lNilima Ragavan, MD FAAPClinical Professor of Pediatrics

Stanford University School of MedicineStanford University School of Medicine

Dharampur,February 2019p , y 9

OBJECTIVES Perinatal glucose metabolism Perinatal glucose metabolism Incidence, definition and controversies Signsg Etiology-transient vs persistent IDM Management and Prognosis Cases

Fetal Glucose Metabolism Glucose is the primary fuel for the fetusGlucose is the primary fuel for the fetusOther substrates include Lactate and Amino Acids Maternal glucose is the only source of fetal glucoseMaternal glucose is the only source of fetal glucose 50% of placental glucose uptake transferred to fetusGl t t d t f t b f ilit t d i di t dGlucose transported to fetus by facilitated carrier-mediated

transportFetal glucose concentration about 70 80% of maternal levelFetal glucose concentration about 70-80% of maternal level

Data from Ashmead et al;Gynecol Obstet Invest 1993

Postnatal Glucose MetabolismPostnatal Glucose Metabolism Glucose levels fall

f d l iafter cord clamping Transition from

continuous glucose l i dsupply to interrupted

periods of feeding and fasting

h f h h Switch from high carb/low fat diet to higher fat/lower carb di tdiet

Adaptation To Fasting Glycogenolysis Glycogenolysis Gluconeogenesis: substrates include Lactate, Amino acids such as

Alanine and Glutamine ,and Glycerol Adipose tissue lipolysis with release of free fatty acids Hepatic ketogenesis Hormonal regulation through Insulin, Glucagon, GH, cortisol ,

epinephrine

GLYCOGENOLYSIS Glycogen accumulates in uter0 inGlycogen accumulates in uter0 in

the liver. Amount increases slowly

throughout gestation with sharpthroughout gestation with sharp increase around 36 weeks.

Breakdown starts 2 to 3 hours postprandialpostprandial

Depleted within 12 hours with starvation in term neonate

faster in preterm or stressed, faster in preterm or stressed

GLUCONEOGENESIS Production of glucose from precursors Production of glucose from precursors Lactate, Alanine and Glutamine , Glycerol Occurs in liver. Small amount in kidney Biotin dependent Pyruvate Carboxylase , PEP-CK, Fructose 1,6

diphosphatase, Glucose- 6- phosphatase PEP CK is the rate limiting enzyme PEP-CK is the rate limiting enzyme PEP-CK induced by falling Insulin and rising Glucagon after birth . Role of

Oxygen in transcription? Adult levels by 24 hours after birth. Long chain fatty acids upregulate transcription

Li l i d K t iLipolysis and Ketogenesis

Occurs in same physiologic conditions causing gluconeogenesis

Lipolysis releases free fatty acids Free fatty acids are oxidized by liver to produce ketones-

acetoacetate and B-hydroxybutyrate Ketones provide alternate source of fuel and are glucose

sparingsparing Ketogenesis delayed in neonate due to delayed expression of

two enzymes , although neonatal brain can utilize ketones Fatty acids provided by feeds activate transcription of these

enzymes

Hormonal Regulation Hormone Glycogenolysi Gluconeogenesis Lipolysis Ketogenesis

s

Insulin Inhibits Inhibits Inhibits InhibitsGlucagon Stimulates StimulatesC ti l Sti l tCortisol StimulatesGH StimulatesEpinephrine Stimulates Stimulates Stimulates Stimulates

Glucose Utilization In Neonates Rates of glucose production and utilization higher Rates of glucose production and utilization higher. 4-6 mg/kg/mt Reflects higher ratio of brain to body weight Rates decrease to adult levels by adolescence Approximately 3.7mg/kg/mt of glucose required to meet the metabolic

demands of the neonatal braindemands of the neonatal brain. Studies of glucose oxidation rates in neonates suggest that during fasting

the brain uses other fuels

Hypoglycemia More common in the newborn particularly in the first 24 hours than at More common in the newborn particularly in the first 24 hours than at

any other age

Hypoglycemia after the first 48 to 72 hours is uncommon and must be investigated and treated

