Transient Neonatal Hypoglycemia

Transient Neonatal
Hypoglycemia, Revisited
GABY FALAKHA
PEDIATRICIAN- NEONATOLOGIST

Outline
1. Glucose homeostasis
2. Physiopathology of neonatal hypoglycemia
3. Types of Neonatal Hypoglycemia
4. Definition of Neonatal Hypoglycemia
5. Management
6. Take home message

Neonatal Hypoglycemia
Why is it a problem?
 Neonatal hypoglycemia is a preventable cause of brain injury.
 It is common, affecting 5–15% of all babies1 and approximately half of at-
risk babies2 and is associated with a range of adverse sequelae3,4
 A lot of neonates with normal “Transitional Hypoglycemia” levels are
overtreated
 The definition and the threshold at which treatment would prevent brain
injury, remains controversial
1. Hay WW, et al. Child Health and Human Development. J Pediatr. (2009) 155:612–7. doi: 10.1016/j.jpeds.2009.06.044
2. Harris D, et al. J Pediatr. (2012) 161:787–91. doi: 10.1016/j.jpeds.2012.05.022
3. Boluyt N, et al. Pediatrics. (2006) 117:2231–43. doi: 10.1542/peds. 2005-1919
4. Shah R, et al. Neonatology. (2019) 115:116–26. doi: 10.1159/000492859

Glycolysis
Glucose is broken
down to Pyruvate
Insulin receptor
Insulin
Nucleus
Mitochondria
Glucose
ATP Krebs cycle
1

Glycolysis
Glucose is broken
down to Pyruvate
Insulin receptor
Insulin
Nucleus
Mitochondria
Glucose
ATP
Glycogenogenesis
Storage form of glucose in the cell
Krebs cycle
2
1
Glycogen

Glycolysis
Glucose is broken
down to Pyruvate
If energy is needed
Insulin receptor
Nucleus
Mitochondria
ATP
Glycogenogenesis
Storage form of glucose in the cell
Krebs cycle
Glycogenolysis
If Hypoglycemia
3
2
1
Glycogen
LIVER

Glycolysis
Glucose is broken
down to Pyruvate
If energy is needed
Insulin receptor
Nucleus
Mitochondria
ATP Krebs cycle
Glycogenolysis
If Hypoglycemia
3
2
1
Gluconeogenesis
Formation of glucose from
non-glucidic substrates such
as amino-acids (5%), lactate
(70%) and glycerol (10%)
4
Glycogen
LIVER
2

3 months Term
8 weeks
8 weeks Hepatic glycogen content Term
3.4 mg/g 50 mg/g
Capkova et al. Biol Neonate 1968;13:129-142

Insulin receptor
Insulin
Nucleus
Mitochondria
Glucose
ATP Krebs cycle
Fatty acids
Beta-oxydation
Insulin

Glycemia
Continuous Glucose supply
Fetal glucose concentrations
are 80% of the maternal level
Fetal Liver
Fetal Pancreas
The fetal insulin level is independent of the mother’s level, as insulin does
not cross the placenta, but it is dependent on the fetal blood glucose level
Fetal Life

Glycemia
Fetal Liver
Fetal Pancreas
Insulin is an
Anabolic
Hormone
Insulin:
• Facilitates Glucose uptake by the cells
• Stimulates Glycogenogenesis
• Stimulates incorporation of amino acids into protein
• Stimulates lipogenesis
Continuous Glucose supply
Fetal Life
Fetal glucose concentrations
are 80% of the maternal level

Glycemia ↓
Liver
Pancreas
Intermittent Glucose supply
Glucagon
Intestine
Glycogenolysis
Glucose
Glycogen
After
Birth

Glycemia ↓
Liver
Pancreas
Intermittent Glucose supply
Glucagon
Intestine
Glycogenolysis
Lipids
Adrenal
Gluconeogenesis
Adrenaline, Cortisol
Lipolysis &
Ketogenesis
Ketones
Alanine, Lactate, Glycerol
Glucose
Glycogen
After
Birth
Growth hormone Pituitary

