Prolonged Neonatal Hypoglycemia Research Articles

Application of the screening test principles to screening for neonatal hypoglycemia.

Severe and prolonged neonatal hypoglycemia can cause brain injury, while the long-term consequences of mild or transitional hypoglycemia are uncertain. As neonatal hypoglycemia is often asymptomatic it is routine practice to screen infants considered at risk, including infants of mothers with diabetes and those born preterm, small or large, with serial blood tests over the first 12-24 h after birth. However, to prevent brain injury, the gold standard would be to determine if an infant has neuroglycopenia, for which currently there is not a diagnostic test. Therefore, screening of infants at risk for neonatal hypoglycemia with blood glucose monitoring does not meet several screening test principles. Specifically, the long-term neurodevelopmental outcomes of transient neonatal hypoglycemia are not well understood and there is no direct evidence from randomized controlled trials that treatment of hypoglycemia improves long-term neurodevelopmental outcomes. There have been no studies that have compared the long-term neurodevelopmental outcomes of at-risk infants screened for neonatal hypoglycemia and those not screened. However, screening infants at risk of hypoglycemia and treating those with hypoglycaemic episodes to maintain the blood glucose concentrations ≥2.6 mmol/L appears to preserve cognitive function compared to those without episodes. This narrative review explores the evidence for screening for neonatal hypoglycemia, the effectiveness of blood glucose screening as a screening test and recommend future research areas to improve screening for neonatal hypoglycemia. Screening babies at-risk of neonatal hypoglycemia continues to be necessary, but as over a quarter of all infants may be screened for neonatal hypoglycemia, further research is urgently needed to determine the optimal method of screening and which infants would benefit from screening and treatment.

Functional Maturation of Pancreatic ß Cells during Development

Insulin is crucial for intrauterine growth of the fetus and insulin secretion must be maintained irrespective of maternal plasma glucose variations. This is achieved through a maturational islet adaptation which persists during the first postnatal days and can lead to prolonged neonatal hypoglycemia. We aimed to investigate the characteristics of insulin release in the fetal and perinatal period. We performed perifusions of human fetal islet samples at 18-20 weeks gestation and of rat islets between embryonic day (e)22 and postnatal day (P)14. Human fetal islets at 18-20 weeks gestation released insulin in response to lower glucose concentrations (1-2 mM), compared to adult islets (3-5 mM). Similarly, rat islets at e22-P1 also had a lower glucose threshold for insulin release (3mM), compared to P14 islets (5 mM). BCH, a leucine analog that activates glutamate dehydrogenase, also stimulated insulin release at a lower concentration in e22-P1 rat islets (1mM), compared to P14 islets (3mM). This suggests that the mechanism of the islet adaptation in intrauterine life lies distal to glycolysis and fuel oxidation, potentially in differences in membrane depolarization or repolarization. In addition, human fetal islets released insulin in response to lactate, while late embryonic rat islets did not, suggesting insulin release in response to other nutrient stimuli may also be part of this maturational islet adaptation. Ongoing experiments are further exploring substrate-induced insulin release in immature islets, in parallel with the characterization of β cell transcriptomic maturation at the single cell level in both human and rat. Understanding the functional maturation of β cells during the fetal and neonatal period, coupled with the insight into the molecular mechanisms responsible for this maturation, can lead of the development of molecular markers of a dysregulated β cell function that is may persist beyond early neonatal period. Disclosure D.E. Stanescu: Employee; Spouse/Partner; GlaxoSmithKline plc.. C. Li: None. J. Yang: None. D. Yau: None. C.A. Stanley: None.

