Neonatal hypoglycaemia: clinical and legal aspects

Transiently low blood glucose levels are common in the neonatal period and may be considered a normal feature of adaptation to extrauterine life. There is no evidence that this causes brain injury in the absence of concurrent clinical manifestations. Conversely, persistent and severe hypoglycaemia may be associated with other underlying pathologies which themselves predispose to brain injury. Attribution of brain injury therefore requires demonstration of both 'significant' hypoglycaemia and a characteristic resulting pattern of brain injury. The prevention of hypoglycaemic brain injury requires early detection in infants considered 'at risk' and appropriate intervention. No single concentration of plasma glucose can be associated universally with either the appearance of clinical signs or causation of cerebral injury. For this reason we suggest that treatment be based upon 'operational thresholds' and guided by clinical assessment, not by the plasma glucose concentration alone. For example, the infant displaying neurological signs requires more urgent elevation of blood glucose concentration than the 'asymptomatic' one, regardless of the absolute plasma glucose value.     

A survey of the management of neonatal hypoglycaemia within the Australian and New Zealand Neonatal Network

Background: Neonatal hypoglycaemia is a common problem linked to both brain damage and death. There is controversy regarding both the definition of and best treatment for neonatal hypoglycaemia. Aim: To determine current management of neonatal hypoglycaemia within the Australian and New Zealand Neonatal Network (ANZNN). Methods: Four questionnaires were sent to the Director of each of the 45 nurseries within the ANZNN. The Director was asked to complete one questionnaire and give the remaining three to other doctors involved with the management of babies with hypoglycaemia in the nursery. Results: One hundred and eighty surveys were sent and 127 were returned (71%), including at least one from each nursery. Almost all respondents (120, 94%) reported using a protocol to treat hypoglycaemia. Only 2 (2%) reported screening all babies for neonatal hypoglycaemia, with the remainder screening babies at risk. Only 67, (53%) reported that blood glucose levels were tested on an analyser generally considered to be reliable at low levels. Most respondents (99, 78%) reported the clinical threshold for treatment was <2.6 mmol/L. However, when provided with clinical scenarios, respondents reported a variety of interventions, including no treatment. Conclusion: Doctors within the ANZNN are consistent about definition and screening for neonatal hypoglycaemia. However, frequently, the diagnosis is made using unreliable analysers. There is also wide variation in treatment, suggesting a lack of reliable evidence on which to base practice.     

A case of familial nesidioblastosis: prenatal diagnosis of foetal hyperinsulinism

Persistent neonatal hyperinsulinaemic hypoglycaemia due to nesidioblastosis is a rare condition probably transmitted by an autosomal recessive inheritance. Recurrent hypoglycaemic episodes become evident after birth and cause severe neurological damage without intensive treatment. The intrauterine detection of hypoglycaemia and hyperinsulinism in newborns subsequently diagnosed as affected by nesidioblastosis has not yet been reported. We describe a case of familial nesidioblastosis in which an intrauterine diagnosis could be suggested by high levels of insulin and C-peptide and low values of glucose in the amniotic fluid.     

Investigation,prevention and management of neonatal hypoglycaemia (impaired postnatal metabolic adaptation)

Blood glucose levels fall in the hours after birth in all babies but for most babies the normal process of neonatal metabolic adaptation mobilizes alternative fuels (eg ketone bodies) from stores so that the physiological fall in blood glucose is tolerated. However, some babies are at risk of impaired neonatal metabolic adaptation and for these babies it is important to prevent hypoglycaemia, to recognize clinically significant hypoglycaemia, and to treat it without causing unnecessary separation of mother and baby or disruption of breast feeding. Investigations for underlying cause of hypoglycaemia should be performed if hypoglycaemia is persistent, resistant or unexpected.     

Investigation and management of impaired metabolic adaptation presenting as neonatal hypoglycaemia

At birth, the newborn baby undergoes many adaptive changes to independent extrauterine life. These include the changes of metabolic adaptation, which must be understood in order to identify and manage the conditions in which metabolic adaptation is delayed, impaired or fails, resulting in low levels of glucose and other metabolic fuels, which in turn affect neonatal neurological function and, if prolonged and severe, cause potential adverse outcome. Babies identified as at risk of impaired metabolic adaptation must undergo clinical monitoring, including accurate blood glucose monitoring, tailored to their condition. Babies who present with abnormal clinical signs in association with a low blood glucose level must be investigated for underlying cause and treated promptly. Prevention and treatment of clinically significant hypoglycaemia must be planned to avoid compromising successful establishment of breast feeding.     

