Neonatal Hypoglycemia

After completing this article, readers should be able to:A term male infant was born after an uneventful pregnancy to a 28-year-old gravida I woman who had no evidence of hyperglycemia and no chronic diseases. The infant had Apgar scores of 7 and 9 at 1 and 5 minutes, respectively. His growth parameters were in the normal range, with weight at the 60th percentile, head circumference at the 50th percentile, and length at the 50th percentile. The baby was taken to the well baby nursery, examined and bathed, and then taken to the mother for nursing at about 2 hours of age. He appeared slightly jittery at that time and was not very interested in nursing or very aware. A blood glucose concentration of 1.39 mmol/L (25 mg/dL) was obtained using a One Touch®instrument. The baby was fed 25 mL of 5% dextrose in water. The blood glucose concentration obtained 1 hour later was 2.22 mmol/L(40 mg/dL), and the baby nursed for about 5 minutes at each breast with apparent satisfaction. Jitteriness and“lack of interest” were improved.Normal nursery routine was followed, with no comment in the chart by the nursing staff about the infant’s feeding or behavior until the second day of life when he again appeared jittery and fussy. Glucose concentration at that time was 1.11 mmol/L (20 mg/dL). The infant was fed by breast or bottle (routine 20 kcal/oz house formula)alternating every 2 hours, and clinical signs improved. One Touch® glucose concentrations obtained over the next 24 hours were variable, but overall the concentration increased, with a predischarge, preprandial value of 2.78 mmol/L (50 mg/dL).The family failed to return to the hospital clinic the next day, but did see their primary care physician on the fifth day of life at which time the infant acted hungry, was noted to be “very active,” and weighed 113.4 g more than birthweight. At 2 weeks of life, the parents noted the infant to be very fussy and jittery and to experience staring spells. At a local emergency department, he was noted to have lost weight,appeared somnolent but fussy when aroused, and started having tonic-clonic jerking movements of all extremities. A “glucose concentration” was less than 0.55 mmol/L(10 mg/dL). The infant was treated with intravenous glucose, and the apparent seizure resolved. Over the next several weeks, the infant returned to the emergency department several times with similar episodes.When finally examined by the primary care physician, the infant had gained 283.5 g and appeared“puffy.” An “office glucose concentration” was 1.94 mmol/L (35 mg/dL). The infant was referred to a pediatric endocrinologist, who noted that the infant’s weight was approaching the 90th percentile,there was definite hepatomegaly,and the infant appeared “apathetic.”In the hospital, several serum glucose concentrations were measured at less than 2.22 mmol/L (40 mg/dL), with plasma insulin concentrations all greater than 144 pmol/L(20 mcU/mL).The infant was treated with diazoxide with only limited success over the next 3 months. Development continued but was “slow.” He was treated in the local emergency department three times for tonic-clonic seizures, all requiring intravenous glucose to correct severe hypoglycemia. At 5 months of age, the infant underwent a subtotal pancreatectomy. While recovering, he had a severe, prolonged seizure and was noted to be in shock, requiring two rounds of resuscitation. Escherichia coli meningitis was diagnosed and treated successfully.At 1 year of age, the infant showed little developmental gain from 6 months of age. At 5 years of age, he exhibited extremely poor growth, had diabetes mellitus that necessitated insulin treatment, and required pancreatic enzyme replacement with feedings to treat malabsorptive diarrhea. He was almost completely deaf and had marked developmental delay. His parents sought legal counsel, claiming that the treating physicians in the birth hospital failed to diagnose a“hyperinsulinism” condition that then led to delayed diagnosis and treatment,followed by severe neurologic damage.Questions to consider (feel free to send in your answers to these questions and any questions of your own for the “experts” to consider and discuss about this case): William W. Hay, Jr, MD, CoeditorGlucose is the major source of energy for organ function. Although all organs can use glucose, the human brain uses it almost exclusively as a substrate for energy metabolism. Because cerebral glycogen stores are limited, maintenance of adequate glucose delivery to the brain is an essential physiologic function. The high brain-to-bodyweight ratio in the newborn results in a proportionately higher demand for glucose compared with the capacity for glucose production than that encountered in the adult,with cerebral glucose use accounting for as much as 90% of total glucose consumption. Although alternate fuels, such as lactate and ketone bodies, can be used as a substrate for energy production, the newborn’s immature counterregulatory response limits the availability of these molecules. Thus, newborns are extremely susceptible to any condition that impairs the establishment of normal glucose homeostasis during the transition from intrauterine to independent extrauterine life.Glucose is one of the major substrates for fetal metabolism. Under normal conditions (ie, normal maternal glucose levels), virtually all of the glucose used by the fetus is supplied from the maternal circulation via facilitated diffusion across the placenta. This results in a fetal blood glucose concentration of approximately 70% of the maternal value. Although the enzymes necessary for both gluconeogenesis and glycogenolysis are present in the human fetus by the end of the first trimester, several studies have demonstrated that there is no significant glucose production in the fetus unless there is a sustained decrease in umbilical glucose uptake. Glucose utilization rates in the fetus have been estimated at 4 to 6 mg/kg per minute. Approximately 60% to 70%of fetal glucose utilization is accounted for by oxidation of glucose carbon to CO2, with the remainder