Neonatal hypoglycaemia

Mirjam van Weissenbruch

 Neonatal hypoglycaemia

o Definitions en physiology

o Analysing the problem

o Differential diagnose
o Risk factors
o Diagnostics

o Treatment
o Prevention
o Direct treatment
o Short- and Long-term effects
 Glucose metabolism

Definitions and physiology

 Glucose
o Glucose is the most important substrate of energy metabolism in
cells

o Other energy suppliers: free fatty acids, ketone bodies

 Definitions

• Glycogenesis: is the process of glycogen synthesis

from glucose

• Glycogenolysis: is the process of glycogen breakdown

and converting into glucose
 definitions
• Glycolysis: is the metabolic pathway that converts
glucose into pyruvate. Pyruvate can be converted into
lactate or acetyl co-A.

• Gluconeogenesis: aminoacids, glycerol and lactate are

converted into glucose.
The physiology
During pregnancy
 During pregnancy

Fetal glucose metabolism

o Foetus does not produce glucose

o Maternal glucose is the only source of fetal glucose

o Fetal bloodglucose is 60-70% maternal serum glucose

range 72-108 mg/dl = 4-6 mmol/l)
 During pregnancy
GLUT 1

Glucose Glucose
Insulin

Insulin
glucagon

glucagon Amino acids

Amino acids

FFA Ketones

Mother Fetus
Ketones
The physiology
After birth
 After birth

Stop maternal glucose supply

Blood glucose nadir

(1-2 hours after birth)
Temporal patterns of cord plasma glucose and
neonatal plasma glucose (NG) concentrations

Metzger B E et al. Pediatrics 2010;126:e1545-e1552

 Healthy term newborn
o Glucose concentration quickly decline in the first 1-2 hours
after birth (P10: 32,5 mg/dl (=1,8 mmol/l))

o Mostly asymptomatic, recovers spontaneously

= ‘normal’ adaptation to the postnatal period

o Alternative energy suppliers e.g. ketones by lipolysis

 Glucose metabolism
after birth
Stop maternal glucose supply

Increase in glucagon, catecholamines, GH

Decrease in insulin

Glycogenolysis (hepatogen glycogen)

Lipolysis (fatty acids, ketones)
Gluconeogenesis (amino acids, glycerol, lactate)

Normal blood glucose

 Healthy term newborn

Continuous supply of nutriënts

Intermittently feeding / fasting

Adaptation metabolism:

Balance in supply and consumption

 Regulation of glucose metabolism

Shortly after feeding:

Increase in glucose  storage in glycogen in the liver and in fat (by insulin)

Between feeding and during starvation:

Glucose deficiency  1. Glucose from the liver to the brain cells


Other body cells shift from using glucose as a primary fuel source, to
fatty acids (by lipolysis)
 Regulation of glucose metabolism
In general:

Hypoglycaemia  glucose and fatty acid combustion except for the brain cells!

Term neonate relatively large CNS, uses preferably glucose as fuel source

Quantitatively: limit of these processes are reached quickly if there is

insufficient glucose supply via glucogenolysis / gluconeogenesis
(e.g. premature / SGA newborn)

Qualitatively : lactate and ketones are alternative by CNS

 Fasting
Proteolysis Glucose Lipolysis
Production
FFA
Glycogenolysis
Amino-
Glycerol
acids

Gluconeogenesis

Ketones

Glucose
 Healthy term newborn
10.0
-2 SD
9.0 -1,3 SD
serum glucose (mmol/l)

0 SD
8.0 +1,3 SD
+2 SD
7.0 2,2 mmol/l
2,6 mmol/l
6.0

5.0

4.0

3.0

2.0

1.0

0.0
0 6 12 18 24 30 36 42 48

postnatal hours
Hypoglycaemia
analysing the problem
 Definition of hypoglycaemia

o Blood glucose concentration < 45 mg/dl (=2,6 mmol/l)

(Ainsley Green 1991)

o In all circumstances and for all categories newborns,

infants and children

o Intervention level = ???

o Depends also on the method of glucose determination!