Hypoglycemic relapse in term infants treated with glucose infusion

Background: Hypoglycemia, being a common, potentially serious problem in neonatology, is screened in at-risk newborzns. However, there is little evidence regarding the screening of hypoglycemic relapse after treatment by glucose infusion. Objectives: We aimed to determine whether measuring blood glucose levels 3, 6, and 9 h after weaning from glucose infusion is appropriate to detect hypoglycemic relapse. Methods: This is a single-center retrospective study (2005–2014) measuring the proportion of infants who experienced hypoglycemic relapse (glucose level <2.5 mmol/L) after withdrawal of glucose infusion as well as the “time to relapse” in a population of 129 consecutive patients treated with glucose infusion for severe or prolonged neonatal hypoglycemia. Results: No newborn (0%, 95% confidence interval [CI]: 0%–2.9%) had hypoglycemic relapse within the first 3 h after weaning from glucose infusion. Five infants (3.9%, 95% CI: 1.7%–8.8%) and three infants (2.3%, 95% CI: 0.8%–6.6%) had hypoglycemic relapse, respectively, 6 and 9 h after weaning. All relapses were of mild severity (blood glucose level: 2.0–2.5 mmol/L). Lower birth weight (BW) (P = 0.008) and small for gestational age (SGA) (P = 0.003) were associated with the increased risk of hypoglycemic relapse. Conclusions: In a population of term newborns presenting with hypoglycemia requiring glucose infusion, only a small proportion presented with mild hypoglycemia relapse after weaning from infusion, lower BW and SGA were the main risk factors. Future research should assess whether it is sufficient to control only at-risk infants for relapse after a progressive weaning from infusion.

Association Between Transient Newborn Hypoglycemia and Fourth-Grade Achievement Test Proficiency

Prolonged neonatal hypoglycemia is associated with poor long-term neurocognitive function. However, little is known about an association between early transient newborn hypoglycemia and academic achievement. To determine if early (within the first 3 hours of life) transient hypoglycemia (a single initial low glucose concentration, followed by a second value above a cutoff) is associated with subsequent poor academic performance. A retrospective population-based cohort study of all infants born between January 1, 1998, and December 31, 1998, at the University of Arkansas for Medical Sciences who had at least 1 recorded glucose concentration (a universal newborn glucose screening policy was in effect) was conducted. Medical record data from newborns with normoglycemia or transient hypoglycemia were matched with their student achievement test scores in 2008 from the Arkansas Department of Education and anonymized. Logistic regression models were developed to evaluate the association between transient hypoglycemia and school-age achievement test proficiency based on perinatal factors. Common hypoglycemia cutoffs of a glucose level less than 35 mg/dL (primary) and less than 40 and 45 mg/dL (secondary) were investigated. All 1943 normoglycemic and transiently hypoglycemic infants (23-42 weeks' gestation) were eligible for inclusion in the study. Infants with prolonged hypoglycemia, congenital anomalies, or chromosomal abnormalities were excluded from the study. Hypoglycemia as a newborn. The primary outcome was proficiency on fourth-grade literacy and mathematics achievement tests at age 10 years. We hypothesized a priori that newborns with early transient hypoglycemia would be less proficient on fourth-grade achievement tests compared with normoglycemic newborns. Perinatal data were matched with fourth-grade achievement test scores in 1395 newborn-student pairs (71.8%). Transient hypoglycemia (glucose level <35, <40, and <45 mg/dL) was observed in 6.4% (89 of 1395), 10.3% (143 of 1395), and 19.3% (269 of 1395) of newborns, respectively. After controlling for gestational age group, race, sex, multifetal gestation, insurance status, maternal educational level and socioeconomic status, and gravidity, transient hypoglycemia was associated with decreased probability of proficiency on literacy and mathematics fourth-grade achievement tests. For the 3 hypoglycemia cutoffs, the adjusted odds ratios (95% CIs) for literacy were 0.49 (0.28-0.83), 0.43 (0.28-0.67), and 0.62 (0.45-0.85), respectively, and the adjusted odds ratios (95% CIs) for mathematics were 0.49 (0.29-0.82), 0.51 (0.34-0.78), and 0.78 (0.57-1.08), respectively. Early transient newborn hypoglycemia was associated with lower achievement test scores at age 10 years. Given that our findings are serious and contrary to expert opinion, the results need to be validated in other populations before universal newborn glucose screening should be adopted.