Normal physiology
 During fetal life glucose, lactate and amino acids are the principal sources of energy.
 The fetus receives glucose from the mother achieving fetal plasma glucose
concentrations 70–80% of the maternal level.
 The fetal insulin level is independent of the mother’s level, as insulin does not cross
the placenta, but it is dependent on the fetal blood glucose level.
 During the last trimester of pregnancy when there is rapid growth, energy stores
(particularly glycogen and adipose tissue) are accumulated in preparation for birth.
 It occurs due to the transition from continuous transplacental glucose supply from
the mother in-utero, to an intermittent supply from milk feeds.
Hawdon JM. Postnatal metabolic adaptation and neonatal hypoglycaemia. Paediatrics & Child Health. 2016;26(4):135-9.

Physiological transition beginning immediately after birth
 Endocrine changes
 Plasma insulin levels fall
 Catecholamines and pancreatic glucagon are released
 Essential enzymes for the production of glucose from stores of glycogen
and fat (glycogenolysis and gluconeogenesis), and the production of free
fatty acids (lipolysis) and ketones (ketogenesis) are switched on
 Importantly, the production of these enzymes is inhibited by insulin, so
persistent high insulin levels prevent this normal adaptation

Physiological transition beginning immediately after birth
 Endocrine changes
 Glycogenolysis: production of glucose by the liver when stored glycogen is
broken down to form pyruvate in response to increased adrenaline and glucagon
concentrations and falling insulin levels
 Gluconeogenesis: occurs during the first 8–12 hours of life when glycogen stores
are depleted
 Stimulation of appetite and adaption to fast and feed cycle and promotion of
oxidative fat metabolism using lipid from fat stores and milk feeds
 Delay in the first feed for 3–6 hours after birth results in approximately 10% of
babies not maintaining their plasma glucose levels above 32mg/dl

Euglycemia
1. Substrates
Glycogen
Amino acids
Lactate
Glycerol
Ketones
2. Intact Pathways
Glycolysis
Glycogenolysis
Gluconeogenesis
Glycogenogenesis
Lipolysis
3. Glucose regulating hormones
Insulin
Glucagon
Growth Hormone
Adrenaline
Cortisol

150
140
130
120
110
100
90
80
70
60
50
40
Insulin secretion is
suppressed
Glucagon is secreted
Adrenaline, GH and
Cortisol secreted
Insulin:
• Stimulates Glycolysis & Glycogenogenesis
• Inhibits Gluconeogenesis & Glycogenolysis
• Prevents fatty acids β-oxidation
• Stimulates uptake and incorporation of
amino acids into protein
Glucagon, Cortisol, Adrenaline and GH:
Stimulate Glycogenolysis & Gluconeogenesis
↑Glycemia
↓Glycemia
stimulated
Healthy, >3-day-old neonates and children

150
140
130
120
110
100
90
80
70
60
50
40
suppressed
Glucagon is secreted
Adrenaline, GH and
Cortisol secreted
Insulin:
• Stimulates Glycolysis & Glycogenogenesis
• Inhibits Gluconeogenesis & Glycogenolysis
• Prevents fatty acids β-oxidation
• Stimulates uptake and incorporation of
amino acids into protein
Glucagon, Cortisol, Adrenaline and GH:
Stimulate Glycogenolysis & Gluconeogenesis
↑Glycemia
↓Glycemia
stimulated
Preterm, < 3-day-old neonates

Glucose Insulin release
Last day of gestation,
and pups on postnatal
day P1
Mature islets from
2-week-old and
adult rats
54mg/dl Nearly half of
the maximal response
to 450mg/dl glucose
90mg/dl Only >90mg/dl
450mg/dl 2-fold increase 4- to 5-fold greater
response at
450mg/dl glucose
Yang J, Hammoud B, Li C, et al. Decreased KATP channel activity contributes to the low glucose threshold for insulin secretion of rat neonatal islets.
Endocrinology 2021;162(9):bqab121
The glucose threshold for GSIS is lower in fetal and newborn rats
54
90
180
450

• An increase in the ATP to ADP ratio,
results in the closure of KATP
channels, membrane depolarization
and subsequent opening of voltage-
gated calcium channels (VGCC).
• The resulting increase in
intracellular calcium triggers insulin
granule exocytosis.
Jonathan E. Campbell et al. Nat Rev Mol Cell Biol. 2021 February ; 22(2): 142–158.

