HINT STUDIES

Hyperglycaemia (high blood glucose concentration) is a common problem in preterm infants and is associated with poor neurodevelopmental outcome. It is currently unclear whether hyperglycaemia itself causes developmental problems or if it is coincidental.

The sickest preterm babies are those most likely to experience hyperglycaemia. Typically, high blood glucose concentrations are treated with insulin. However insulin treatment can cause blood glucose concentrations to fall too low (hypoglycaemia), which also impacts upon future neurodevelopment. Dysregulated blood glucose concentrations in the neonatal period may also affect the developing pancreas, leading to altered glucose metabolism in later life and an increased risk of diabetes.

The first Hyperglycaemia and Insulin in Neonates Trial (HINT) ran from July 2005 to October 2008 at the Neonatal Intensive Care Unit at Auckland City Hospital. The aim was to discover whether tightly controlling the blood glucose concentrations in hyperglycaemic preterm infants led to improved growth compared with standard NICU treatment.

88 hyperglycaemic preterm infants were included in the study, randomised to either a control group or an intervention group. Babies in the study had a birth weight less than 1500g; gestation less than 30 weeks and hyperglycaemia (two consecutive blood glucose concentrations ≥ 8.5 mM).

The results from the HINT trial showed that infants in the intervention group, whose blood glucose concentrations were tightly controlled, had better head growth and better weight gain at 36 weeks post-menstrual age when compared to the infants who had received standard treatment. However, these infants also had a decreased rate of lower leg growth, suggesting that the increased weight gain might be due to excess fat deposition. They were also twice as likely to have at least one episode of hypoglycaemia (low blood glucose concentrations). Thus, the risk-benefit ratio of tight blood glucose control remains unclear.

The HINT children were followed up once they reached school age. Their neurological, psychological and metabolic development was assessed to determine whether the treatment received as a preterm newborn had any long-term effects on body composition, insulin sensitivity and insulin secretion, physical health and overall development.

The children in this follow-up study, the PIANO study, included the 81 children in the HINT study who survived to childhood, along with 81 non-hyperglycaemic matched controls.

Results from the PIANO study showed tight glycaemic control for neonatal hyperglycaemia did not change survival without neurodevelopmental impairment, but reduced height, increased height-adjusted lean mass, and reduced fasting blood glucose concentrations at school age.

HINT2 follows on from the HINT trial completed in 2008. The HINT2 trial will determine if a computer model, developed by engineers in Canterbury, is effective at maintaining blood glucose concentrations in the target range and reducing hypoglycaemia in hyperglycaemic preterm babies on insulin.

Recruitment is ongoing for HINT2, with babies eligible who are born with a birthweight ≤1500g or at ≤30 week’s gestation who go on to develop hyperglycaemia and for whom insulin is not contraindicated.

Alsweiler JM, Harding JE, Bloomfield FH. Tight glycemic control with insulin in hyperglycemic preterm babies: a randomized controlled trial. Pediatrics 2012;129(4):639-47. DOI: 10.1542/peds.2011-2470.

Tottman AC, Bloomfield FH, Cormack BE, Harding JE, Slim MAM, Weston AF, Alsweiler JM. Relationships between early nutrition and blood glucose concentrations in very preterm infants. Journal of Paediatric Gastroenterology and Nutrition 66: 960-966, 2018. DOI : 10.1097/MPG.0000000000001929

Tottman AC, Alsweiler JM, Bloomfield FH, Gamble G, Jiang Y, Leung M, Poppe T, Thompson B, Wouldes T, Harding JE on behalf of the PIANO Study Group. Long-term outcomes of hyperglycemic preterm infants randomized to tight glycemic control. Journal of Pediatrics 193: 68-75, 2018.

Tottman AC, Alsweiler JM, Bloomfield FH, Pan M, Harding JE. Relationship between measures of neonatal glycemia, neonatal illness and 2-year outcomes in very preterm infants. Journal of Pediatrics 188: 115-21, 2017. doi: 10.1016/j.jpeds.2017.05.052

Tottman AC, Alsweiler JM, Bloomfield FH, Harding JE on behalf of the PIANO Study team. Scarring at school age in children born very preterm. Archives of Disease in Childhood Fetal and Neonatal Edition 103: F277-279, 2018. doi:10.1136/archdischild-2016-311999