A case of glycogen storage disease type Ib presenting with prolonged neonatal hypoglycaemia and minimal metabolic abnormalities

A case of glycogen storage disease type Ib presenting with prolonged neonatal hypoglycaemia and minimal metabolic abnormalities

Hyperinsulinisme de l'enfant et de l'adolescent: quand la détermination de la concentration en insuline n'est pas toujours suffisante (version française)

Hypoglycemia in infants and children can lead to seizures, developmental delay, and permanent brain damage. Hyperinsulinism (HI) is the most common cause of both transient and permanent disorders of hypoglycemia. HI is characterized by dysregulated insulin secretion, which results in persistent mild to severe hypoglycemia. The various forms of HI represent a group of clinically, genetically, and morphologically heterogeneous disorders. Congenital hyperinsulinism is associated with mutations of SUR-1 and Kir6.2, glucokinase, glutamate dehydrogenase, short-chain 3-hydroxyacyl-CoA dehydrogenase, and ectopic expression on beta-cell plasma membrane of SLC16A1. Hyperinsulinism can be associated with perinatal stress such as birth asphyxia, maternal toxemia, prematurity, or intrauterine growth retardation, resulting in prolonged neonatal hypoglycemia. Mimickers of hyperinsulinism include neonatal panhypopituitarism, drug-induced hypoglycemia, insulinoma, antiinsulin and insulin-receptor stimulating antibodies, Beckwith-Wiedemann Syndrome, and congenital disorders of glycosylation. Laboratory testing for hyperinsulinism may include quantification of blood glucose, plasma insulin, plasma beta-hydroxybutyrate, plasma fatty acids, plasma ammonia, plasma acylcarnitine profile, and urine organic acids. Genetic testing is available through commercial laboratories for genes known to be associated with hyperinsulinism. Acute insulin response (AIR) tests are useful in phenotypic characterization. Imaging and histologic tools are also available for diagnosing and classifying hyperinsulinism. The goal of treatment in infants with hyperinsulinism is to prevent brain damage from hypoglycemia by maintaining plasma glucose levels above 700 mg/L (70 mg/dL) through pharmacologic or surgical therapy. The management of hyperinsulinism requires a multidisciplinary approach that includes pediatric endocrinologists, radiologists, surgeons, and pathologists who are trained in diagnosing, identifying, and treating hyperinsulinism.

Associated factors in neonatal hypoglycemic brain injury

Although associated factors are important for the occurrence of neural damage in neonatal hypoglycemia, they are not fully understood. Sixty patients with neonatal hypoglycemia were studied through a review of their medical records in Tottori University Hospital. The patients were classified into two main groups: Group I were patients who had mental retardation, developmental delay, cerebral palsy or epilepsy while Group II were those who were normal in their follow-up. Group I consisted of 12 patients while Group II consisted of 48 patients. The median gestational age was 38 weeks in Group I and 36.7 weeks in Group II. The frequencies of small for gestational age were similar in both groups. Blood glucose levels less than 15 mg/dl were more frequent in Group 1 (50.0%) than in Group 2 (14.6%) ( P = 0.015). Duration of hypoglycemia was longer in Group I (median, 14 h) than in Group II (median, 1.75 h) ( p < 0.001). The following factors were more frequent in Group I than in Group II: toxemia (33.3% and 8.3%, p = 0.043), fetal distress (58.3% and 14.5%, p = 0.004), an Apgar score of less than 5 at 1 min (33.3% and 6.4%, p = 0.025), neonatal seizure (53.8% and 4.3%, p < 0.001) and pathological jaundice (41.7% and 6.4%, p = 0.006). Cranial CT or MRI revealed cerebral lesions in 8 of the 9 Group I patients in follow-up examinations. This study indicates that severe and prolonged neonatal hypoglycemia can cause cerebral lesions and other perinatal risk factors, such as hypoxia, neonatal seizure and pathological jaundice, would exacerbate hypoglycemic brain injuries.

Hiperinsulinismo na infância: quando apenas uma dosagem de insulina não é suficiente