PHD: Prolyl hydroxylases
Hif1a: Hypoxia inducible factor
vHL: Von Hippel-Lindau
Yang J, Hammoud B, Li C, et al. Decreased KATP channel activity contributes to the low glucose threshold for insulin secretion of rat neonatal islets.
Endocrinology 2021;162(9):bqab121
• Hypoxia inducible factor HIF1a is
constitutively expressed but rapidly
degraded under normoxia via the von
Hippel-Lindau proteosomal pathway.
• Under hypoxic stress, HIF1a combines
with other transcription factors to
induce expression of various
mediators of the hypoxic response.
Hypoxia inducible pathway and sites of activation

The pathway of KATP channel trafficking from the Golgi to
the plasma membrane surface
• Increased trafficking of KATP channels on
the plasma membrane surface by leptin
or low glucose decreases insulin
secretion.
• In contrast, decreased trafficking in the
PHPT1 knockout mouse model cause
severe neonatal hyperinsulinemic
hypoglycemia
PHPT1: Phosphohistidine phosphatase 1
Park SH, et al. Leptin promotes K(ATP) channel trafficking by AMPK signaling in pancreatic beta-cells. Proc Natl Acad Sci U S A 2013; 110(31):12673–8.
Srivastava S, et al. Regulation of KATP channel trafficking in pancreatic beta-cells by protein histidine phosphorylation. Diabetes 2018;67(5): 849–60.

• Exposure to hypoxia
from E18 to P6 lowers
the glucose threshold
for GSIS in freshly
isolated islets from
newborn rat pups
Data from Yang J, Hammoud B, Ridler A, et al. Postnatal activation of hypoxia pathway disrupts b-cell functional maturation
Hypoxia in the perinatal period causes persistence of fetal
low glucose threshold for insulin release

Insulin in the fetal & neonatal period
 Insulin is a growth hormone in fetal life
 There is a hyper-insulinemic state in all newborns
 There is a low glucose threshold for insulin release (insulin secretion is not
suppressed until very low levels of glucose)
 Hypoxia in the perinatal period causes persistence of fetal low glucose
threshold for insulin release

Harris DL, Weston PJ, Harding JE. Alternative Cerebral Fuels in the First Five Days in Healthy Term Infants: The Glucose in Well Babies
(GLOW) Study. J Pediatr 2021;231:81-86
Plasma glucose and ketone levels in the first 5 days of life
in normal newborns
Shown are median glucose and BOHB levels in 67 mostly breastfed babies followed sequentially for 5 days
• The first phase is the period of hypo-
ketonemic hypoglycemia due to
Transitional Hyper-Insulinism during the
first 24–36 h after birth.
• In breast-fed newborns, this is followed
by a second phase of hyper-ketonemic
hypoglycemia between 48 and 72 h
after birth which then resolves as
plasma glucose rises into the normal
range for older infants and children

Harris DL, Weston PJ, Harding JE. Alternative Cerebral Fuels in the First Five Days in Healthy Term Infants: The Glucose in Well Babies
(GLOW) Study. J Pediatr 2021;231:81-86
• The first phase is the period of hypo-
ketonemic hypoglycemia due to
Transitional Hyper-Insulinism during the
first 24–36 h after birth.
• In breast-fed newborns, this is followed
by a second phase of hyper-ketonemic
hypoglycemia between 48 and 72 h
after birth which then resolves as
plasma glucose rises into the normal
range for older infants and children
Insulin inhibits Lipolysis
and Ketogenesis
in normal newborns

100
90
80
70
60
50
40
Good
Caution
Danger
Neurogenic (neuroendocrine hormone-
mediated) responses
Neuroglycopenic (impaired cognition)
responses