Why should we screen and treat?H l i d i th b i f itHypoglycemia can deprive the brain of its

primary source of metabolic fuelHypoglycemia can be the presenting feature of

serious diseases including IBM and endocrine gdisorders

Normal Glucose ValuesNormal Glucose Values

Srinivasan G et al. J Peds1986;109:114

DEFINITIONDEFINITION

YEAR

0100

0

Why is the definition controversial? Spontaneous decrease after birth Spontaneous decrease after birth Cut off value ?Higher with concomitant insults[HIE] Asymptomatic hypoglycemia vs Symptomatic Signs are non specific Relationship to long term neurologic outcome

St ti ti l d fi iti th%il l th th th Statistical definition-<5th%ile or less than the 10th Transient or persistent Operational definitionp

Incidence of HypoglycemiaIncidence of HypoglycemiaAuthor Year Cut off Incidence Patient Type

ValuePildes 1967 31 mg/dl.

1.7mM6% Small babies

L b h % R dLubchenco 1971 11% Random selection

Srinivasan 1983 35mg/dl 10% AGA termSexson 1984 40 mg/dl 29% High RiskSexson 1984 40 mg/dl

2.2 mM29% High Risk

babiesKaiser 1998 35 mg/dl

40mg/dl/dl

6%10%

%

All babies

45 mg/dl 19%Harris 2012 47 mg/dl 51% High risk

babies

Sugar Babies Study 51% in at risk group using 2 6 mM[47 mg] 51% in at risk group using 2.6 mM[47 mg] 19% using 2mM[36mg] 50% of the episodes in this study were in the first 6 hours of life and

80% in the first 24 hours 80% were asymptomatic. 15% had lethargy and difficulty feeding About 20% had recurrent episodes About 20% had recurrent episodes Incidence did not vary by reason for being at risk

Clinical Symptoms and SignsAbnormal crying GruntingAbnormal crying IrritabilityApnea Cyanotic spells

GruntingSeizuresHypothermiaApnea, Cyanotic spells

Jitteriness, TremorsF di diffi lt

HypothermiaSweatingH t iFeeding difficulty

Lethargy,stuporHypotoniaTachycardia

T hTachypnea

Transient Hypoglycemia-Neonatal FactorsIUGRIUGR

PrematurityAsphyxia/stress

Hypothermia- cause/ effect?Infection ?

Polycythemiay yCardiac Disease

IatrogenicE th bl t iErythroblastosis

Transient Hypoglycemia-Maternal Factors

Glucose containing IVFTerbutaline Diabetes in pregnancy

Oral HypoglycemicsPropranolol

Thi id

Maternal obesity

ThiazidesSalicylates

Persistent or Recurrent Hypoglycemia

Hyperinsulinism Endocrine Inborn ErrorsHyperinsulinism

• Genetic• SGA

B k i h

Endocrine

• Pituitary• Cortisol

Gl

Inborn Errors

• Carbohydrate• Amino acid

F id• Beckwith Weidemann

• Glucagon• Epinephrine

• Fatty acid

Persistent HyperinsulinemiaPersistent Hyperinsulinemia

Persistent Hyperinsulinemia Incidence varies from 1 in 50 000 to 1 in 2500 Incidence varies from 1 in 50,000 to 1 in 2500 Mutations identified in 9 significant genes Genes encoding K ATP channel located on chromosome 11p14-15 45% of cases result from inactivating mutations in the ABCC8 gene

encoding SUR1 5% cases from mutations in KCNJ11 gene encoding Kir6 2 5% cases from mutations in KCNJ11 gene encoding Kir6.2

Persistent HyperinsulinemiaB k ith Wi d S dBeckwith Wiedemann Syndrome

Macroglossia 80% Visceromegaly Macroglossia 80% Visceromegaly Ear anomalies, 75% Abdominal wall defects 80% Prenatal / postnatal gigantism

75% Hypoglycemia 50% Hypoglycemia 50% Cardiac defects 25% Renal anomalies

Beckwith Wiedemann Syndrome Cryptorchidism Cryptorchidism Clitoromegaly Tumors Facial nevus flammeus Maxillary underdevelopment Prominent occiput Hemihypertrophy

