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Hypoglycemia in the Neonate
Marvin Cornblath and Rebecca Ichord

After a brief history of the development of neonatal hypoglycemia, this review emphasizes the current approach to the anticipation, diagnosis, and management of the neonate with a low plasma glucose concentration. Current techniques for studying the neurophysiological and endocrine-metabolic effects of significant hypoglycemiaprovide new approaches for establishing relevant definitions of significant hypoglycemia, its prognosis, and pathogenesis. The inadequacy of glucose oxidase strips for screening, the definition of high-risk infants, new definitions for low plasma glucose concentrations, and their treatment are presented as well as the ability of the neonate to respond to significantly low glucose values. New dataconcerning the hereditary aspects of hyperinsulinemia (Glaser, this issue), hereditary defects in branched-chain amino acid, 3-methylglntaconic aciduria and mitochondrial ~oxidation, and degradation of fatty acids (Ozand, this issue), the role of glucose transporters (Vannucci and Vannucci, this issue), and the newer computed tomography and magnetic resonance imaging techniques (Kinnala, this issue)to study neonatal hypoglycemia are reviewed elsewhere in this issue. Copyright 9 2000 by W.B. Saunders Company
n 1937, H a r t m a n n a n d J a u d o n ~ first r e p o r t e d 286 neonates a n d infants with significant hypoglycemia who had clinical manifestations a n d / o r r e c u r r e n t or persistent low "true" b l o o d sugar values. These authors defined degrees of severity ofhypoglycemia as: "mild" between 40 m g / d L and 50 m g / d L (2.2 to 2.8 m m o l / L ) , "moderate" between 20 m g / d L and 40 m g / d L (1.1 to.2.2 m m o l / L ) , and "extreme" less than 20 m g / d L (1.1 m m o l / L ) . This a p p r o a c h e m p h a sized the c o n c e p t that all deviations f r o m biologic n o r m s r e p r e s e n t a c o n t i n u u m of abnormality f r o m mild to severe.Multiple studies between 1929 and 1955 confirmed that the b l o o d sugar values were lower in p r e m a t u r e a n d low birth weight infants and infants of diabetic m o t h e r s than those in t e r m neonates. Blood sugar values in t e r m newborns were less than in older infants and children. However, little or no clinical significance was attributed to these low values. W h e n the firstneonates were recognized as having significant hypoglycemia in the mid-

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From the Division of Neonatology, Departments of Pediatrics and Department of Neurology, Johns Hopkins University School of Medidne, Baltimore, MD. Address reprint requests to Rebecca Ichord, MD, Department of Pediatric Newrology, Harvey 811, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287-8811; e-mailrichord@jhmi.edu Copyright 9 2000 by W.B. Saunders Company O146-0005/00/2402-0006510. 00/0 doi: 10.1053/sp. 2000. 6364

1950s, the infants had striking clinical manifestations, often seizures, and their b l o o d sugar values were almost always less than 20 to 25 m g / d L (1.1 to 1.4 m m o l / L ) . T h e a b n o r m a l signs cleared p r o m p t l y after restoring the b l o o d glucose concentration ton o r m a l ( > 4 0 m g / d L [2.2 m m o l / L ] ) ? -3 T h e presence of clinical manifestations, a reliable significantly low b l o o d glucose value and a p r o m p t response to a d e q u a t e therapy fulfill the requirements o f W h i p p l e ' s Triad, 4 a criteria still critical in m a k i n g a diagnosis of significant hypoglycemia at any age. T h e initial skepticism as to whether or nottransient symptomatic hypoglycemia existed was dispelled as verification was r e p o r t e d f r o m nurseries a r o u n d the world. 5-12 Infants at risk were p r e d o m i n a n t l y boys, small for gestational age (SGA), the smaller o f twins and being b o r n to toxemic mothers. 7,1s-17 T h e i r associated p r o b l e m s (pre- or coexisting) included central nervous system damage,...