100
90
80
70
60
50
40
Good
Caution
Danger
Neurogenic (neuroendocrine hormone-
mediated) responses
Neuroglycopenic (impaired cognition)
responses
Neurogenic
Hypothermia
Sweating
Pallor
Tachycardia
Poor feeding
Irritability
Jitteriness
Neuroglycopenic
Cyanosis
Apnea
Lethargy
Stupor
High-pitched cry
Seizure
Coma

Hypoglycemia-associated autonomic failure
 Recurrent episodes of insulin-induced hypoglycemia have been shown to
blunt or completely prevent the secretion of counter-regulatory hormones
Cryer PE. Hypoglycemia-associated autonomic failure in diabetes. Am J Physiol Endocrinol Metab. 2001;281(6):E1115–E1121.

Plasma glucose values during the first
week of life in 344 healthy term
newborns
G, Pildes S, Cattamanchi G, Voora S, Lilien D. Plasma glucose values in normal neonates: A new look. The Journal of Pediatrics.
1986;109(1):114-117
Maternal Glucose Concentrations
Fetal Glucose Concentrations
The mean of fetal glucose levels persists
neonatally for the first 48 hours

Glucose Profiles in Healthy Term Infants in the First 5 Days:
The Glucose in Well Babies (GLOW) Study
Glucose Profiles in Healthy Term Infants in the First 5 Days: The Glucose in Well Babies (GLOW) Study. Deborah L. Harris et al. J Pediatr 2020;223:34-41
• A prospective masked observational
study 67 Healthy, term, AGA singletons
had continuous glucose monitoring and
repeated heel-prick plasma glucose
measurements (4 in the first 24 hours
then twice daily) from birth to 120
hours.
• Mean birth weight of 3584 ± 349 g, and
gestational age of 40.1 ± 1.2 weeks

Numbers of infants who experienced low and high plasma and
interstitial glucose concentrations over the first 120 hours after birth
Plasma Glucose concentration
Postnatal age
(in Hours)
Number of
infants
<27
mg/dl
<36
mg/dl
<47
mg/dl
>144
mg/dl
0-4 64 0 5% 19% 0
4-12 62 0 2% 18% 0
12-24 67 0 3% 12% 0
24-48 67 0 3% 13% 0
48-72 67 0 3% 10% 0
72-96 67 0 0% 1% 8%
96-120 67 0 0 0 0

Glucose Profiles in Healthy Term Infants in the First 5 Days:
The Glucose in Well Babies (GLOW) Study
Conclusions:
1. Healthy, term, AGA infants seem to complete their transition at 72 Hours.
2. Many have glucose concentrations below the accepted thresholds for
treatment of hypoglycemia

Early neonatal hypoglycemia in term and late preterm
small for gestational age newborns
 690 SGA neonates
 19.42% SGA neonates developed hypoglycemia (<40mg/dl)
 3.7% neonates had to be transferred to the neonatal ward,
requiring IV glucose.
 97% of hypoglycemic episodes occur during the first 2 h of
life.
 2% neonates had symptomatic hypoglycemia
 Risk Factors : C-section, small head circumference, low 1
minute Apgar score
Early Neonatal Hypoglycemia in Term and Late Preterm Small for Gestational Age Newborns
Lin-Yu Wang, Lin-Yen Wang, Yu-Lin Wang, Chung-Han Ho DOI: https://doi.org/10.1016/j.pedneo.2022.09.021
Hypoglycemia NICU admission Normal

Continuous glucose monitoring
in 102 newborn babies at risk of hypoglycemia
Results:
• Low glucose concentrations (<47mg/dl) were
detected in 32% with blood sampling and in 44%
with continuous monitoring.
• There were 265 episodes of low glucose
concentrations, 81% of which were not detected
with intermittent blood glucose measurement.
• 107 episodes in 34 babies lasted >30 minutes, 73%
of which were not detected with blood glucose
measurement.
Harris Et al.J Pediatr. 2010 Aug;157(2):198-202.e1.

