Neonatal Hypoglycemia:
Evidences and Practice
Prof. Pushpa Raj Sharma
Department of Child Health
Why This Topic is Important?
•Inability to breast feed and weight <2500 g were
independently associated with hypoglycaemia. Mortality
was 45.2% compared to 19.6% in normoglycaemic neonates
(p < 0.001).
Osier FH, Berkley JA, Ross A, Sanderson F, Mohammed S, Newton CR.
Abnormal blood glucose concentrations on admission to a rural Kenyan district
hospital: prevalence and outcome.
Arch Dis Child. 2003 Jul;88(7):621-5.
•41% newborn infants had mild (less than 2.6 mmol/l) and
11% had moderate hypoglycaemia: Hospital based study.
Pal DK, Manandhar DS, Rajbhandari S, Land JM, Patel N, de L Costello AM.
Arch Dis Child Fetal Neonatal Ed. 2000 Jan;82(1):F46-51.
Koivisto M, Blaco-Sequeiros M, Krause U. Neonatal
symptomatic hypoglycaemia: a follow-up study of 151
children. Dev Med. Child Neurol 1972; 14:603-14
Their conclusions? TIME is most
important factor affecting onset of sx and
SYMPTOMATIC hypoglycemia with
convulsions has poor prognosis for
permanent CNS damage, while
asymptomatic hypoglycemia without
convulsions appears to have no influence
on CNS pathology
Long term neurological outcomes
 Lucus A, Morley R, Cole TJ. Adverse
neurodevelopmental outcome of moderate neonatal
hypoglycemia. British Medical Journal 1988;
297:1304-1308
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661 preterm infants (BW <1850 g) surviving >48hrs
Weekly glucose level taken; reagent strips q6h for first
48-72 hours (if <1.5 or 2 low values below 2.5  blood
test)
Treated by feeds/iv or bolus if less than 1 mmol/l or sx
At 18 months  92% assessed with Bayley motor and
development scale
Results examined by statistical adjustment for
differences between infants with and without
hypoglycemia
Lucus A, Morley R, Cole TJ.
Their findings?
<2.6 on 3 to 30 separate days  associated
with reductions in Bayley motor ad mental
development scores even after adjusting
for confounding factors
<2.6 on 5 or more consecutive days 
increased risk (3.5 fold) of CP
Kinnala et al. Cerebral magnetic resonance
imaging and ultrasonography findings after
neonatal hypoglycemia. Pediatrics 103; 1999
Investigated neuroradiologic changes in the
brains of infants after transient neonatal
hypoglycemia via MRI and U/S
Def’n of hypoglycemia: <2.5 mM WITH symptoms
Treatment included feeds, IV, hydrocortisone
MRI and US at fullterm and at 2m in 18
symptomatic fullterms (6 babies with SGA, 2
infants of diabetic mom) without any other
pathology and 19 term controls
Kinnala et al. Cerebral magnetic resonance
imaging andultrasonography findings after
neonatal hypoglycemia. Pediatrics 103; 1999
Results?
 39% of hypoglycemic infants had abnormalities detected
on MRI  4 showed patchy hyperintensity lesions in
occipital periventricular white matter of the thalamus;
lesions recovered by 2 months with only 1 neurologically
affected
 Controls  10% had caudothalamic cysts
 Relative risk of hypoglycemic child compared with
normoglycemic child to have ay abnormality detected in
the brain was 3.7 (4x more often)
 Developmental assessment at 11 months  94% normal; 1
infant had rightsided hemiplegia ad tremors
Glucose Physiology in a Nutshell!
FETUS:
 Energy as glucose, lactate, FFAs, ketones,
surplus amino acids
 Gluconeogenesis & ketogenesis virtually
absent
 Energy stored at rapid rate (100 cal of
fat/day in 9th month!)
AT DELIVERY:
 Adaptive response  surge in plasma
glucagon & decrease in plasma insulin 
mobilizes glucose & fatty acids from
glycogen & triglyceride depots
Glucose Physiology II….
NEONATE:
 Stores become insufficient so must rely on
gluconeogenesis
 Glucose is main oxidative fuel, but
neonates can oxidize ketone bodies,
lactate & amino acids
 Glucose requirements exceed those of
adults mainly b/c of increased ratio of brain
to body mass
 Low blood glucose values are usually NOT
related to any significant problem but are
20 to normal process of metabolic
adaptation to extrauterine life
Definition of neonatal
hypoglycemia
• The definition of clinically significant
hypoglycemia remains one of the most
confused and contentious issues in
contemporary neonatology.