CLINICAL ASPECTS OF NEONATAL HYPOGLYCAEMIA

ABSTRACT. Fluge, G. (Department of Paediatrics, University of Bergen, Bergen, Norway). Clinical aspects of neonatal hypoglycaemia. Acta Paediatr Scand, 63: 826, 194.—Fifty cases of neonatal hypoglycaemia were detected by routine blood glucose determination in 323 low birth weight infants during a three-year period (15.4%) and, in addition, hypoglycaemia was diagnosed in 17 full-term infants. The patients were divided in three groups according to clinical findings, with special reference to age at diagnosis, pretreatment blood glucose values and duration of hypoglycaemia. In asymptomatic hypoglycaemia the diagnosis was made during the first few hours after birth, and the mean pretreatment blood glucose value was 14 mg/100 ml. Except for one patient, the hypoglycaemia was of short duration. Symptomatic, transient hypoglycaemia was characterized by a delay in onset of symptoms until the second and third day after birth, low pretreatment blood glucose level and hypoglycaemia of long duration. Hypoglycaemia associated with other neonatal disorders classified as secondary hypoglycaemia usually was noted during the first few hours of life, and tended to he of short duration. Frequency of hypoglycaemia in small for gestational age infants was markedly higher when toxaemia of pregnancy was noted, compared with infants born to non-toxaemic mothers.     

Neurodevelopmental outcome of hypoglycaemia in healthy, large for gestational age, term newborns

AIMS: To evaluate the effects of transient hypoglycaemia on the first day of life in 75 healthy term large for gestational age (LGA) infants, born to non-diabetic mothers, on their neurodevelopmental outcome at the age of 4 years. METHODS: Screening for hypoglycaemia was performed 1, 3, and 5 hours after birth, and continued if blood glucose levels were low. Treatment with intravenous glucose for hypoglycaemia was started if hypoglycaemia was severe or symptomatic. Patients' development and behaviour was examined at the age of 4 years by the Denver Developmental Scale, a non-verbal intelligence test, and the Child Behaviour Check List. RESULTS: There were no significant differences between children with neonatal normoglycaemia (n = 15) and hypoglycaemia (plasma glucose <2.2 mmol/l 1 hour after birth, or <2.5 mmol/l subsequently; n = 60) in Denver developmental scale scores and child behaviour checklist scores. Although total IQ did not differ between hypoglycaemic and normoglycaemic children, one subscale (reasoning) did (mean difference 9.3, 95% CI 1.3 to 17.2). The correlation between reasoning IQ and neonatal blood glucose levels was weak and not statistically significant. When other definitions for hypoglycaemia were applied, the difference in reasoning IQ was not found. There were no differences in any of the test scores between hypoglycaemic children who had and who had not been treated with intravenous glucose. CONCLUSION: Transient mild hypoglycaemia in healthy, term LGA newborns does not appear to be harmful to psychomotor development at the age of 4 years.     

Moderate hypoglycemia in the preterm infant: is it relevant?]

Glucose monitoring and management of hypoglycaemia in preterm infants remain controversial. However, recent animal studies have shown that hypoglycaemia is associated to increased generation of reactive oxygen and nitrogen species, to inhibition of cellular maturation and to apoptosis in brain. Despite potential consequences of hypoglycaemia on brain development in preterm infants, only few studies are available on this topic. Available clinical studies on neurological development of hypoglycaemic preterm infants are not conclusive but suggest detrimental effect of repeated mild hypoglycaemia on brain development. Both experimental and clinical arguments are sufficient to mind to this problem with great awareness. Therefore, routine repeated measurements of blood glucose concentration are necessary and active intervention is proposed if glucose plasma level decreases below 2.5 mmol/l.     

Postischemic hyperglycemia is not protective to the neonatal rat brain.