Newborns “at risk” for “hypoglycemia”
Transient neonatal hypoglycemia
1. Preterm birth
2. Small or large for date
3. Infant of diabetic mother
4. Perinatal stress (birth asphyxia,
hypothermia, respiratory
distress, sepsis)
5. Poor feeding
6. Maternal use of beta blockers
Persistent neonatal hypoglycemia
1. Congenital hyperinsulinism
2. Hypopituitarism
3. Glycogen storage disease
4. Disorders of Fatty acid oxidation
defects
5. Other, rare genetic disease
Harris DL, et al. Incidence of neonatal hypoglycemia in babies identified as at risk. J Pediatr 2012;161:787-91.

Babies at risk
Generally, neonatal hypoglycemia is caused by one or more of:
 Increased levels of insulin
 Inadequate glucose supply
 Inadequate body stores (glycogen, fat)
 Decreased levels of counter-regulatory hormones (e.g. growth hormones,
cortisol, adrenergic hormones)
 Disorders of glycogen metabolism (glycogenolysis)
 Disorders of glucose production (gluconeogenesis)
 Congenital anomalies, or mixed causes
Adamkin DH. Neonatal hypoglycemia. Seminars in Fetal and Neonatal Medicine 2017;22(1):36-41.

The incidence of neonatal hypoglycemia in babies
with different combinations of risk factors
J Pediatr 2012;161:787-91
IODM49%
LGA 39% SGA 56%
Preterm 59%
44% 50%
88% 44%
47%
52%

MEASUREMENT OF GLUCOSE
 Whole blood glucose concentrations are up to 10% to 12% lower than
plasma values.
 A higher hematocrit can lead to lower glucose concentrations, as does
marked hyperbilirubinemia.
 Glucometers provide quick results at low cost, are readily available in
neonatal units, user-friendly and require small volumes of blood
 Treatment in a markedly symptomatic infant should not be delayed until
laboratory confirmation of hypoglycemia.
Eustratia M. Hubbard et al. Clin Perinatol 48 (2021) 665–679
Beardsall K. Measurement of glucose levels in the newborn. Early Hum Dev. (2010) 86:263–7.

Definition of Hypoglycemia
0-4 Hours 4-24 Hours
American Academy of Pediatrics < 25 mg/dl < 35 mg/dl
The British Association of Perinatal
Medicine
< 36 mg/dl
World Health Organization < 47 mg/dl
Pediatric Endocrine Society (USA) < 50 mg/dl
(<48 Hours)
< 60 mg/dl
(>48 Hours)
Haute Autorité de Santé (France) <36 (if asymptomatic)
0-48 Hours
<45 (if symptomatic)
> 48 Hours
Adamkin DH. Pediatrics 2011;127:575-9.
British Association of Perinatal Medicine; 2017.
Williams AF. Bull World Health Organ 1997;75:261-90
Thornton PS, J Pediatr 2015;167:238-45.
Protocole National de Diagnostic et de Soins (PNDS)

G, Pildes S, Cattamanchi G, Voora S, Lilien D. Plasma glucose values in normal neonates: A new look. The Journal of Pediatrics.
1986;109(1):114-117
• The PES uses the mean values while
neonatologists use the 5th percentile
value to define Neonatal Hypoglycemia
• PES specialists care for small groups of
babies at very high risk of hypoglycemic
brain damage from rare congenital
disorders
• Neonatologists, are responsible for large
numbers of mostly low-risk newborn
babies.
• An additional concern is the potential
risk of medicolegal suits
Mean
5th %

Should be correlated to:
• Intra Uterine Growth
• Gestational age
• Postnatal age (in hours)
• Concurrent metabolic demands
• Co-morbidities
• Availability of alternative fuels

Hour specific nomogram (adapted from Bhutani et al.)
Analogous to
Should be correlated to:
• Intra Uterine Growth
• Gestational age
• Postnatal age (in hours)
• Concurrent metabolic demands
• Co-morbidities
• Availability of alternative fuels

Operational Threshold
1. A retrospective study of 661 preterm babies (birthweight < 1,850 g), which
reported that a glucose concentration of <47 mg/dl on three or more days was
associated with an increased risk of developmental delay at 18 months’
corrected age1
2. Another study recorded evoked potentials in 17 infants, of whom only five were
newborns2
 None showed flattening of evoked potentials with a glucose concentration of >47
mg/dl, although some with a glucose concentration below this, still had normal
evoked potentials.
 Both studies concluded that a glucose concentration of >47 mg/dl (2.6 mmol/l)
was likely to be safe.
1. Lucas A, et al. Br Med J. (1999) 318:195.
2. Koh TH, et al. Arch Dis Child. (1988) 63:1353–8.

