Neonatal hypoglycemia and its effects on the immature brain

1. Neonatal hypoglycemia and its effects on the immature brain September 4, 2003.

2. Objectives: • To discuss the definition of neonatal hypoglycemia and the pathophysiology of hypoglycemia and its effects on the neonatal brain. • To discuss what is known to date regarding the long-term neurodevelopmental outcome of hypoglycemia in the neonatal period.

3. Definition of Hypoglycemia Difficulty in determining a significant definition of neonatal hypoglycemia. How do we define significant hypoglycemia? Koh et al. A survey of 36 pediatric textbooks and 178 pediatric consultants produced a range from 1-4 mmol/L • “Critical hypoglycemia” • What degree of hypoglycemia is significant? • What is our threshold for treated asymptomatic hypoglycemia? • What levels which will impact on neurodevelopmental outcome? Koh TTHG, Eyre HA, Aynsley-Green A. Neonatal hypoglycemia: the controversy regarding definition. Arch Dis Child 1988;63:1386-8.

4. Definition of Hypoglycemia • Four approaches to defining hypoglycemia, all flawed: • Clinical approach- changed level of consciousness, irritability, lethargy, stupor, apnea/cyanotic spells, coma, poor feeding, hypothermia, hypotonia/limpness, tremor, seizures • Epidemiological approach- less than 5th percentile from statistical calculations • Approach based on acute metabolic, endocrine, and neurological function- still inadequate evidence • Approach based on long-term neurologic outcome- still inadequate evidence

5. Operational Thresholds Cornblath M, Mawdon JM, Aynsley-Green A, Ward-Platt MP, Schwartz R, Kalhan SC. Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds. Pediatrics. May 2000, 105(5). • Term Infant: • No investigation suggested. • Infant with abnormal clinical signs: • Intervention suggested for plasma glucose < 2.5 mmol/L, and pathological processes considered. • Infants with risk factors: • Routine screening for hypoglycemia suggested for infants with risk factors for compromised metabolic adaptation. • Screening prior to feeding and within 2-3 hours of birth or if signs

6. Operational thresholds (cont’d) • Plasma glucose concentrations: • < 2.0 mmol/L • close surveillance required • treatment suggested if levels do not improve with feeding • treatment suggested if abnormal clinical signs develop • < 1.1-1.4 mmol/L • intravenous glucose infusions to raise levels to 2.5 mmol/L • Maintaining levels > 3.3 mmol/L may be useful in symptomatic infants with documented profound, recurrent, or persistent hyperinsulinemic hypoglycemia.

7. Operational Thresholds (cont’d) • Preterm infants: • Some studies suggest a cutoff of 2.6 mmol/L, but inadequate evidence • Infants on parenteral nutrition: • Results in persistent high insulin levels, and inadequate lipolysis and ketogenesis. Higher thresholds should be used (2.5 mmol/L).

8. Risk Factors for Hypoglycemia • Changes in maternal metabolism: • Intrapartum administration of glucose • Drug treatment with terbutaline, ritodrine, propanolol, oral hypoglycemics • Diabetes in pregnancy • Associated neonatal problems: • Idiopathic condition / failure to adapt • Perinatal hypoxia-ischemia • Infection • Hypothermia • Hyperviscosity • Erythroblastosis fetalis, hydrops fetalis • Iatrogenic causes • Congenital cardiac malformations • Intrauterine growth restriction • Hyperinsulinism • Endocrine disorders • Inborn errors of metabolism

9. Clinical types • Early transitional hypoglycemia • often in LGA babies, diabetic mothers • within first few hours of life • resolve with feeding or IV glucose • Secondary associated hypoglycemia • term/preterm AGA babies in first day of life • asphyxia, intracranial hemorrhage, congenital heart disease • Due to: • Anaerobic glycolysis depleting glucose stores • Increased catecholamines and glycogen depletion • Insulin hypersecretion • Classic transitional hypoglycemia • SGA babies with chronic intrauterine malnutrition • Depleted glycogen and lipid stores • Usually in latter part of 24 hours of life

10. Clinical types – Severe recurrent hypoglycemia • Least common group and most worrisome, variable onset. • DDx: • Hyperinsulinism • Beta-cell hyperplasia • Nesidioblastosis • Macrosomia • Beckwith-Weidmann Syndrome • Endocrine abnormalities • Panhypopituitarism • Hypothyroidism • Growth hormone deficiency • Cortisol deficiency • Hereditary metabolic disorders • Abnormalities in carbohydrate metabolism • Amino acid disorders (maple syrup urine disease) • Organic acid disorders • Fatty acid oxidation disorders • Glucose transporter defects