Brain glucose concentration during and after hypoxia-ischemia may be one of the variables affecting outcome of asphyxial insults. Glucose given before global ischemic forebrain injury to adult rats increases morphologic brain damage, and postischemic insulin administration reduces selective neuronal necrosis and cortical infarction. Because glucose infusions are routinely used in the clinical management of perinatal asphyxia, we evaluated the role of glucose administration after ischemic neuronal damage to neonatal rat brain. Sprague-Dawley rat pups (postnatal d 7) were subjected to left common carotid artery ligation followed by 2.5 h of 8% oxygen (Levine procedure). The experimental group was subdivided so that pups received either systemic injections of glucose or saline immediately after the hypoxic insult. Animals were killed on postnatal d 12 and brain areas of ipsi- and contralateral cortex and caudate were calculated from camera lucida tracings. There was no significant difference in size of brain infarction between postischemic glucose-treated and post-ischemic saline-treated pups. However, hypoxic-ischemic brains did show more severe neuronal damage when hyperglycemia was induced after asphyxia. Because post-ischemic hyperglycemia does not attenuate and may exacerbate injury, we recommend careful monitoring of blood glucose so that hyperglycemia does not occur during resuscitation of asphyxiated infants.     

Survey of the definition and screening of neonatal hypoglycaemia in Australia

Objective : To determine the approach to identifying neonatal hypoglycaemia and the definition of neonatal hypoglycaemia used by neonatal paediatricians in Australian Level 3 neonatal intensive care units (NICU).
Methodology : A questionnaire was sent to the 101 neonatal paediatricians in the 22 Level 3 NICU in Australia asking their method of screening for, and definition of, neonatal hypoglycaemia.
Results : Responses were received from 70 neonatal paediatricians, including all 22 directors. A bedside glucose meter is used in 19 of 22 NICU to screen for hypoglycaemia, whilst one NICU uses a glucose analyzer and another NICU uses a visual colour comparison method. One NICU does not screen, but has blood glucose measured in a satellite laboratory. If the screening method suggests hypoglycaemia, 62 of 63 neonatal paediatricians proceed to blood glucose determination in a laboratory, mostly using plasma samples. Based on the laboratory measurement, the definition of neonatal hypoglycaemia ranged from <1.1 to 3.0 mmol/L.
Conclusions : The majority of neonatal paediatricians in Australian NICU screen for neonatal hypoglycaemia using a bedside glucose meter. There is a wide range in the definition of neonatal hypoglycaemia from <1.1 to 3.0mmol/L.     

Glucose and the newborn baby: Sweet justice?

Abstract: Neonatal hypoglycaemia remains a controversial issue. Uncertainty surrounds what constitutes the optimal safe blood glucose for newborn babies. There are good reasons and evidence for maintaining blood glucose greater than 2.5mmol/L in newborn babies. Since 1986 neonatal paediatricians have changed in their definition of neonatal hypoglycaemia. Ideally, screening of blood glucose in neonatal intensive care units should be done with an on-site glucose analyzer.     

The investigation and management of neonatal hypoglycaemia

Assessment of neonatal glycaemic status requires accurate and reliable measurement of blood glucose concentrations. Most point-of-care technologies are, however, unsuitable for use in neonates. Although the definition of hypoglycaemia remains elusive, current knowledge allows adoption of pragmatic threshold blood glucose concentrations when clinical intervention should be considered. The vast majority of instances of neonatal hypoglycaemia are due to problems with the normal processes of metabolic adaptation after birth, and strategies to enhance the normal adaptive processes should help prevent such episodes. Further investigations and specific interventions should be considered when hypoglycaemia is of unusual severity or occurs in an otherwise low-risk infant.     

Management of the vulnerable baby on the postnatal ward and transitional care unit

Many guidelines for the prevention and management of neonatal hypoglycaemia focus on the sick infant admitted to the intensive care unit and pay scant attention to what is known about normal neonatal physiology. It is questionable whether treatment guidelines for low blood glucose levels for sick infants can be applied to a population of well infants on the postnatal ward, especially if such guidelines interfere with the establishment of breastfeeding, which has well recognised long and short term health benefits for mother and baby. What then of the baby who is at risk of abnormal postnatal adaptation, but is not unwell? Can the complications which occur in such infants, such as hypoglycaemia, be safely managed without resorting to admission to a baby unit? Can such vulnerable infants be safely managed in an environment that promotes mother and baby bonding and facilitates breastfeeding?     