Cornblath M, Hawdon JM, Williams AF, Aynsley-Green A, WardPlatt MP, Schwartz R, Kalhan SC. Controversies regarding
definition of neonatal hypoglycemia: suggested operational
thresholds.
Pediatrics. 2000 May;105(5):1141-5.
Approaches to defining neonatal
hypoglycemia!
Clinical Manifestations
 Must fulfill Whipple’s Triad
a) Low glucose
b) S&S consistent with hypoglycemia
(eg. Jitteriness, tremors, lethargy, seizures, apnea,
cyanotic spells, hypotonia, difficulty feeding,
hypothermia, coma)
c) Resolution of S&S after restoring glucose
Serum level?
Epidemiological Approach
 Def’n based on statistical definition of glucose values
< or = to 2 SD below the mean in the population of
well full term & LBW infants
“in neonates any value below 40 mg/dL (2.8 mM) be
viewed with suspicion”:
Sperling MA. in Hypoglycemia; Chapter 77,
page 420. Nelson’s Textbook of Paediatrics, 15th ed.
Operational Threshold
• Indication for intervention
 Based on evidence currently available in the literature
Concentration of glucose in the blood or plasma at which
the individual demonstrates a unique response to the
abnormal milieu caused by the inadequate delivery of
glucose to a target organ
Cornblath et al. Controversies regarding definition of neonatal
hypoglycemia: suggested operational thresholds. Pediatrics 105:
153-157, 2000
 Provides large margin of safety by designating the
lower level of glucose that a neonate can safely
tolerate based on physical maturity and influence of
pathology
Proposed Operational Thresholds
1st 24 hours of life:
Healthy preterm*/full term neonate:
a) NO clinical signs: <2.0 mM
b) Abnormal clinical signs: <2.5 mM
Sick, Hypoxic, LBW, Infant of
diabetic mom or premature neonate:
<2.5 mM
* >34 weeks
Proposed Operational Thresholds
>24 hours of life:
2.2  2.8 mM
Others:
TPN: <2.5 mM
Note: Level can be  in asymptomatic breast fed
neonates because of concentrations of ketones
(<1.7 or <2.0 mM  but there is controversy!!)
Operational Thresholds: How to use
them?
 Remember: INDICATION FOR ACTION!
But, what is your goal?
 THERAPEUTIC OBJECTIVE
Raise glucose to > 2.6 mmol/l
IF Recurrent, profound, sick
or symptomatic neonates: > 2.8  3.3
Why is your Therapeutic Objective different
from your Operational Threshold?
 Higher therapeutic goal is chosen to include a
significant margin of safety
 Note: Response to Rx is NOT necessary
Who’s at Risk? What could be the
cause?
At Risk Groups:
A. Increased Insulin
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Intrapartum glucose
Drug Treatment (eg. Propranolol)
Infant of Diabetic Mother
Asphyxia ,SGA
Insulinomas
Beckwidth’s syndrome
Familial or sporadic hyperinsulinemia
Familial or sporadic hyperammonemic
hyperinsulinemia
Severe erythroblastosis fetalis
Panhypopituitarism
At Risk Infants/Causes II…
B. Decreased Stores
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Placental abnormalities
IUGR
Preterms <32 weeks, <1500g
Smaller of discordant twins (especially if discordant by
>25% with wt <2kg)
C. Increased Needs
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Very immature, SGA (high brain:liver ratio)
Severely ill (RDS, Septic)
Brain injury  meningitis, trauma, hemorrhage, hypoxiaischemia (increased brain glucose needs)
Hypothermia
Cyanotic heart disease
Drug withdrawal, CNS irritability
At Risk Infants/Causes III…
D. Inadequate production or substrate delivery
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Delayed/ inadequate feedings
Transient developmental immaturity of critical metabolic
pathways
Deficient brain glucose transporters: posthypoxiaischemia, inherited glucose transporter defects
Galactosemia
Glycogen storage disease
Fructose intolerance
Maple syrup urine disease
Long- or medium-chain acyl-CoA dehydrogenase
deficiency
To name a few!!! Many more ……………………..!!
When do you screen these “at risk”
babies?
