1. Neonatal Hypoglycemia
Alaa Al Nofal, M.D
Assistant Professor of Pediatrics Pediatric Endocrinology University of South Dakota – Sanford School of Medicine

3. Objectives Transitional Neonatal Hypoglycemia
Prolonged and Permanent Hypoglycemia
Causes of Permanent Hypoglycemia
Genetics Causes of Hyperinsulinemic Hypoglycemia
Other Causes of Hypoglycemia
Diazoxide

4. What is The Definition of Hypoglycemia in a Full Term Neonate <48h Old?
1. Plasma glucose concentration less than 40 mg/dl 2. Capillary glucose concentration less than 35 mg/dl 3. Plasma glucose less than 47 mg/dl 4. Plasma glucose less than 60 mg/dl 5. Symptomatic neonate with glucose level less than 60 mg/dl 6. All/none of the above

5. Koh et al, Arch Dis Child 1988
Cornblath et al, Pediatrics 1990

6. WHO, hypoglycemia of the newborn 1997
Duvanel et al, JPeds 1999
Cornblath et al, Pediatrics 2000

7. Hay, JPeds 2009
Sweet et al, J pediatrics pharmacol ther. 2013
Rozance, Curr Opin Endocrinol Diabes Obes 2015

8. Al Nofal, SDPA conference 2018

9. Definition of Hypoglycemia in neonates
No consensus exists as to the optimal definition of hypoglycemia in infants and children
Some authors have suggested that the definition of hypoglycemia should be a blood glucose concentration of <40 mg/dL
Other investigators have suggested an even higher value of <47 mg/dL
Few other authors suggested raising the lower limit of normal to > 60 mg/dl as there is no evidence to prove that the newborn has a unique physiologic adaptation to low blood glucose levels
Harris et al JPeds 2012
Cornblath et al Pediatrics 2000
Cole et al J Perinatol 1994
Sweet et al, J pediatrics pharmacol ther. 2013

11. It is known that plasma glucose concentration is lower in the first 1-3 days of life in normal newborn infants than at later age

12. Plasma glucose was checked fasting at 3-6 hour of age
Mean glucose level in term AGA infants was found to be 54 mg/dl – 126 newborn
Pediatrics 1971

13. But why?

14. It All Starts in The Womb

15. Basics of Fetal Glucose Metabolism
Fetal fuel metabolism is based primarily on
oxidation of glucose
The fetus depends entirely on maternal supply and placental transfer of glucose
There is no fetal glucose production under normal conditions
In most cases, gluconeogenesis appears only after birth
The fetal brain is exposed to circulating glucose concentrations only slightly below those of maternal plasma
~9 mg/dl lower than mother’s glucose
- with normal maternal glucose concentrations of mg/dL ( mmol/L), the mean fetal-maternal plasma glucose difference at term is only 9 mg/dL (0.5 mmol/L).
Stanley, Jpeds 2015
Hay Jpeds 2009

16. Basics of Fetal Glucose Metabolism
Fetal insulin secretion is responsive to fetal plasma glucose concentrations
Fetal glucose concentrations are determined primarily by maternal glucose concentration
Fetal insulin primarily functions to regulate growth
Continuous fetal secretion of insulin would be important to maintain fetal growth
- with normal maternal glucose concentrations of mg/dL ( mmol/L), the mean fetal-maternal plasma glucose difference at term is only 9 mg/dL (0.5 mmol/L).
Stanley, Jpeds 2015
Hay Jpeds 2009

17. Basics of Fetal Glucose Metabolism
Pregnant women produce higher amount of ketones.
The generation of high plasma ketone levels would provide the fetus with an alternative fuel to protect the brain when plasma glucose is low
Making it unnecessary for the fetus to switch off insulin secretion and thereby avoid limiting growth
Stanley, Jpeds 2015

18. Transitional Neonatal Hypoglycemia
In normal newborns, the mean plasma glucose drops immediately after birth
This is likely due to mild and transient form of hyperinsulinemia
The mean plasma glucose for suppression of insulin secretion is mg/dl shortly after birth
This is ~80-85 mg/dl in older infants, children, and adults.
Thornton, Jpeds 2015

19. Transitional Neonatal Hypoglycemia
As the glucose-stimulated insulin secretion mechanism matures, mean plasma glucose concentration in normal newborns increase.
It is similar to those of infants and children by 72h of life
The standard for normal neonates must never be extrapolated beyond 2-3 days of life
If possible, delay diagnostic evaluation for persistent hypoglycemia until 2-3 days of life
Thornton, Jpeds 2015

20. Basics of Fetal Glucose Metabolism
Fetus needs glucose from the mother
Fetus needs insulin to grow
Continuous fetal secretion of insulin would be important to maintain fetal growth
Fetus’ glucose level is ~9 mg/dl lower than mother’s
- with normal maternal glucose concentrations of mg/dL ( mmol/L), the mean fetal-maternal plasma glucose difference at term is only 9 mg/dL (0.5 mmol/L).
Fetus has lower glucose threshold to turn off insulin secretion
Stanley, Jpeds 2015
Hay Jpeds 2009