Assessment of Effects of Neonatal Hypoglycaemia: A Study of 41 Cases with Matched Controls

41 infants who had experienced neonatal hypoglycaemia (blood glucose less than 20 mg/100 ml) were reviewed at a mean age of 51 months and compared to a group of matched controls. Symptomatic and asymptomatic infants were represented in the hypoglycaemic group in a similar ratio to that found during a previous study of the incidence of hypoglycaemia in a special care unit.Evidence of cerebral damage was found in 6 of the children who had been hypoglycaemic (14·6%) and in 5 of the controls (12·2%). This difference is not significant. The mean IQ and locomotor scores of the two groups were identical, and there was no difference in the incidence of behaviour disorders or convulsions.It is concluded that, while it is important to identify and treat cases of `true'' symptomatic hypoglycaemia, the large majority of infants tolerate low blood glucose levels without sequelae. The prognosis for infants with asymptomatic hypoglycaemia is particularly good, none of the 12 infants in this series showing any evidence of cerebral damage.     

Neonatal hypoglycaemia in Nepal 2. Availability of alternative fuels

AIMS: To study early neonatal metabolic adaptation in a hospital population of neonates in Nepal. METHODS: A cross sectional study was made of 578 neonates, 0 to 48 hours after birth, in the main maternity hospital in Kathmandu. The following clinical and nutritional variables were assessed: concentrations and age profiles of blood glucose, hydroxybutyrate, lactate, pyruvate, free fatty acids (FFA) and glycerol; associations between alternative fuel levels and hypoglycaemia; and regression of possible risk factors for ketone availability. RESULTS: Risk factors for impaired metabolic adaptation were common, especially low birthweight (32%), feeding delays, and cold stress. Blood glucose and ketones rose with age, but important age effects were also found for risk factors like hypothermia, thyroid hormone activities, and feeding practices. Alternative fuel concentrations, except FFA, were significantly reduced in infants with moderate hypoglycaemia during the first 48 hours after birth. Unlike earlier studies, small for gestational age (SGA) infants had significantly higher hydroxybutyrate:glucose ratios which suggested counter regulatory ketogenesis. Hypoglycaemic infants were not hyperinsulinaemic. Regression analysis showed risk factors for impaired counter regulation which included male and large infants, hypothermia, and poorer infant thyroid function. SGA infants and those whose mothers had received no antenatal care had increased counter regulation. CONCLUSIONS: Alternative fuels are important in the metabolic assessment of neonates, and they might provide effective cerebral metabolism even during moderate hypoglycaemia. Hypoglycaemic infants generally had lower concentrations of alternative fuels through either reduced availability or increased consumption. SGA and post term infants increased counter regulatory ketogenesis with early neonatal hypoglycaemia, but hypothermia, male gender, and low infant T4 were associated with impaired counter regulation after birth.     

Definition of neonatal hypoglycaemia: Is there a change?

Objective : To compare the definitions of neonatal hypoglycaemia in textbooks and among paediatricians in 1992 with those used in 1986. Methodology : A questionnaire was sent to 420 neonatal paediatricians in the UK and to 88 Australian neonatal paediatricians in 1992 asking for their definition of hypoglycaemia in term babies and preterm/small-for-gestational-age (SGA) babies. Fourteen textbooks on neonatal paediatrics (published since 1990) were also surveyed for the definition of hypoglycaemia used in the text. The UK paediatricians were also asked, ‘Do you believe that a baby who is hypoglycaemic but has no abnormal clinical signs is at less risk of neurological damage than a baby who is hypoglycaemic with abnormal signs?’ The 1992 results were compared with the published results of a similar survey in 1986. Results : There was a 68% response from neonatal paediatricians both in the UK and Australia. Similar to the 1986 results there continued in 1992 to be a wide range in the definition for hypoglycaemia (<1-4mmol/L) among neonatal paediatricians and in textbooks. The median of the definition of hypoglycaemia for both term and preterm/SGA babies among paediatricians and in textbooks in 1992 was significantly different from the results in 1986. Compared with 1986 there was a significant increase in 1992 in the number of paediatricians and textbooks defining a safe blood glucose concentration as being at least 2mmol/L. Sixty per cent of UK neonatal paediatricians believe that a baby who is hypoglycaemic but has no abnormal clinical signs is at less risk of neurological damage than a baby who is hypoglycaemic with abnormal signs. Conclusions : From 1986 to 1992 there was a significant change in the definition of hypoglycaemia both among paediatricians and in neonatal textbooks compared with the definition in use during 1965-86. The findings suggest that neonatal paediatricians do change in their practice. The changes in the definition of hypoglycaemia may be due to the data available and discussion on hypoglycaemia since 1988. Neonatal paediatricians still attach significance to clinical signs associated with hypoglycaemia.     