Persistent or Recurrent Hypoglycemia

Hyperinsulinism Endocrine Inborn Errorsyp

• Genetic• Beckwith

Weidemann

• Pituitary• Cortisol• Glucagon

• Carbohydrate• Amino acid• Fatty acidWeidemann

• SGA• Glucagon• Epinephrine

• Fatty acid

H l i i IUGR/SGA i f tHypoglycemia in IUGR/SGA infant

Decreased Glycogen Decreased Glycogen stores

Decreased GluconeogenesisGluconeogenesis

Hyperinsulinemia Incidence varies 18%-

67% depending on gestational age

MManagementA ti i ti f bl i hi h i kAnticipation of problem in high risk groupCorrectionInvestigation and treatment of cause

High Risk Group Prematurity Prematurity LGA IDM SGA/IUGR Delayed feeds

Si k i f t Sick infants Maternal IVF/medications Neonatal Polycythemiay y

Committee on Fetus and Newborn Pediatrics2011;127:575-579

Pediatric Endocrine SocietyFor neonates without associated congenital disorderFor neonates without associated congenital disorder

,goal >50 mg/dl at <48 hours and >60 at >48 hours or if IVF requiredif IVF required. For neonates with a congenital disorder, goal is >70

/dlmg/dlSafety fast test of 6-8 hours for at risk

Work UpSerial glucose checks Confirm withSerial glucose checks. Confirm with

lab testing. Whole blood glucose is 15% lower than plasma. Delay in 5% p yanalysis can lower levelsCBC with diff, CRP,Insulin, Betahydroxybutyrate,GH,

Cortisol levels with Glucose when hypoglycemic

Work Up of persistent hypoglycemia Thyroid function Thyroid function Acylcarnitine profile , Serum amino acids , FFA,lactate,NH3. Urine Ketones, reducing substances , organic acids, g , g Genetic studies as appropriate Endocrinology consultation 18F-DOPA PET scan useful for localization of focal disease Safety Fast test?

Management – Harris et al Lancet 2013 Harris et al. Lancet 2013 Inexpensive, noninvasive, easy to give. Can be applied directly to the buccal mucosa for rapid correction Dosing is weight based (0.5ml/kg) Provides 400 mg/kg glucose (40% glucose + water and glycerin)

D b il di id d Dose can be easily divided Sublingual absorption rate is equal to IV dextrose Promotes continued breast feeding and maternal bonding. g g

Dextrose Gel decreased NICU admission

Sugar babies study-Dextrose gel vs placebo 184 children with hypoglycemia F/U at 2 years 184 children with hypoglycemia F/U at 2 years No difference between dextrose gel and placebo High rate of neurosensory impairment[38% and 34%] mostly mild in both

groups. Lower rate of NICU admission for hypoglycemia and formula feeding at 2

weeks in dextrose gel group.weeks in dextrose gel group.

IV GlIV Glucose 6-8 mg/kg/minute corresponds to 3 6-4 8ml/kg/hr of 10%Dextrose 6-8 mg/kg/minute corresponds to 3.6-4.8ml/kg/hr of 10%Dextrose Minibolus of 2ml/kg of D10 over 1 minute if symptomatic or glucose <25.

Follow with continuous IV infusion Maintain glucose >50 Increase infusion rate by 1-2 mg/kg/mt Central line if higher infusion rates needed Central line if higher infusion rates needed. Wean IV once levels stable at 50-70. Follow levels

IV Glucose -2 Treatment Regimens

Management of Persistent Hypoglycemia

Glucagon 20-50 mcg/kg IV IM or SCGlucagon 20-50 mcg/kg IV,IM or SCDiazoxide trial 15mg/kg/day.Side effects:Fluid

retention,hypertrichosis, PPHN., yp ,Octreotide 15mcg/kg/day.Long acting analog of

Somatostatin which inhibits insulin release. Associated with NECNEC

GlucocorticoidsSurgerySurgery

Outcome Data In The Main At Risk Groups

There are studies in most of these groups which show worse outcomes There are studies in most of these groups which show worse outcomes than healthy term newborns.

In some of these studies an association exists between low glucose i d d l lconcentrations and worse neurodevelopmental outcomes.

BUT none of these studies have conclusively demonstrated that worse outcomes are caused by the hypoglycemia. y yp g y

No studies have robustly tested whether treating asymptomatic hypoglycemia improves neurodevelopmental outcomes.