Lower Treatment Threshold for Neonatal Hypoglycemia
Multicenter, Randomized, Noninferiority Trial
689 Newborns
≥ 35 weeks gestation and
at risk for hypoglycemia
Glucose <36mg/dl Glucose <47mg/dl
Mean cognitive score at
18 months
102.9± 0.7 102.2± 0.7
Mean motor score at 18
months
104.6± 0.7 104.9± 0.7
Lower Glucose threshold (36 mg/dl) are noninferior to
traditional threshold (47 mg/dl)
A.A.M.W van Kempen et al. N Engl J Med 2020;382:534-44.

• All infants born in 1998, at the University
hospital of Arkansas
• Had at least 1 recorded glucose concentration
in the first 3 hours of life
• Stratified to 3 glucose levels: < 35, < 40 and
<45mg/dL
• Data was matched with student achievement
test scores in 2008
• Conclusion: Approximately 50% reduction in
the odds of achieving proficiency in literacy
and numeracy at the age of 10 years
Association Between Transient Newborn Hypoglycemia
and Fourth-Grade Achievement Test Proficiency
Kaiser et al. JAMA Pediatr. doi:10.1001/jamapediatrics.2015.1631

Brain damage percentage in Hypoglycemic newborns
50
10
6 5
0
10
20
30
40
50
60
Symptomatic with seizures Symptomatic without
seizures
Asymptomatic Controls
Koivisto et al. Develop. Med. Child Neurol. 1972, 14,603-614

Brain damage percentage in Hypoglycemic newborns
50
10
6 5
0
10
20
30
40
50
60
Symptomatic with seizures Symptomatic without
seizures
Asymptomatic Controls
Koivisto et al. Develop. Med. Child Neurol. 1972, 14,603-614
All symptomatic babies with seizures
had ≥ 2 blood glucose <20mg/dl
None of the babies who had only one blood
glucose < 20mg/dl had brain damage

The three major forms of Neonatal Hypoglycemia, are all
due to Hyperinsulinism
Adapted from Stanley CA, Thornton PS and De Leon DD (2023) New approaches to screening and management of neonatal hypoglycemia based on
improved understanding of the molecular mechanism of hypoglycemia. Front. Pediatr. 11:1071206.
1. Transitional neonatal
hyperinsulinism
2. Perinatal stress-induced
hyperinsulinism in high-risk newborns
3. Genetic forms of
hyperinsulinism
Healthy Full-term Newborns High-risk infants: IODM, SGA, LGA, Preterm,
Perinatal asphyxia
Congenital Hyperinsulinism
Majority 10% 1/10,000-1/40,000
Transient, < 72 hours Prolonged, few days to few weeks Persistent, lifelong
Decreased trafficking of
KATP-channels to the beta-cell
plasma membrane
Exaggeration of the normal low fetal glucose
threshold for insulin release due to more severe
and prolonged exposure to perinatal hypoxemia
Permanent genetic defects in
various steps controlling beta-cell
insulin release
Feeding & Observation Screening/Management Dx before discharge
No brain damage Possible subtle cognitive deficiencies Severe brain damage

1. Transitional neonatal hyperinsulinism
Healthy Full-term Newborns
Incidence Majority
Duration Transient, < 72 hours
Mechanism Low glucose threshold for Insulin secretions because of
a decreased trafficking of KATP-channels to the beta-cell
plasma membrane
Management Feeding & Observation
Sequalae None