available for synthesis of glycogen and other macromolecules. In the human fetus, oxidation of glucose accounts for approximately 80% of fetal oxygen consumption,demonstrating that glucose is the major substrate for fetal oxidative metabolism.The rate at which the fetus uses glucose is primarily a function of glucose concentration, although changes in insulin concentration may have a modest influence as well. Studies have demonstrated that levels of fetal pancreatic insulin secretion correlate with changes in fetal glucose concentration, but the pancreatic response is blunted compared with the newborn or adult. Insulin secretion in response to fetal hyperglycemia increases glucose utilization and oxidation rates, but it has little effect on fetal metabolic rate or the rate of oxygen consumption, suggesting that oxidation of other substrates is reduced under these conditions. Decreased oxidation of substrates such as amino acids and lactate results in increased availability of those substrates for tissue accretion and may account in part for the increased somatic growth associated with fetal hyperinsulinemia.In animal models, administration of glucagon does not appear to have a direct effect on fetal glucose metabolism. However, the ratio of insulin to glucagon in the fetal circulation plays a critical role in regulating the balance between glucose consumption and energy storage. The high insulin:glucagon ratio in the fetal circulation results in activation of glycogen synthesis and suppression of glycogenolysis by regulating the activity of the enzymes used for these of insulin glycogen in and glycogen in via on and glycogen synthesis and In glycogen stores during and with a in glycogen during the of fetal The marked in glycogen synthesis during this is associated with an in concentrations of both insulin and Because the in to be necessary for activation of glycogen fetal may glycogen in Under conditions associated with fetal glucose concentrations and increased glucagon such as chronic or glycogen is and is to glycogen synthesis and glycogenolysis with of fetal glycogen The high insulin:glucagon ratio which for energy to be in the of Thus, the fetal and metabolic a substrate that can be used during the metabolic transition from fetus to of the fetus on a of maternal glucose significant changes in of glucose at birth the of umbilical glucose Although the is a of physiologic changes the newborn for maintenance of glucose concentrations delivery glucagon with a decrease in the insulin:glucagon is and glycogen is to of glycogenolysis and of glycogen of glucose from glycogen a available source of glucose for the newborn in the first hours However, it has been estimated that term have only glycogen to the glucose for about other are required to glucose The high ratio synthesis of the enzymes required for the of the of acids by the high concentrations that to a marked in availability and the availability of free amino acids in the the infant of significant gluconeogenesis by 4 to 6 hours of However, enzyme not levels until 1 to 2 weeks of glucose utilization rates in the newborn infant are 4 to 6 mg/kg per almost the rates in the first hours of life, blood glucose concentrations from the fetal which the blood glucose concentration, to as as mmol/L the infant the metabolic transition to independent glucose production and glucose an of substrate is by feedings or administration of intravenous glucose as the significant source of glucose to metabolic normal levels of glucose production, the infant have adequate stores of glycogen and amino and concentrations of the enzymes required for gluconeogenesis and and a of any of these to of glucose in of the of in the newborn both on the of the condition and the by which blood glucose concentrations are The overall has been estimated at 1 to 5 per but it is higher in of of and of and who have intrauterine growth have been as having the in the of may be as high as concentration of blood glucose at which the diagnosis of should be has been in term has been as a blood glucose value of less than mmol/L as a plasma glucose value of less than mmol/L mg/dL). However, a of in the demonstrated no as to the of blood glucose that concentrations from 1 mmol/L (20 mg/dL) to 4 mg/dL) as the of of are primarily on studies of blood or plasma glucose concentrations during the first to hours of as a blood glucose more than 2 the have only limited physiologic is present when glucose delivery is to glucose demand and can over a of glucose on the of the infant who has a blood glucose of mg/dL) not organ but a infant physiologic at a blood glucose concentration of mg/dL) the rate of glucose delivery to organs the is less than the rate of glucose studies to have an blood glucose concentration at which or organ although animal studies that concentrations less than 1 mmol/L mg/dL), sustained over a of hours, may be associated with brain evidence to an no blood glucose value can be used to physiologic of blood glucose concentrations for a of newborns on the feeding in that the value for normal blood glucose concentrations in term from studies years was than in the This is not of a in but no the of feedings from newborns for a prolonged after than glucose these demonstrated the of the of in the normal transition to metabolism. that demonstrated blood glucose in of compared with term was to that than In these of glucose production in in response to an of At that feeding had not been for this and intravenous was not the time at which the blood glucose concentration is measured the value blood glucose concentrations over the first 24 to hours of life in term as a of both the of feeding and of Thus, a value that be at 3 hours of life be at a diagnosis of is by the of used to blood glucose concentrations Although the the used by this is as a of the time required to the and to the the is not to the and the glucose be by blood the glucose the in a that a such as can this such are not available or not use glucose to newborns for blood glucose A of blood on the for the time a that with blood glucose The blood glucose concentration can be