Recent Meta-analysis Neonatal hypoglycaemia is associated with a two- to threefold increased Neonatal hypoglycaemia is associated with a two- to threefold increased

risk of specific cognitive deficits in early childhood (2–5 years), including visual-motor impairment and executive dysfunction,

d l i i i i d li d bl i and general cognitive impairment and literacy and numeracy problems in later childhood (6–11 years).

Although the overall quality of evidence was low to very low, this review g q y ynevertheless suggests that neonatal hypoglycaemia may have important long-lasting adverse effects on neurodevelopment

Shah,McKinlay 2018.

PrognosisTransient asymptomatic mild hypoglycemiaTransient asymptomatic mild hypoglycemia-

generally good prognosisP l d d h l i i b dProlonged and severe hypoglycemia is bad

CHYLD study[2006-10] 2 year follow up of > 35 weeks gestation at risk infants enrolled in Sugar2 year follow up of > 35 weeks gestation at risk infants enrolled in Sugar

babies study and BABIES study. 404 infants Treated to maintain >47[dextrose gel feeds IV] Treated to maintain >47[dextrose gel, feeds, IV] Used intermittent and continuous interstitial 2 year follow up Primary outcomes :Neurosensory impairment and processing

difficulty[visual perception and executive function].Not increased in hypoglycemia group.

? Higher glucose effect in treated infants

Study Overview

• In this prospective cohort study, neonatal hypoglycemia, when yp g y ,treated to maintain a blood glucose concentration of at least 47 mg per deciliter was not associated with andeciliter, was not associated with an adverse neurologic outcome at 2 years.y

• Also, risks were not increased among children with unrecognized hypoglycemiahypoglycemia.

But at 4 year follow up Neonatal Glycemia And Neurodevelopmental Outcomes At 4 5 Years Neonatal Glycemia And Neurodevelopmental Outcomes At 4.5 Years Mckinlay, et. al., JAMA Pediatrics 2017 Hypoglycemic (<47 mg/dL) babies had worse executive function and worse

i l f i d l i b bivisual motor function compared to normoglycemic babies at two years. There were not significant differences in parental assessment of their children. However, the poor executive function and visual motor performance may p p y

impact learning and school achievement. The other associations reported at 2 years of age were not reported at 4.5 years

of age. o age.

CNS Sequelae Involvement of the occipital lobes or parietal occipital Involvement of the occipital lobes or parietal-occipital

cortex but spectrum is wide with symptomatic severe hypoglycemia and includes diffuse WM injury,corticalyp g y j y,neuronal injury,and basal ganglia/thalamic lesions.

MRI findings in hypoglycemiaMRI findings in hypoglycemia

Hyperglycemia Suppressed endogenous glucose production and increased peripheral Suppressed endogenous glucose production and increased peripheral

utilization of glucose generally prevents hyperglycemia 180-200mg/dl,Renal glycosuria variable In VLBW ,related to stress and increased counterregulatory hormones Correlation with adverse long term outcome Rarely treatment with insulin needed but look for primary cause Rarely treatment with insulin needed but look for primary cause Randomized trial of early insulin for 7 days in VLBW :No benefit ,more

hypoglycemia and 28 day mortality in insulin group led to early di i i B d ll l NEJMdiscontinuation . Beardsall et al NEJM 2008

Transient Neonatal Diabetes Mellitus

IUGR SGA low insulin levels may present earlyIUGR , SGA, low insulin levels, may present earlyGenetic anomalies: Chromosome 6 includingPaternal uniparental isodisomy of chromosome 6Paternal uniparental isodisomy of chromosome 6Unbalanced paternal duplications of 6q24M th l ti d f t t 6Methylation defects at 6q24

Permanent Diabetes MellitusPresent later but usually within 3 monthsPresent later but usually within 3 monthsActivating mutation in Kir6.2Severe developmental delay and muscle weaknessSevere developmental delay and muscle weaknessMutations in genes encoding Glucokinase in a minority

New DevicesAccurate devices to measure glucose concentrationsAccurate devices to measure glucose concentrations

Role of newer generation bedside glucometers.

Continuous interstitial glucose monitoring sensors

Take Home Message Re Glucose Screen at risk infantsScreen at risk infantsDevelop a policy for screening and management. Individualize Individualize.Not too high ,Not too low, Just right for each baby I ti t i t t h l i Investigate persistent hypoglycemia