INTRODUCAO: A hipoglicemia em bebes e criancas pode causar convulsoes, atraso de desenvolvimento e dano cerebral permanente. O hiperinsulinismo (HI) e a causa mais comum de hipoglicemia, seja transitoria ou permanente. A HI e caracterizada pela secrecao inadequada de insulina, o que resulta em hipoglicemia persistente, de leve a grave. As diferentes formas de HI representam um grupo de doencas clinica, genetica e morfologicamente heterogeneo. CONTEUDO: Hiperinsulinismo congenito esta associado as mutacoes de SUR-1 e Kir6.2, glucoquinase, glutamato desidrogenase, 3-hidroxiacil-CoA desidrogenase de cadeia curta e expressao ectopica de SLC16A1 na membrana plasmatica das celulas beta. O HI pode estar associado ao estresse perinatal, como asfixia do nascimento, toxemia materna, prematuridade ou retardo do crescimento intra-uterino, resultando em hipoglicemia neonatal prolongada. Mimetismo de HI neonatal inclui pan-hipopituitarismo, hipoglicemia induzida por farmaco, insulinoma, anticorpos antiinsulina e estimuladores do receptor de insulina, sindrome de Beckwith-Wiedemann e disturbios congenitos de glicosilacao. Exames laboratoriais para HI podem incluir quantificacao de glicose, insulina, β-hidroxibutirato, acidos graxos, amonia e perfil de acilcarnitinas plasmaticos, alem de acidos orgânicos urinarios. Os exames geneticos estao disponiveis em laboratorios comerciais para os genes sabidamente associados a hiperinsulinemia. Testes de resposta insulinica aguda (RIA) sao uteis na caracterizacao fenotipica. Exames de imagem e histologicos tambem estao disponiveis para diagnosticar e classificar o HI. O objetivo do tratamento de criancas com HI e prevenir os danos cerebrais da hipoglicemia, mantendo niveis de glicose plasmatica acima de 70mg/dl por terapia farmacologica ou cirurgica. CONCLUSAO:A terapeutica do HI requer abordagem multidisciplinar que inclui endocrinologistas pediatricos, radiologistas, cirurgioes e patologistas, os quais sao treinados para diagnosticar, identificar e tratar o hiperinsulinismo.

Hyperinsulinism in Infancy and Childhood: When an Insulin Level Is Not Always Enough

Hypoglycemia in infants and children can lead to seizures, developmental delay, and permanent brain damage. Hyperinsulinism (HI) is the most common cause of both transient and permanent disorders of hypoglycemia. HI is characterized by dysregulated insulin secretion, which results in persistent mild to severe hypoglycemia. The various forms of HI represent a group of clinically, genetically, and morphologically heterogeneous disorders. Congenital hyperinsulinism is associated with mutations of SUR-1 and Kir6.2, glucokinase, glutamate dehydrogenase, short-chain 3-hydroxyacyl-CoA dehydrogenase, and ectopic expression on beta-cell plasma membrane of SLC16A1. Hyperinsulinism can be associated with perinatal stress such as birth asphyxia, maternal toxemia, prematurity, or intrauterine growth retardation, resulting in prolonged neonatal hypoglycemia. Mimickers of hyperinsulinism include neonatal panhypopituitarism, drug-induced hypoglycemia, insulinoma, antiinsulin and insulin-receptor stimulating antibodies, Beckwith-Wiedemann Syndrome, and congenital disorders of glycosylation. Laboratory testing for hyperinsulinism may include quantification of blood glucose, plasma insulin, plasma beta-hydroxybutyrate, plasma fatty acids, plasma ammonia, plasma acylcarnitine profile, and urine organic acids. Genetic testing is available through commercial laboratories for genes known to be associated with hyperinsulinism. Acute insulin response (AIR) tests are useful in phenotypic characterization. Imaging and histologic tools are also available for diagnosing and classifying hyperinsulinism. The goal of treatment in infants with hyperinsulinism is to prevent brain damage from hypoglycemia by maintaining plasma glucose levels above 700 mg/L (70 mg/dL) through pharmacologic or surgical therapy. The management of hyperinsulinism requires a multidisciplinary approach that includes pediatric endocrinologists, radiologists, surgeons, and pathologists who are trained in diagnosing, identifying, and treating hyperinsulinism.

Is There a Role for Oral Antihyperglycemics in Gestational Diabetes and Type 2 Diabetes during Pregnancy?