11. Four approaches to defining hypoglycemia, all flawed: • Clinical approach- changed level of consciousness, irritability, lethargy, stupor, apnea/cyanotic spells, coma, poor feeding, hypothermia, hypotonia/limpness, tremor, seizures • Epidemiological approach- less than 5th percentile from statistical calculations • Approach based on acute metabolic, endocrine, and neurological function- still inadequate evidence • Approach based on long-term neurologic outcome- still inadequate evidence

12. “Critical hypoglycemia” Lucas A, Morley R, Cole TH. Adverse neurodevelopmental outcome of moderate neonatal hypoglycemia. BMJ 1988, 297:831-8 Hypoglycemia at less than 2.6 mmol/L occurred in 433 of 661 preterm infants studied. Strong correlation was found between the number of days with recorded hypoglycemia and reduced mental and motor development scores at 18 months. Duvanel CB, Fawer C-L, Cotting J, et al. Long-term effects of neonatal hypoglycemia on brain growth and psychomotor development in small-for-gestational age preterm infants. J Petiatr 1999, 134;492-8. 73% of the 85 SGA preterm newborns tested had hypoglycemia at < 2.6 mmol/L. Strong correlation was found between recurrent episodes of hypoglycemia and persistent neurodevelopmental and physical growth deficits at 5 years of age. What level of hypoglycemia will impact on long term neurodevelopmental outcome?

13. Glucose and the CNS Many such studies are difficult to perform in human subjects, thus much of this work has been done on laboratory animals. • Normal glucose metabolism • Fetus utilizes both maternal glucose, as well as lactate and amino acids. • Upon birth, there is a mobilization of glycogen and fatty acids. • Doubling of glycogen stores occurs at 36 weeks gestation. • These stores are depleted in first 24 hours of life. • Evolving functional maturity • In 5 week old infants, cerebral glucose utilization (CGU) is greatest in the sensorimotor cortex, thalamus, midbrain-brainstem, and cerebellar vermis. • At 3 months, maximal CGU shifts to parietal, temporal, and occipital cortices and the basal ganglia. • By 8 months, there is incresaed frontal and association region CGU.

14. Resistance to brain injury The neonatal brain differs with adult brains with the following mechanisms providing increased resistance to brain injury: • Enhanced cerebral blood flow (CBF) and cerebral uptake of glucose • Enhanced ability to use alternate substrates • Decreased requirement for glucose utilization • Preservation of cerebral high-energy phosphates

15. 1. CBF and Glucose uptake Pryds O, Greisen G, Friis-Hansen B. Compensatory incrase of CBF in preterm infants during hypoglycemia. Acta Paediatr Scand 1988, 77:632-7. Human infants can increase CBF by 200% above normal when blood glucose falls < 1.6 mmol/L Mujsce DJ, Christensen MA, Vannucci RC. Regional cerebral blood flow and glucose utilization during hypoglycemia in newborn dogs. Am J Physiol 1989, 256:H1859-66. Similar findings in newborn dogs with glucose concentrations at 1.0 mmol/L. CBF increased 170% in white matter to 250% in the thalamus.

16. 2. Alternate energy sources • Perinatal brain also uses lactate, β-hydroxybutyrate, and acetoacetate. • Animal and human studies indicate enhanced ketone body uptake in the perinatal brain. However, hepatic ketone synthesis is limited. • Lactate is an important source of energy during hypoglycemia. • In rats and dogs preferential use of lactate over glucose and ketone bodies during hypoglycemia. • In insulin-induced hypoglycemia, lactate was able to support 58% of cerebral oxidative metabolism, without significant decline in ATP levels. Vannucci RC, Nardis EE, Vannucci SJ, et al. Cerebral carbohydrate and energy metabolism during hypoglycemia in newborn dogs. Am J Physiol. 1981, 240:R192-9.

17. 3. Decreased glucose needs • Hernandez MJ, Vannucci RC, Salcedo A, et al. Cerebral blood flow and metabolism during hypoglycemia in newborn dogs. J Neurochem 1980, 35:622-8. • In newborn dogs, hypoglycemia < 1.0 mmol/L resulted in: • a preserved cerebral metabolic rate for oxygen • decrease of glucose metabolism by 50% • lactate metabolism increased 10-fold

18. 4. Stable ATP levels Vannuci RC, Nardis EE, Vannucci SJ, et al. Cerebral carbohydrate and energy metabolism during hypoglycemia in newborn dogs. Am J Physiol 1981, 240:R192-9 Similar investigations showed high energy phosphate (phosphocreatine and ATP) reserves reamined within normal during hypoglycemia in newborn dogs.

19. Concomitant disorders Hypoglycemia is more deleterious when superimposed on hypoxia-ischemia or seizures, according to animal studies. Vannucci RC, Vannucci SJ. Cerebral carbohydrate metabolism during hypoglycemia and anoxia in newborn rats. Ann Neurol 1978, 4:73-9. In newborn rat pups subjected to anoxia, normoglycemic pups survived 10x longer than hypoglycemic ones. Young RS, Cowan BE, Petrof OA. In vivo 31P and in vitro 1H nuclear magnetic resonance study of hypoglycemia during neonatal seizure. Ann Neurol 1987, 22:622-8. 31P NMR studies showed significant depletion of high-energy phosphate stores when seizures occurred in conjunction with hypoglycemia as compared to without.