2. Perinatal stress-induced hyperinsulinism in high-risk
newborns
High-risk infants: IODM, SGA, LGA, Preterm, Perinatal
asphyxia
Incidence 10%
Duration Prolonged, few days to few weeks
Mechanism Exaggeration of the normal low fetal glucose threshold
for insulin release due to more severe and prolonged
exposure to perinatal hypoxemia
Management Screening/Management
Sequalae Possible subtle cognitive deficiencies

Adapted from Harris DL, Weston PJ, Harding JE. Alternative Cerebral Fuels in the First Five Days in Healthy Term Infants: The Glucose in
Well Babies (GLOW) Study. J Pediatr 2021;231:81-86
Term, healthy newborns
“At risk” newborns
in normal newborns

3. Genetic forms of hyperinsulinism
Congenital Hyperinsulinism
Incidence 1/10,000-1/40,000
Duration Persistent, lifelong
Mechanism Permanent genetic defects in various steps controlling
beta-cell insulin release
Management Dx before discharge and lifelong treatment(± surgical)
Sequalae Severe brain damage

Hx & PE in Persistent Hypoglycemia
 History should include the episode’s timing and its relationship to food,
birth weight, gestational age, and family history.
 Physical examination should include looking for evidence of
hypopituitarism (micropenis or cleft lip or palate, short stature),
glycogenosis (hepatomegaly), adrenal insufficiency (recurrent abdominal
pain, hyperpigmentation, anorexia, weight loss), or Beckwith-Wiedemann
syndrome (omphalocele, hemihypertrophy, macroglossia). Congenital
adrenal hyperplasia (Ambiguous genitalia). Metabolic disorder (Perinatal
stress Shock, acidosis, seizures)

Screening for Hypoglycemia
 The purpose of screening :
1. Identify infants with pathological forms of hypoglycemia
2. Prevent hypoglycemic brain injury.

David H. Adamkin, MD and COMMITTEE ON FETUS AND NEWBORN Pediatrics 2011;127:575–579

Patient Category Age Serum Glucose Level
Symptomatic patients <48 Hours <50 mg/dl (2.8 mmol/L)
> 48 Hours <60 mg/dl (3.3 mmol/L
Asymptomatic patients < 4 Hours <25 mg/dl (1.4 mmol/L)
4 to <24 Hours <35 mg/dl (1.9 mmol/L)
24 to < 48 Hours <50 mg/dl (2,8 mmol/L
≥ 48 Hours <60 mg/dl (3.3 mmol/L)
Suspected primary Hypoglycemia disorder Any < 70 mg/dl (3.9mmol/L)
Target Range During Treatment
Lower Limit Upper Limit
Same as thresholds above 90 to 100 mg/dL (5 to 5.5 mmol/L)
Threshold and target blood glucose levels used for management of
neonatal hypoglycemia in term and late preterm infants born at
≥35 weeks gestation
© 2023 UpToDate

Oral dextrose gel
 Oral dextrose gel 200 mg/kg (0.5 ml/kg of 40% dextrose), in combination
with feeding, is increasingly recommended as a first-line treatment for
asymptomatic neonatal hypoglycemia
 A randomized trial of 237 late preterm and term babies at risk of neonatal
hypoglycemia (<47 mg/dl)
 Compared with feeding alone, 40% oral dextrose gel plus feeding resulted in
fewer treatment failures (hypoglycemia after two treatment attempts),
reduced admission to NICU for hypoglycemia
Harris D, Weston PJ, Signal M, Chase JG, Harding JE. Dextrose gel for neonatal hypoglycaemia (the Sugar Babies Study): a randomised,
double-blind, placebo-controlled trial. Lancet. (2013) 382:2077–83.

