Neurodevelopmental Defects In Early Childhood Due To Neonatal Hypoglycemia – A Prospective Study

Recurrent and severe neonatal hypoglycemia could cause learning and behavioral difficulties at school, however with normal intelligence, according to a study conducted by an international research team led by Distinguished Professor Jane Harding at the Liggins Institute, University of Auckland, New Zealand. The findings of the study appear in the journal JAMA Pediatrics, and form part of a major long-term study, dubbed the “CHYLD” study (Children with Hypoglycaemia and their Later Development).

Importance of Early Diagnosis and Treatment of Neonatal Hypoglycemia

Neonatal hypoglycemia is a fairly common occurrence and more importantly is a preventable cause of brain damage in infancy.

It is diagnosed clinically by performing a heel-prick blood test and if glucose levels are found to be low (less than 47 mg/dl), the baby is given dextrose gel till normal levels are restored. In fact, this treatment was pioneered by Prof. Harding and her team in 2013.

Currently there is no internationally accepted value for neonatal blood glucose level that is considered unsafe to necessitate immediate intervention. Values vary from less than <2.6 mmol/L (most commonly used and followed in this study), but authorities from other countries have recommended cut-offs as low as 1.4 mmol/L and as high as 3.3 mmol/L.

The team therefore embarked on this study to assess the risk of neurodevelopmental defects associated with neonatal hypoglycemia in this prospective cohort study and to determine whether current criteria for diagnosis of neonatal hypoglycemia have to be revisited and standardized to achieve better outcomes for these babies.

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Assessing Neurodevelopmental Effects Of Neonatal Hypoglycemia – The Study Design

• The Children With Hypoglycemia and Their Later Development (CHYLD) Study is a prospective cohort study conducted among moderate to late preterm and term infants born at risk of hypoglycemia.
• It was done at a regional perinatal center in Hamilton, New Zealand between the months of December 2006 to November 2010. Follow-up periods were from September 2011 to June 2015.
• The study included 614 neonates born from 32 weeks’ gestation with at least 1 risk factor for hypoglycemia, including preterm, small, large, diabetic mother, or acute illness.
• Whole blood and masked interstitial glucose concentrations were estimated for up to 7 days after birth.
• Neonatal hypoglycemia is defined as at least 1 consecutive blood glucose level of less than 47 mg/dL, a severe episode with levels <36 mg/dL, and recurrent episodes were said to occur if there were three or more instances. Interstitial hypoglycemia was defined as an interstitial glucose concentration less than 47 mg/dL for at least 10 minutes.
• Neonates with hypoglycemia (blood glucose concentration <47 mg/dL) were treated to maintain blood glucose concentration at a minimum 47 mg/dL.
• Cognitive function, executive function, motor function and visual function were then assessed at 4 ½ years.

Findings of The Study - Neurodevelopmental Outcomes Associated With Neonatal Hypoglycemia

• Overall, 477 of 604 eligible children (79.0%) were assessed. Their mean age at the time of assessment was 4.5 years, and 228 (47.8%) were females.
• Infants exposed to neonatal hypoglycemia (280 [58.7%]) did not have an increased risk of neurosensory impairment.
• However, neonatal hypoglycemia was associated with higher risk of low executive function and visual motor function with the greatest risk in children exposed to severe, recurrent, including clinically undetected (interstitial episodes only)
• hypoglycemia.

The findings seem to suggest that neonatal hypoglycemia may not be associated with neurosensory impairment at 4 ½ years of age but could cause a dose-dependent increase in the risk of poor executive function (skills for problem-solving, planning, memory and attention) and visual motor function (skills for fine control of movement, and understanding what you see) even though not detected clinically by heel-prick (only interstitial episodes), which could affect learning at school.

Says Professor Harding. “At two years there was no relationship between blood sugar levels and later brain development, but at age 4.5 years, it’s clear that the children who experienced low blood sugar levels were more likely to have specific difficulties.”

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She goes on to add, “We don’t know yet what these impairments mean for the child in practical terms, but executive function and visual motor integration are believed to be important for learning at school, particularly for math and reading.” 

Scope of The Study and Future Plans

• The current study raises serious doubts that neonatal hypoglycemic episodes could indeed cause problems at school, with some of the episodes not detected clinically.

“What was especially concerning in our 4.5 year results was the four-fold increase in risk of executive function difficulties in children who had experienced low blood sugars that were not detected in routine testing,” says the paper’s lead author, Dr Chris McKinlay, also from the Liggins Institute. “This is the first time this has been shown.”

• The team plans to enlarge upon the current study and conduct further tests at 9-10 years of age to see if these children have significant math and reading difficulties and behavioral problems.

Professor Harding opines that if the 9-10 year studies throw up significant neurodevelopmental outcomes linked to neonatal hypoglycemia, then an urgent rethink would become essential to re-evaluate and establish standardized diagnostic threshold glucose levels for neonatal hypoglycemia.

• Moreover, if treated infants also show neurodevelopmental impairments, this raises the possibility of brain damage being already present even before dextrose treatment was given.

The findings therefore, of another ongoing study that Prof Harding is heading become all the more significant. The study plans to assess whether dextrose gel could be routinely given to all neonates at risk of hypoglycemia before brain damage could occur.

Reference:

1. Nataliia Burakevych, PhD1; Arijit Chakraborty, PhD1,4; J. Geoffrey Chase, PhD5; Gregory D. Gamble, MSc1; Deborah L. Harris, Robert J. Jacobs, Yannan Jiang,  Nabin Paudel, Ryan J. San Diego, Benjamin Thompson,  Trecia A. Wouldes, Jane E. Harding. Association of Neonatal Glycemia With Neurodevelopmental Outcomes at 4.5 Years. JAMA Pediatrics (2017). doi:10.1001/jamapediatrics.2017.1579

Source-Medindia