21. The mean plasma glucose at 8 hours of fasting after birth was 57+/-12 mg/dl
Stanely et al Pediatrics 1979

22. The mean plasma glucose in normal newborn infants who fasted 24h after birth was 57-69 mg/dl.
Murdina et al Jpeds 1954

23. Hypoglycemia After 2 Days of Life
After the first 24h of life, PG concentration does not differ at great extent with age
Mean PG in normal neonates after ~2 days of life is ( mg/dl)
Infants and children <4 years of age have limited fasting tolerance.
Thornton, Jpeds 2015

24. Etiology of neonatal hypoglycemia
Transient neonatal hypoglycemia
Day 1 of life: developmental immaturity of fasting adaptation
First 2 days of life: transient hypoglycemia due to maternal factors
- Maternal diabetes
- Intravenous glucose administration during labor and delivery
- Medications: oral hypoglycemics, terbutaline, propranolol

25. Etiology of neonatal hypoglycemia
2. Prolonged neonatal hypoglycemia
Perinatal stress-induced hyperinsulinism (low birth weight, birth asphyxia, maternal toxemia or pre-eclampsia, prematurity)
Beckwith–Wiedemann syndrome/Overgrowth syndromes
Hypopituitarism

26. Etiology of neonatal hypoglycemia
3. Permanent neonatal hypoglycemia
Congenital hyperinsulinism
- ATP-sensitive potassium channel hyperinsulinism
- Glutamate dehydrogenase hyperinsulinism
- Glucokinase hyperinsulinism
- Short-chain 3-hydroxyacyl-CoA dehydrogenase hyperinsulinism
- Congenital disorders of glycosylation
Counter-regulatory hormone deficiency
- Hypopituitarism
- Adrenal insufficiency
Gluconeogenesis or glycogenolysis enzyme defects
Fatty acid oxidation disorders

27. Workup for Neonatal Hypoglycemia
Thorough History and Chart Review
Gestational age
Birth Weight
Maternal History
Family History
Feeding History

28. Workup for Neonatal Hypoglycemia
Physical Exam
Macrosomia
Signs of hypopituitarism (cleft palate, micropenis)
Hepatomegaly
Signs of Adrenal Insufficiency (hyperpigmentation)
Signs of Beckwith-Wiedemann syndrome (omphalocele, hemihypertrophy, macroglossia)

29. Workup for Neonatal Hypoglycemia
Laboratory Evaluation (critical sample)
Newborn screen
Confirmatory plasma glucose
HCo3
BOHB
Lactate
FFA

30. Workup for Neonatal Hypoglycemia
BOHB, HCO3, Lactate, FFA
Adedmia
Prolonged fasting
GSD
GHD
Adrenal insufficiency
Gluconeogenesis defect
Elevated Lactate
Elevated BOHB

31. Workup for Neonatal Hypoglycemia
BOHB, HCO3, Lactate, FFA
No Adedmia
Hyperinsulinism
Hypopituitarism
Perinatal stress
Low BOHB
Low FFA
Low BOHB
Elevated FFA
FA oxidation defects

32. Hormonal Causes of Neonatal Hypoglycemia
Hyperinsulinism
Adrenal Insufficiency
Growth Hormone Deficiency

33. Congenital Hyperinsulinemia

34. Insulin secretion process
Glucose
SUR1
Kir6.2 K+ GK
VDCC
↑ATP/ADP
Ca++
GLUT2
Krebs cycle
Leucin
ADP
Insulin +
a-ketoglutarate
GDH
Glutamate
Amino Acids

35. ATP-sensitive potassium channel congenital hyperinsulinism
What is the most common form of congenital hyperinsulinemic hypoglycemia?
ATP-sensitive potassium channel congenital hyperinsulinism

36. Genetic forms of Congenital Hyperinsulinemic Hypoglycemia “CHI”
Mutations in at least nine genes have been found to cause congenital hyperinsulinism. Most common are:
The sulfonylurea receptor 1 (SUR-1, encoded by ABCC8- Chromosome 11)
Kir6.2 (encoded by KCNJ11- Chromosome 11)
Glutamate dehydrogenase (GDH; encoded by GLUD-1- Chromosome 10)
Glucokinase (encoded by GCK- Chromosome 7)
ABCC8 (ATP-Binding cassette, subfamily C, member 8)
KCNJ11 (Potassium inward rectifying channel, subfamily J, member 11)

37. ATP-sensitive potassium channel congenital hyperinsulinism
Glucose
SUR1
Kir6.2 K+ GK
VDCC
↑ATP/ADP
GLUT2
Insulin
Amino Acids

38. ATP-sensitive potassium channel congenital hyperinsulinism
The most common and severe form of CHI
More than 100 mutations of ABCC8 and 20 mutations of KCNJ11 have been found
Most reported mutations of ABCC8 and KCNJ11 are recessive; however, a few dominantly expressed mutations of ABCC8 and one of KCNJ11 have been reported
The dominant defects retain responsiveness to diazoxide and tend to be milder

39. ATP-sensitive potassium channel congenital hyperinsulinism
Two histologic forms present:
- Focal
- Diffuse
Large for gestational age
Neonatal onset hypoglycemia
Unresponsive to diazoxide (usually)
Usually require pancreatectomy to control hypoglycemia.