FIRST OF ALL in ANY BABY:
If symptomatic: SCREEN IMMEDIATELY
If asymptomatic but AT HIGH RISK including infant
of diabetic mom, septic, premature (<32 wks),
<1500g: Screen at 30-60 min of life
If asymptomatic but AT RISK:
Screen baby at 3-4 hrs of life
ALWAYS CHECK VALUE WITH LAB TEST!!
ONE VALUE IS SUFFICIENT FOR ACTION!
Practical Points for Blood
Glucose Estimation
• Can it be used for neonate? Dextrostix.
• False positive: hematocrit <35%,
contamination with isopropylalcohal.
• False negative: hematocrit >55%.
• Glucose level can fall by 14-18 mg/dl/hr.
• False results if done < 18degree C or >35
degree C.
So……..
you’ve got a low glucose,
Now WHAT DO YOU DO???
All others at risk:
Glucose <2 mM:
CONFIRM in lab, tell senior  FEED:
1) If still <2.0 (FF) or <1.5-1.7 (BF):
• Consider IV D10W 4-6 mg/kg/min
• Supplement BF & Feed q3h
• Recheck in 1 hour
• If <2.0,  IV 2 mg/kg/min
•  1 ml/hr if >2.5 mM
2) If now 2.0-2.5  feed q3h and supp. if BF
Just some tips….
• Frequent boluses of D10W will induce a
INSULIN SURGE and REBOUND
HYPOGLYCEMIA  Try to use a max of 2
boluses of D10W
• Always think about your maintenance fluid.
If at TFI 120cc/kg/day for premie and
100cc/kg/day in term in first 24 hours,
consider switching to D12.5W or D15W.
What can be done to prevent it?
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Early feeding
Supplements by gavage if can’t suck
IV D10W >60 cc/kg/day (if can’t feed)
Prevent cold stress
What if hypoglycemia occurs prolonged,
recurrent or persistent?
Recurrent of Persistent Hypoglycemia:
1) Require infusions of large amts of glucose
(>1216 mg/kg/min) to maintain
normoglycemia
What if hypoglycemia occurs prolonged,
recurrent or persistent?
1) Persisting or recurring beyond the first 7-14
days of life
**Prompt recognition is essential!!
These conditions are associated with severe
disease at substantial risk of developing
severe mental retardation and epilepsy.
These include many conditions stated previously
including: Hormone deficiencies, Hyperinsulinism
syndromes, Defects in carbohydrate, amino acid,
fatty acid metabolism
What tests should you do?
What is your management?
 Assay for insulin, C-peptide, cortisol, growth hormone, Bhydroybutyrate, lactate, free fatty acids, T4, TSH, gas
 Urine for reducing substances, ketones, organic acids
Management includes:
 Glucagon (0.3 mg/kg/dose bolus or infusion 1-2 mg/day);
Add 1 mg to 24 ml of D10W and run at 1 ml/hour through
separate lie
 If resistant to glucagon or unable to wean: problem of
reference (no endocrinal clinic at present in Nepal)
 Consider Diazoxide 8-15 mg/kg/day PO TID-QID,
Hydrocortisone 5 mg/kg/day IV QID or Prednisone 2
mg/kg/day PO
Research Topic for Anyone?
Department? MD Thesis?
• Need long term prospective controlled study to
resolve questions and allow correlation between
plasma glucose, acute changes in neurological
function and outcomes in Nepalese Children.
• Relation of cord blood glucose with blood
glucose during first two/three hours of life.
Great References…
http://www.neonatology.org
Koivisto M, Blaco-Sequeiros M, Krause U. Neonatal symptomatic
hypoglycaemia: a follow-up study of 151 children. Dev Med. Child
Neurol 1972; 14:603-14
Lucas A, Morley R, Cole TJ. Adverse deurodevelopmental outcome of
moderate neonatal hypoglycemia. BMJ 297: 1304-1308, 1988.
Pal DK, Manandhar DS, Rajbhandari S, Land JM, Patel N, de L Costello
AM. Neonatal hypoglycaemia in Nepal 1. Prevalence and risk factors.
Arch Dis Child Fetal Neonatal Ed. 2000 Jan;82(1):F46-51.
Cornblath et al. Controversies regarding definition of neonatal
hypoglycemia: suggested operational thresholds. Pediatrics 105:
153-157, 2000
Conrblath M and Ichord R. Hypoglycemia in the neonate. Seminars in
Perinatology 24: 136-151, 2000
“A man with a watch knows
what time it is. A man with
two watches is never sure”
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