20. Neuropathology in hypoglycemia • Acute changes: • Pathological studies of severely hypoglycemic neonatal brains showed: • neuronal injury in cerebral cortex, hippocampus, basal ganglia, thalamus, brainstem, and spinal cord. • neuronal necrosis occurred more than ischemic injury • widespread glial cell degeneration • periventricular leukomalacia in a few cases • Chronic changes: • Pathological studies long after the neonatal period showed: • significant microcephaly • diffuse loss of neurons in cortex • increase in astrocytes and microglia • calcifications in the necrotic zones • sparing of the cerebellum Anderson JM, Milner RDG, Strich SJ. Effects of neonatal hypoglycemia on the nervous system: a pathological study. J Neurol Neurosurg Psychiatry 1967, 30:295-310. Banker BQ. The neuropathological effects of anoxia and hypoglycemia in the newborn. Dev Med Child Neurol 1967, 9:544-550.

21. Neuroimaging in hypoglycemia • Spar et al. (1994) were the first to describe neuroimaging changes in neonatal hypoglycemia. • Case report of one infant with symptomatic hypoglycemia at 58 hours of age, with hypoglycemia well-documented at over 15 hours. • MRI at DOL#19 showed: • bilateral occipital lobe parenchymal tissue loss • near complete absence of cerebral cortex in posterior parietal and occipital areas • generalized thinning of the cerebral cortex • No other factors were found to explain this brain damage, and thus was attributed to the hypoglycemic insult. Spar HA, Lewine JD, Orrison WW. Neonatal hypoglycemia: CT and MR findings. AJNR 1994, 15:1477-1478.

22. Neuroimaging in hypoglycemia (cont’d) Symptomatic hypoglycemia is associated with parieto-occipital white matter abnormalities, as well as abnormal signals in the deep grey matter structures of the thalamus and basal ganglia. CT image source: Yager JY. Hypoglycemic injury to the immature brain. Clinics in Perinatology 2002, 29:651-674.

23. Neuroimaging in hypoglycemia (cont’d) • Kinnala A, Rikalainen H, Lapinleinu H, Parkkola R, Kormano M, Karo P. Cerebral magnetic resonance imaging and ultrasonography findings after neonatal hypoglycemia. Pediatrics 1999, 103:724-9. • In a study of 18 term infants with symptomatic hypoglycemia: • 39% showed MRI or ultrasound abnormalities • 4 showed patchy hyperintense lesions on MRI in occipital periventricular white matter or thalamus • 3 of 4 did not show these lesions on follow-up MRI

24. Outcome? Lucas A, Morley R, Cole TG. Adverse neurodevelopmental outcome of moderate neonatal hypoglycemia. BMH 1988, 297:1304-8. Multi-center study of 661 preterm infants weighing < 1850 g, with outcomes determined at 18 months of age. Reduced mental and motor developmental scores were found to be related to increasing number of days with glucose levels < 2.6 mmol/L. Relative risk for neurodevelopmental impairment was 3.5x greater in infants with blood glucose < 2.6 mmol/L for > 5 days.

25. Outcome long term? • Stenninger E, Flink R, Eriksson B, Sahlen C. Long term neurological dysfunction and neonatal hypoglycemia after diabetic pregnancy. Arch Dis Child 1998, 79:F174-9 • Long-term study of 13 children with neonatal hypoglycemia of < 1.5 mmol/L, compared to 15 children without neonatal hypoglycemia. • Assessments done at an average of 7.75 years of age showed: • significantly more difficulties in a screening test for minimal brain dysfunction • more hyperactivity, impulsivity, and inattentiveness • lower developmental scores • Compared to controls.

26. Conclusions • Hypoglycemia is a common disorder in neonates, however no clear definition for the condition exists. • The level of blood glucose that warrants treatment depends much on other factors including gestational age, concomitant risk factors, and condition of the patient. • Significant neurodevelopmental deficits can occur in neonates who experience numerous days of hypoglycemia. • Neuropathological and neuroradiological findings, both acute and chronic, occur in neonatal hypoglycemia. • Much work still needs to be done to clarify all of these areas, including the definition, thresholds to treatment, utility for neuroimaging, and prognostication of neonatal hypoglycemia.

27. Additional Sources Vannucci RC & Vannucci SJ. Hypoglycemic brain injury. Semin Neonatol 2001, 6:147-155. Yager JY. Hypoglycemic injury to the immature brain. Clinics in Perinatology. 2002, 29:651-674.