40. Insulin secretion process
SUR1
Kir6.2 K+ GK
VDCC
Glucose
↑ATP/ADP
Ca++
GLUT2
Krebs cycle
Leucin
ADP
Insulin +
a-ketoglutarate -
GDH
GTP
Glutamate
Amino Acids

41. Glutamate dehydrogenase hyperinsulinism
a-ketoglutarate
+ NH3
GDH
Glutamate
Liver cell

42. Glutamate dehydrogenase hyperinsulinism
Normal glucose-stimulated insulin secretion.
Protein induced hypoglycemia
Fasting hypoglycemia

43. Glutamate dehydrogenase hyperinsulinism
The second-most-common form of CHI
Also known as the hyperinsulinism and hyperammonemia syndrome

44. Glutamate dehydrogenase hyperinsulinism
Normal birth weight
Hypoglycemia does not often manifest until later in infancy
Recurrent episodes of fasting and postprandial hypoglycemia associated with persistent asymptomatic elevation of plasma ammonia levels
Patients respond well to diazoxide
Patients are instructed to avoid pure protein meals and to eat carbohydrates before protein

45. Glucokinase congenital hyperinsulinism
Glucose
SUR1
Kir6.2 K+ GK
VDCC
↑ATP/ADP
Ca++
GLUT2
Insulin
Amino Acids

46. Glucokinase congenital hyperinsulinism
GK is expressed exclusively in the liver and pancreas
Consider the B-Cell “glucosensor”
Activating mutations result in increased affinity of glucokinase for glucose and inappropriate secretion of insulin (Lower threshold for insulin secretion)
Diazoxide is usually effective

48. OTHER FORMS OF HYPERINSULINISM IN NEONATES
Perinatal stress-induced hyperinsulinism
Birth asphyxia, maternal toxemia, prematurity, intrauterine growth retardation
Continuous feeding might be needed to maintain blood glucose
Usually resolve in 3-4 months

49. OTHER FORMS OF HYPERINSULINISM IN NEONATES
Infant of the diabetic mother
Infant is exposed to hyperglycemia in utero
Fetus up regulates insulin secretion macrosomia
Glucagon deficiency may contribute to hypoglycemia in infant of a diabetic mother
Hypoglycemia generally resolves within 2 days
Responds to diazoxide, but generally not needed
Usually treated with intravenous dextrose

50. OTHER FORMS OF HYPERINSULINISM IN NEONATES
Beckwith–Wiedemann syndrome
Characterized by somatic overgrowth, macroglossia, hemihypertrophy and transverse creases of the ear lobes, hypoglycemia, and predisposition to childhood tumors
Hypoglycemia occurs in up to 50% of patients with BWS
Diazoxide should be attempted

51. Diazoxide
Suppresses insulin secretion by maintaining the KATP channel in the open position
Dose 5-15 mg/kg/day orally divided into 2-3 doses
Response is evident in 48 hours
Side effects are
1. Primarily cosmetic
- Hypertrichosis
- Coarsening of the face
2. DKA
3. Fluid retention- particularly in preterm infants
4. Rarely leukopenia and thrombocytopenia

52. Other Treatment Options
Therapy
Dosage
Side effect
Diazoxide
5-15 mg/kg/day PO divided Q8
Fluid retention
Hypertrichosis
Hyperglycemia
Coarse facial features
Leukopenia
Octreotide
5-40 mcg/kg/day SQ divided Q4-6
Tolerance
Abdominal distention
Steatorrhea
Suppression of other hormones
Calcium Channel blockers
Nifedipine mg/kg/day PO divided Q8
Hypotension
No long term data

53. Summary
No consensus exists as to the optimal definition of hypoglycemia in newborns
Transitional Hypoglycemia most closely resembles congenital hyperinsulinism
There are many Genetic forms of Congenital Hyperinsulinemic Hypoglycemia - Diazoxide is the main treatment for most of them
Other causes of hyperinsulinemic hypoglycemia include, infants of diabetic mothers, Beckwith-Wiedemann syndrome, congenital disorders of glycosylation
Surgical intervention may be needed in case of failure of medical treatment

54. THANK YOU QUESTIONS