estimated by with a chart or more by the of the with a that has been using a Although use of a to the studies have that the between blood glucose and obtained using This is at blood glucose results are susceptible to in the used to the in the of blood to the or of the by on the has been estimated that with approximately of of although the rate may be as high as Thus, to of blood glucose a should be to a a value is with or the is in the normal but clinical the of is as these the or of signs that a blood glucose A of signs may be in of severe or prolonged and in who have and are are and from in one or more of function. such as or such as or and neurologic and of these signs can from other and be in an infant who one or more of these signs can have and the is and has limited However, for newborn of in the are diagnosed during routine of to be at but who appear normal at the time of of can be to associated in one or more of the required for normal glucose production that may to or prolonged of glycogen stores are limited in both have not the of glycogen during and who have not had adequate substrate available for glycogen these newborns at for hypoglycemia. to with of normal head an demand on the infant’s glycogen stores of the increased brain-to-bodyweight and of may be at of the of In to glycogen studies in and have of insulin substrate and to changes in blood glucose concentration compared with term who have to or or who have increased of to may have but the of glycogen available may be to their increased to levels of glucose may in these available glycogen has been used to the metabolic there has been a of with associated consumption of glucose via is for levels of to be a in glucose production in the newborn appear to have amino and enzymes are more in of ketone is in response to hypoglycemia. may have of ketone when blood glucose but the concentrations of correlate with the of hypoglycemia. a of gluconeogenesis to glucose production may be limited in of are at increased for to in enzyme that or function can be by a of and metabolic the may have increased secretion of pancreatic insulin of to increased maternal glucose concentrations in glucose is increased, to fetal which in secretion of insulin by the fetal have pancreatic insulin secretion in response to a glucose compared with in maternal such as changes in serum amino may a role in the metabolic in increased blood glucose concentrations no are but the a high insulin:glucagon ratio a glycogenolysis and are enzymes are not and glucose production at levels in the of blood glucose Insulin increases glucose utilization in such as to of available The of increased glucose utilization and glucose production in which may for 24 to hours insulin secretion maternal diabetes is the of in the insulin secretion may be to several other who have have increased levels of insulin and an in the of pancreatic The for this is but one is that from insulin in the which more insulin secretion and the may the blood is with a of dextrose and other the the infant a significant glucose insulin response from the At the end of the rate of dextrose administration to but insulin levels to of such as is associated with in the the was used for more than 2 weeks and was less than 1 to appear to have reduced glycogen which the and on glucose that for more than 5 to 7 is and is to who have or that may for as as 4 weeks, but such are and the is of have been and are to be the of the first of of has been to a in the or A on the of has been in the in other have been associated with a of other in the An of has been The for the of has not been but the from the in that it does not appear to from function. A of and associated with in the has been is associated with of the increased insulin may from an normal of may the availability of or the function of the enzymes required for production of that may present with of glycogen oxidation several of the amino and of other such as and can in of the of the response to and to glucose However, these conditions are very and should be after more a is the first in the of in the The of such as results on a maternal glucose administration of associated with or the diagnosis parameters should be to the infant is should be in the term infant who has but no other apparent for more than 1 the of other and of should be the is to it is to insulin levels be during of to the of insulin of the for growth are in the of of serum levels of in the diagnosis of and for metabolic and such as serum amino and of and growth may be necessary to the of in treating the infant who has are to blood glucose concentrations as as and to of by adequate substrate until normal glucose homeostasis can be The to this is a function of both the clinical of the infant and the of the term who have an at feeding may be in blood glucose Although a in blood glucose concentrations can be a feeding with a 5% dextrose and the dextrose is and may normal feedings can be of a infant not only in the of but and are more a sustained of glucose and to a of normal glucose is estimated that blood glucose concentrations should by approximately mmol/L mg/dL) the first hour after a feeding of to mL of infant blood glucose concentrations an feeding should to have blood glucose concentrations each feeding for to 24 the concentration is but the value the next feeding is again in the feeding should be a and the infant is a for of glucose in these of preprandial hypoglycemia. This may be studies of who have that of blood glucose concentrations are more to be associated with than a should be the first used in to and those in the in glucose homeostasis is severe or is to more than a The who have of who have and who have for such as or of or or of an of mg/kg of dextrose and of should be by of dextrose to 5 to mg/kg per of glucose (ie, a rate to the glucose utilization rate of a has been to return blood glucose concentration to normal more than a is to the glucose the of glucose as a it is to which insulin secretion and hypoglycemia. The blood glucose concentration should be approximately minutes after the then every 1 to 2 hours until and