 Pathophysiology hypoglycaemia
disbalance between glucose supply and consumption
Two main causes that
could lead to
hypoglycaemia
 Main causes of hypoglycaemia

o Reduced production of glucose

o Increased consumption of glucose

 How to approach the problem
In practice:

o Transient neonatal hypoglycaemia (<72 hrs

pn)
o reduced glucose production
o increased glucose consumption

o Persistent/recurrent neonatal hypoglycaemia

o reduced glucose production
 Transient hypoglycaemia
o Insufficient glycogen reserve; o Excessive metabolism of glucose
immature enzyms involved in glucose – Polycythemia
homeostasis; disproportionate high
insulin concentration – Sepsis
– Preterm birth – Hypothermia
– IUGR – Congenital heart disease
– Perinatal asphyxia – Perinatal asphyxia
o Maternal or neonatal ß adrenergic
blocker
o Excessive insulin secretion
– DM mother
– LGA
– Beckwith-Wiedeman
Increased glucose
Reduced glucose production
consumption
 Persistent/ recurrent
o Insufficient glucose production;
Defects in glucose consumption;
Defects in alternative energy
production
– Glycogen storage disease
– Respiratory chain defects
– Fatty acid metabolism disorder
o Galactosemia
Reduced glucose production
o Imbalans between insulin; growth
hormone and cortisol
– Glucagon deficiency
– Cortisol deficiency
• primary
• secundary
o Hyperinsulinism
– persistent hypoglycaemic
hyperinsulinaemia of infancy
(PHHI)
Increased glucose consumption
 Clinical presentation
Often symptomless
(in the acute phase and during short-term hypoglycaemia)
Non specific symptoms
o Neuroglycopenic symptoms:
Apnea, hypotonia, jittering, lethargia, somnolence, abnormal cry, feeding
intolerance, convulsions, coma
o Autonome (sympaticomimetic) symptoms:
pale, transpire, tremor, restless, tachycardia, hypothermia, tachypnea
(in general not prominent in a neonate)
o Macrosomia + ...
o Midline defects, micropenis, icterus dd panhypopituitarism
o Etc etc
 Hypoglycaemia

how to approach the problem?

 How to approach the problem
In practice:

o Healthy term newborn with a normal birth weight

blood glucose is not determined

o In a term newborn with symptoms of hypoglycaemia,

measurements of the bloodglucose concentration is
indicated
 High risk patients

Prevention and treatment

 High risk newborns
o Mother with Diabetes Mellitus or diabetes gravidarum
o Maternal treated with a β-adrenergic agonist or antagonist
o IUGR (<P3 of <2500 grams)
o LGA (>P97 of 4250 grams)
o Premature newborn
o Polycythemia
o Asphyxia
o Persistent feeding intolerance
o “Sick newborn”
 screening

o Risk patients

o Patients with symptoms that might be appropriate for

hypoglycaemia
 Three different causes to discuss
1. Macrosomia due to pregnancy induced diabetes
2. IUGR due to placenta insufficiency
3. Prematurity
http://topibuzz.com/article-71604/voici-les-15-bebes-les-plus-gros-du-monde
 Newborn of a diabetic mother
High maternal glucose during pregnancy

Fetus
•Stimulation of fetal insulin secretion and β-cel hyperplasia
•Macrosomia (fat mass > lean mass)

Early neonatal phase

•hyperinsulinism
•catecholamin response hypoglycaemia
•ketogenic response to fasting urine ketones --
 Newborn after IUGR
Placenta dysfunction during pregnancy