Thornton PS, Stanley CA, De Leon DD, et al. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent
Hypoglycemia in Neonates, Infants, and Children
Hypoglycemia
HCO3, BOHB, Lactate, FFA
No Acidemia Acidemia
BOHB ↓
FFA ↓
BOHB ↓
FFA ↑
Transient neonatal Hypoglycemia
Perinatal stress Hyperinsulinism
Genetic Hyperinsulinism
Fatty acid oxidation defects
Lactate ↑ BOHB ↑
Gluconeogenesis defects Ketotic Hypoglycemia
Glycogenosis
GH deficiency
Cortisol deficiency
“Skip a feed test”

Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children
Hypoglycemia
HCO3, BOHB, Lactate, FFA
No Acidemia Acidemia
BOHB ↓
FFA ↓
BOHB ↓
FFA ↑
Transient neonatal Hypoglycemia
Perinatal stress Hyperinsulinism
Genetic Hyperinsulinism
Fatty acid oxidation defects
Lactate ↑ BOHB ↑
Gluconeogenesis defects Ketotic Hypoglycemia
Glycogenosis
GH deficiency
Cortisol deficiency
Hypoketotic
Hypoglycemia
99.9%

Inborn errors of Metabolism
 Glycogen storage diseases: These are a group of genetic disorders in which
the body is unable to store or release glycogen properly, leading to low
blood sugar levels. Examples include glycogen storage disease type I and III.
 Disorders of fatty acid oxidation: These are a group of rare genetic disorders
in which the body is unable to break down fats for energy. Examples include
medium-chain acyl-CoA dehydrogenase deficiency and carnitine palmitoyltransferase deficiency.
 Disorders of gluconeogenesis: Gluconeogenesis is the process by which the
body produces glucose from non-carbohydrate sources. Examples include fructose-
1,6-bisphosphatase deficiency and pyruvate carboxylase deficiency.
American Academy of Pediatrics Committee on Fetus and Newborn. (2011). Clinical report: Postnatal glucose homeostasis in
late-preterm and term infants. Pediatrics, 127(3), 575-579.
Saudubray, J.-M., Garcia-Cazorla, A., & de Lonlay, P. (2006). Inborn errors of metabolism overview. In P. Caballero, L. Allen, &
L. J. P. Dary (Eds.), Encyclopedia of Food Sciences and Nutrition (pp. 3489-3496)

Inborn errors of Metabolism
 Congenital hyperinsulinism: This is a rare genetic disorder in which the
pancreas produces too much insulin.
 Organic acidemias: Rare genetic disorders in which the body is unable to
break down certain amino acids and fatty acids. Some of these disorders
can also cause hypoglycemia. Examples include propionic acidemia and methylmalonic
acidemia
American Academy of Pediatrics Committee on Fetus and Newborn. (2011). Clinical report: Postnatal glucose homeostasis in
late-preterm and term infants. Pediatrics, 127(3), 575-579.
Saudubray, J.-M., Garcia-Cazorla, A., & de Lonlay, P. (2006). Inborn errors of metabolism overview. In P. Caballero, L. Allen, &
L. J. P. Dary (Eds.), Encyclopedia of Food Sciences and Nutrition (pp. 3489-3496)

Srinivasan G, Pildes RS, Cattamanchi G, Voora S, Lillen LD. Plasma glucose values in normal neonates: a new look. J Pediatr 1986;109:114e7.
What is the purpose of the transient neonatal Hypoglycemia?
Why all mammals have transient hypoglycemia in the first days of life?
 Adaptation from continuous to intermittent glucose supply?
 Stimulate appetite for feed-fast cycles?
 Promote Gluconeogenesis?
 A positive adaptation for the fetus that ensures secretion of adequate
insulin secretion to maintain growth?

Take home message
1. Anticipate Hypoglycemia in “at risk” newborns in the first hour of life
2. Screen “at risk” newborns 30 minutes after feeding them, in the first 2 hours
3. Symptomatic newborns <40mg/dl and asymptomatic ones with a glucose level
<25mg/dl (after first feed) should receive IV Dextrose
4. If after 4 hours of life Glucose is <35 mg/dl, give IV Dextrose
5. Asymptomatic infants with blood glucose levels of 36-45mg/dl should receive
enteral supplementation (D10%, Dextrose gel 40%)
6. Infants with hypoketotic hypoglycemia persisting beyond the first 72 hours,
should be investigated.

Transient Neonatal Hypoglycemia

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Transient Neonatal Hypoglycemia