in the normal a value in the range, the should be and the rate increased by to is not for who have or sustained to as much as to mg/kg per of glucose to In such it may be necessary to an umbilical or a to administration of with dextrose concentrations greater than there are about or the to requiring for should be to are several to this it an transition from a to an source of blood glucose concentrations have as of the that be in and other who have have that the pancreatic insulin response to is less than the response to an of a normal blood glucose concentration has been and the for glucose has been for to 24 hours, the infant can be from this by preprandial blood glucose concentrations and the rate by to each time the blood glucose is greater than to mmol/L to mg/dL). to from glucose the of a as a metabolic or and should other have been used to treat encountered in one of the 5 to mg/kg per day in two to three or mg/kg per are associated with glucose utilization and increased blood glucose but have a of other metabolic that be of as an to glucose may be when glucose are greater than mg/kg per a in blood glucose in who have adequate glycogen but this is only a and be to when it and who have have limited glycogen stores and are to experience an in blood glucose concentration administration of An of may a response in but those who have may a higher to the of high insulin levels and of glucagon is in those who have severe as a until can be obtained the of a other may be for of in the diagnosis of is and who in of administration of glucose at to 20 mg/kg per minute. at a of 5 mg/kg every hours pancreatic insulin or insulin as well as growth and glucagon secretion and is used in requiring for and or may be required to of to or However, in to of treated and to diabetes mellitus later in is associated with a of physiologic the are in the glucose is the major substrate for energy and both local energy stores and the of alternate substrates are in the newborn is associated with in brain the and The in are not but brain to from a of that are when blood glucose concentrations decrease A in blood glucose concentration is associated with increases in cerebral blood that have been to a of delivery of cerebral In such changes in cerebral blood may to and may have little effect on glucose of glucose across the on the activity of the glucose on the and Glucose levels are in the fetus and newborn compared with and may be for cerebral glucose glucose to the brain is not there may be a decrease in cerebral with of free and amino increased production of which is one of the amino only in the is to a major role in the of brain is associated with increased concentrations in the to a of increased from and by to of second via the and changes in via the Although there are several of the is associated with an that and the and of the in immature In all the of increases during brain to increased of in the fetal and newborn the role of the as one of the primary of a that is associated with and activity may be in regulating the of or changes in and In the human fetus, the of fetal and are by and of and of associated with increased levels of activity are critical to the of the immature However, activation of by increases concentrations of and to levels that the capacity of increases the of to activation by may in a for for normal of and of the of and associated with hypoglycemia. and free changes of and may in is evidence that changes in function may a significant role in the to Decreased of substrate the results in availability of in a there is of oxygen and increased of oxygen free which both and of with synthesis of such as of and that are for by the Thus, the of the to levels is of as well as changes in the to of by the as may to by the of studies have that of from is required to the enzymes that and that is as oxidative brain during of cerebral in immature in cerebral is associated with of increased activation of and increased and In during of glucose in the Thus, the of and be to in Although to be during cerebral in studies in immature have demonstrated that brain by of of cerebral blood that oxygen delivery to the brain during of Although is these results that maintenance of is critical in at for of such as those who have significant physiologic associated with in the newborn in a of and glucagon and and glycogenolysis in an to substrate availability for normal metabolic in are significant on the infant that may in of the infant to physiologic In term a of increased activity and is well. However, in the or the physiologic associated with a blood glucose concentration may be to and of blood glucose concentrations is required to the and metabolic a normal blood glucose concentration can be in a the of a of can be of of as are in who have been associated with and of and function. studies poor in However, more that does not in were to the of are available the in the of who have that is on routine and is treated Studies in normal have that function is during glucose who have a of of have been to have as well as that have not been in who have not significant studies in limited in have failed to any in term who have of hypoglycemia. in were in several to 5 during of of were at blood glucose concentrations from to mmol/L to in two for several hours after glucose had been However, no was on these A second which at months of in a of that those who had at one blood glucose value less than mmol/L mg/dL) on 5 or more had scores on of and and a higher of cerebral than those who had of or those who had a of more severe hypoglycemia. The significant when other such as and were accounted Thus, there is evidence to that may at in of glucose homeostasis that in are of that to for of those at that can be treated the of severe or which is associated with However, of is by the of a on the blood glucose value that as well as the in used to blood glucose A is is associated with on brain function in the studies of in term but it is that to in who have other for brain as or brain In these blood glucose concentrations well the for may neurologic studies are necessary to the of in term