Diabetes mellitus is a heterogeneous disorder of glucose intolerance that is generally classified into the following categories: type 1 and type 2 diabetes and gestational diabetes (GDM). Currently, the number of pregnancies complicated by type 2 diabetes and GDM exceed those affected by type 1 diabetes. Numerous studies have established a direct relationship between maternal glycemic control and neonatal outcomes for all types of diabetes. Therefore, modern treatment protocols during pregnancy emphasize strict glycemic control by a combination of diet and medication. Traditionally, insulin therapy has been considered the gold standard for management because of its efficacy in achieving tight glucose control and the fact that it does not cross the placenta. Since GDM and type 2 diabetes are characterized by insulin resistance and relatively decreased insulin secretion, treatment with oral antihyperglycemic agents that target these defects is of potential interest. However, because of concerns regarding transplacental passage and, therefore, the possibility of fetal teratogenesis and prolonged neonatal hypoglycemia, these agents are not currently recommended in pregnancy. There are no randomized controlled trials on which to draw conclusions regarding the teratogenicity of these oral agents. However, most retrospective studies and the published clinical experience have not demonstrated an increased risk of malformed infants among women treated with oral antihyperglycemic agents. Rather, the data indicate that the increased risk for major congenital anomalies appears to be related to maternal glycemic control prior to and during conception. These studies and currently available data on the use of both metformin and sulfonylureas in pregnancy have also failed to demonstrate an increased risk of neonatal hypoglycemia and other neonatal morbidities. To date, there has only been one randomized controlled trial to test the effectiveness and safety of sulfonylurea therapy (glyburide [glibenclamide]) in the management of women with GDM. Both the insulin- and glyburide-treated women were able to achieve satisfactory glucose control and had similar perinatal outcomes. Glyburide was not detected in the cord serum of any infant in the glyburide group. In summary, based on the currently available data, it appears that glyburide could be safely and effectively utilized in the management of GDM. However, more intensive investigation regarding the safety and feasibility of oral agents in pregnancies complicated by type 2 diabetes is necessary. It is important to emphasize that it is the level of metabolic control achieved and not the mode of therapy that is crucial to improving outcomes in these pregnancies.

Anesthetic considerations of an infant with Beckwith-Wiedemann syndrome

The case of a 3-day-old infant with Beckwith-Wiedemann syndrome who required anesthetic care during closure of an abdominal wall defect is presented. Beckwith-Wiedemann syndrome comprises a constellation of clinical features, including macroglossia, macrosomia, omphalocele, visceromegaly, mild microcephaly, facial nevus flammeus, horizontal earlobe creases, and renal medullary dysplasia. Due to the high rate of omphalocele in this syndrome, anesthetic care is frequently required during the neonatal period. Many of these infants (greater than 50%) are born prematurely. Therefore, their anesthetic care may be further complicated by associated diseases of prematurity, such as hyaline membrane disease. Additional anesthetic implications of this syndrome relate to the occurrence and management of hypoglycemia and polycythemia. Careful intraoperative management of glucose homeostasis is particularly important, since eventual neurologic outcome and intelligence will be normal provided prolonged neonatal hypoglycemia is avoided. Preoperative evaluation of the cardiac and genitourinary system, including echocardiography and renal ultrasound, are recommended because of the frequent occurrence of associated anomalies with omphalocele.

Effects of in-utero exposure to oral hypoglycaemic drugs

The observation that several Mexican-American women were taking oral hypoglycaemic agents while pregnant led to a study to confirm reports of associations between these agents and congenital abnormalities. 20 non-insulin-dependent (NIDDM) pregnant diabetic women with exposure to oral hypoglycaemic drugs during embryogenesis and 40 pregnant NIDDM women matched for age, race, parity, weight, and glycaemic control but not exposed to oral hypoglycaemic drugs were followed up. 10 infants (50%) in the exposed group had congenital malformations, compared with only 6 (15%) in the control group (p<0·002). 5 (25%) infants in the exposed group had ear malformations, anomalies not commonly described in diabetic embryopathy. Hyperbilirubinemia (p<0·04), polycythaemia, and hyperviscosity requiring partial exchange transfusions (p<0·03) were commoner among babies in the exposed than in the control group. 3 babies in the exposed group but none in the comparison group had severe prolonged neonatal hypoglycaemia lasting 2, 4, and 7 days; 2 of the 3 had been exposed for 22 and 28 weeks during gestation, whereas the third had been exposed throughout the first trimester. Although exposure to oral hypoglycaemic drugs during fetal life seems to be associated with congenital malformations and neonatal hypoglycaemia, a large, prospective study is needed to exclude the confounding effect of maternal metabolic derangement secondary to diabetes.