Fetus
o glycogen and fat reserves are absent or diminished

o Relative insulin deficiency

o Cord blood: lower glucose and insulin levels and higher

insulin sensitivity compared to appropriate for
 Newborn after IUGR
Early neonatal phase
o Energy need by the brain
hypoglycaemia
o Risk for hypoxia and polycythemia urine ketones +

o Lipolysis and ketogenic response

 Premature newborns

Fetus

o Glycogen and fat reserves are reduced or absent

(they miss the third trimester in utero)

o High brain - body ratio

o Immature enzym systems

 Premature newborn

Early neonatal
phase
Premature newborn

A Lucas 1978
Premature newborn

A Lucas 1978
prematurity
o Preterms:
postponement of giving
normal enteral feeding

o By giving parenteral feeding

(and so also glucose): no stimulation
of incretins

o As soon as oral feeding is increased an improvement in

glucose metabolism is observed.
 Prevention in high risk patients
Start early oral feeding (mothers milk
induces a quicker postnatal
metabolic adaptation compared to
formula)
– Frequent feeding (8x or more
unless...)
– Extra feeding besides
breastfeeding
If oral feeding is insufficient or
impossible start intraveneus glucose
minimal 4-6 mg/kg/min
o min. 4 mg/kg/min for term
newborn
o min. 6 mg/kg/min for
premature newborn
 How to monitor blood glucose
o Blood glucose directly after birth, and before feeding
(1, 4, 7 hours after birth) or in case of hypoglycaemia symptoms

o Depending on the results within 1 – 1,5 hours after intervention

o If needed please repeat (minimal 2

subsequent normal glucose levels (60 mg/l)
 Treatment
Normal need: 2 mg/kg/min =
o Nutrition: 40 ml/kg/day
o Glucose 10%: 30 ml/kg/day
o min. 4 mg/kg/min : term newborn
o min. 6 mg/kg/min : premature newborn

Hypoglycaemia

Increase glucose-intake with 1-2 mg/kg/min,

preferably enteral,
 normal glucose intake

o Minimal glucose intake 4-6 mg/kg/min

o normal glucose intake 6 – 12 mg/kg/min

o Maximal glucose intake 12-14 mg/kg/min

If there is still hypoglycaemia:

Further investigation is needed!!
 Calculate Glucose intake

• Term newborn, 3.5 kg

• Day 3: 7 x 30 ml MM/formula Nutrilon 1 = 210 ml

• 100 ml contains 7.5 gram carbohydrates  15.75 grams

• Intake carbohydrates: 3.1 mg/kg/min

 Calculate Glucose intake
term SGA newborn 37+2 weeks and GG 2 kg

o Glucose 10% solution = 10 grams/ 100 ml

o To administer 4 mg/kg/min for 24 hours

o Per day 4 x 2 x1440 mg = 11.520 mg = 11,52 gram

o 11,52/10 x 100 = 115,2 ml per day

o 115,2 ml: 24 = 4,8 ml/hr

Treatment

Lilien J Pediatr 1980

Diagnostics
&
pitfalls
 Glucose concentration assay
o Lab: plasma assay
o Bedside: whole blood: 15% lower than plasma value
Sometimes bedside a plasma value is calculated!

(Pre-)analytic pitfalls:
o Sampling-technique: warm the feet, let alcohol dry, wipe off the first drop

o Transport: delay >>> glycolysis by erytrocytes

o Prevent Glycolysis: (fluoride), ice, get rid of proteins, no delay

o High hematocrit and bilirubin can disturb the bedside assay

Short- and longterm
consequenses
 Short- and long term consequences
Acute consequences:
Neurocognitive defects that occur during hypoglycaemia i.e.
A reduced auditive and sensoric evoked potentials

Long term consequences:

reduced growth in head circumference, lower IQ,
abnormalities in specific brain regions (MRI)
 In summary
o The lower limits of glucose levels to determine
hypoglycaemia is for everyone the same.

o Neonates are at risk for neurologic damage.

Fast diagnostics and prevention are needed!

o In case of extreme and/or persistent hypoglycaemia

despite high glucose intake further investigation into
endocrine and metabolic disorders is indicated
 Conclusion
o Glucose is the most important substrate of energy metabolism in cells

o Lack of glucose can induce irreversible brain damage

o Glucose depends on the intake especially the newborn risk groups

o Hypoglycaemia is often asymptomatic

o Glucose controls especially in newborn risk groups are therefore

indicated!
Thank you for your attention