology: around 25% of all newborns are at risk for hypoglycemia. In the Netherlands this means that around 40.000 newborns are at risk annually. Because hypoglycemia can lead to permanent brain damage, 'high risk' infants 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.

Objective:
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.

Research questions:
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.

Study Design:
Multi-centre randomized controlled trial.

Study Population:
Four groups of 200 'high risk' newborn infants with moderate hypoglycemia >35 weeks gestational age and birth weight >2000 gram, without serious co-morbidity:

  1. (Near)term small-for-gestational-age infants (SGA, birth-weight-for-gestational-age
  2. (Near)term large-for-gestational-age infants (LGA, birth-weight-for-gestational-age >P90);
  3. Near-term infants 35 0/7 to 36 6/7 weeks gestational age with a birth weight >2000 gram, who are appropriate for gestational age (AGA);
  4. (Near)term infants of diabetic mothers (IDM).

These infants are routinely screened for neonatal hypoglycemia in current clinical practice.
Birth-weight-for-gestational-age is defined according to the Kloosterman growth charts.

Interventions:
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. In the expectant arm the aim is to maintain the glucose concentration above 1.9 mmol/l by the usual oral nutrition protocol.

Outcome measures:
Primary outcome is neurodevelopment at 18 months, assessed with the Bayley Scales of Infant Development. Secondary outcomes are costs for medical treatment and hospital admission until 18 months of age.

Power/Data Analyses:
Infants will be allocated to 4 groups by birth-weight-for-gestational-age and maternal diabetes. To be able to test a difference of 7.5 points (1/2 SD) or more with the Bayley test (alpha 0.025, Power 0.90) power analysis revealed that 200 infants need to be included per group: 100 in each treatment arm. Therefore, a total of 800 infants must be included.

Economic Evaluation:
The economic evaluation will be performed as a cost-minimisation analysis from a provider perspective.

Time Schedule:
Total study time 36 months.

Projectleaders:
A.A.M.W. van Kempen - kinderarts-neonatoloog AMC / OLVG
N. Boluyt - kinderarts-epidemioloog
D.H.G.M. Nuytemans - Onderzoekscoordinator

Project members:
L. Gunning-Schepers - voorzitter Raad van Bestuur AMC
Anneloes van Baar - hoogleraar kinderpsychologie Tilburg
Ron van Beek - kinderarts-neonatoloog Breda
Marcel Dijkgraaf - methodoloog AMC
Joke Kok - kinderarts-neonatoloog AMC
Harry Lafeber - kinderarts-neonatoloog VUMC
Pien Offerhaus - verloskundige, afgevaardigde KNOV
Martin Offringa - kinderarts-neonatoloog, epidemioloog AMC
Joris van der Post - gynecoloog AMC
Ben Semmekrot - kinderarts Nijmegen
Aleid van Wassenaer - kinderarts (follow up) AMC
Ingrid Maas - Kwaliteitsbureau NVK

Subsidy:
ZonMw - www.zonmw.nl