Isolated ACTH deficiency. Metabolic and endocrine studies in a 7-year-old boy.

Metabolic and endocrine studies on a 7-year-old boy who presented with hypoglycaemic convulsions are reported in detail, proving the diagnosis of isolated ACTH deficiency--a rare cause of hypoglycaemia in childhood. Adrenaline secretion during insulin-induced hypoglycaemia was reduced. Low blood alanine levels occurred during starvation-induced hypoglycaemia, together with raised total blood ketone bodies; blood glucose did not increase adequately after oral alanine at this time. Hypoglycaemia in isolated ACTH deficiency appears to be due to a combination of impaired alanine mobilisation and a decreased rate of gluconeogenesis.     

Neontal hypoglycaemia in infants of insulin-dependent diabetic mothers.

Neonatal hypoglycaemia (blood glucose smaller than 20 mg/100 ml) occurred in the first 6 hours of life in 25 of 34 infants born to diabetic mothers receiving insulin. Despite severe hypoglycaemia (blood glucose smaller than 10 mg/100 ml) in 17, clinical features of hypoglycaemia were absent in all but 2. Hypoglycaemia was not related either to the level of plasma insulin in cord blood, determined as nonextracted immunoreactive insulin, or to the degree of control of maternal blood glucose during pregnancy. The frequent occurrence of severe neonatal hypoglycaemia in the infants born to diabetic mothers receiving insulin appears to be due rather to failure to maintain basal glucose homoeostasis after birth than to hyperinsulinism.     

Diagnosis and management of hypoglycaemia beyond the neonatal period

Hypoglycaemia in childhood beyond the neonatal period is a relatively common problem and is defined as a plasma glucose level of less than 2.8 mmol/litre. If it is not recognised and treated promptly, it can lead to significant morbidity and mortality. Hypoglycaemia has many and varied causes, including endocrine disorders, inborn errors of metabolism, poisoning, severe infections and ketotic hypoglycaemia (which should be a diagnosis of exclusion). When possible, blood and urine samples to determine the cause of hypoglycaemia should be taken before treatment is instigated, as some abnormalities are unmasked only during the episode of low blood sugar. Once the cause has been identified, treatment may involve avoidance of prolonged fasting, dietary manipulation, medication or even surgery.     

Exploration of glucose homeostasis during fasting in growth hormone-deficient children

In order to define more precisely the risk of hypoglycaemia in GH-deficient children and to clarify the role of growth hormone (GH) in glucose homeostasis, a 24-h fast was monitored in 10 GH-deficient children aged 1.1–6.5y. Asymptomatic hypoglycaemia (blood glucose ≤ 2.6mmol/l) occurred in 9/10 children, 2 of whom prematurely interrupted the test. Blood glucose profile was not reproducible between children and had no correlation with age ( p = 0:48). Gluconeogenesis was considered as non-altered as read from the normal plasma lactate and pyruvate concentrations throughout the test. Plasma ketone body concentrations increased during the test, but were lower than expected with respect to the decrease of blood glucose. This suggests insufficient ketogenesis which could exacerbate hypoglycaemia in GH-deficient children if brain glucose utilization were not alleviated by ketone body oxidization, as is normally the case. The positive glucose response after glucagon stimulation in 6/10 patients indicated normal hepatic glycogen content. However, these responses were unexpected following the prolonged fast and its concomitant hypoglycaemia, and would therefore tend to suggest a defect in glycogenolysis. These results confirm the tendency to hypoglycaemia, even after infancy, in GH-deficient children. These hypoglycaemias may occur by different types of malfunctioning, such as insufficient ketogenesis or a defect in glycogenolysis. These hypotheses require confirmation by a more systematic study of the metabolic and hormonal changes that occur during fasting in both GH-deficient and normal children.