Clinical Pediatrics 1–6 © The Author(s) 2019 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/0009922819875540 journals.sagepub.com/home/cpj Commentary Background Attempt to define “significant hypoglycemia” was made by Hartmann et al in 1937. 1 In the 1940s, reports described increased mortality among infants born to mothers with diabetes. 2 Suggestions were made to treat these infants with sugar water or breastfeeding to prevent mortality. 3 Important updates about the definition, clinical presenta- tion, and management of neonatal hypoglycemia have been reported since the middle of the 20th century. It remains one of the most controversial topics in the field of neonatology, especially regarding the numerical defini- tion of neonatal hypoglycemia, which may result in long- term neurological and developmental consequences. 4-7 Therefore, the American Academy of Pediatrics (AAP) and the Pediatric Endocrine Society (PES) recommend using arbitrary glucose levels, for which interventions are needed to increase the “blood glucose” (BG) levels. 8,9 The main goal of these recommendations is to reduce the potential adverse events associated with persistent, pro- longed, or symptomatic hypoglycemia. In healthy pregnancies, maternal glucose is the pri- mary source of glucose supply to the fetus. 8,10 During fetal life, glucose follows carrier-mediated transport pat- tern from the mother to the fetus. At birth, the newborn BG is about 70% of the maternal BG level. 9 Previous studies have shown that there is a gradual physiological drop in the BG level in healthy infants during the first few hours after birth. 11-13 Higher insulin levels after birth in infants at risk for hypoglycemia compared with children and adult augment this drop. 14 Multiple theories have been proposed to explain the persistence of higher insulin levels. These include insulin transfer through the placenta from mother to the fetus, stress response at birth, and hypersensitivity of pancreatic B-cell. Associated with this higher insulin levels is the lower serum ketone levels. 15 The low BG and ketones result in less available energy fuel for cellular function. However, the majority of new- borns remain asymptomatic during this period of these “physiological” low BG levels. Epidemiology Neonatal hypoglycemia is one of the most common diagnoses that require admission to the neonatal intensive care unit. The true incidence of neonatal hypoglycemia varies significantly among different studies because differ- ent levels of BG were used to define hypoglycemia. 16-18 Harris et al. 19 reported incidence of 51% and 19% in infants with risk factors for hypoglycemia when the BG levels of <47 mg/dL and <36 mg/dL were used, respec- tively, for the diagnosis of hypoglycemia. Glucose is the primary source of energy, and the BG level depends on demand and supply. Therefore, any interference with either a decrease in production/supply or increase in consumption can result in hypoglycemia, as shown in Table 1. 20-24 Clinical Presentation Clinical signs and symptoms of neonatal hypoglycemia are nonspecific and mimic many other conditions in neonates 25,26 (Table 2). Therefore, it is essential to rule out other potentially severe or treatable conditions such as sepsis and asphyxia that can have manifestations similar to hypoglycemia or result in hypoglycemia. Diagnosis Blood glucose level testing is not required in healthy infants who lack the risk factors mentioned in Table 1. When deciding the glucose level for which interven- tions are required, it is essential to remember that the values obtained from the whole blood (point-of-care devices) are usually 15% lower than those obtained from plasma (central laboratory values). 27-29 Another factor to consider that can affect the accuracy of glu- cose-level measurement is the method used to obtain these values. Glucose oxidase and peroxidase chromo- gen test strips (the most common method used in most nurseries) have been reported to have less accuracy, especially with the low values when compared with 875540CPJ XX X 10.1177/0009922819875540Clinical PediatricsAlsaleem et al research-article 2019 1 The State University of New York, University at Buffalo, Buffalo, NY, USA 2 UT Health San Antonio, San Antonio, TX, USA Corresponding Author: Mahdi Alsaleem, Children’s Mercy Hospital, University of Kansas, 3600 E Harry St. Wichita, KS 67218, USA. Email: [email protected] Neonatal Hypoglycemia: A Review Mahdi Alsaleem, MD 1 , Lina Saadeh, MD 1 , and Deepak Kamat, MD, PhD, FAAP 2
Neonatal Hypoglycemia: A Review
Oct 25, 2022
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Neonatal Hypoglycemia: A ReviewCommentary
Background
Attempt to define “significant hypoglycemia” was made by Hartmann et al in 1937.1 In the 1940s, reports described increased mortality among infants born to mothers with diabetes.2 Suggestions were made to treat these infants with sugar water or breastfeeding to prevent mortality.3 Important updates about the definition, clinical presenta- tion, and management of neonatal hypoglycemia have been reported since the middle of the 20th century. It remains one of the most controversial topics in the field of neonatology, especially regarding the numerical defini- tion of neonatal hypoglycemia, which may result in long- term neurological and developmental consequences.4-7 Therefore, the American Academy of Pediatrics (AAP) and the Pediatric Endocrine Society (PES) recommend using arbitrary glucose levels, for which interventions are needed to increase the “blood glucose” (BG) levels.8,9 The main goal of these recommendations is to reduce the potential adverse events associated with persistent, pro- longed, or symptomatic hypoglycemia.
In healthy pregnancies, maternal glucose is the pri- mary source of glucose supply to the fetus.8,10 During fetal life, glucose follows carrier-mediated transport pat- tern from the mother to the fetus. At birth, the newborn BG is about 70% of the maternal BG level.9 Previous studies have shown that there is a gradual physiological drop in the BG level in healthy infants during the first few hours after birth.11-13 Higher insulin levels after birth in infants at risk for hypoglycemia compared with children and adult augment this drop.14 Multiple theories have been proposed to explain the persistence of higher insulin levels. These include insulin transfer through the placenta from mother to the fetus, stress response at birth, and hypersensitivity of pancreatic B-cell. Associated with this higher insulin levels is the lower serum ketone levels.15 The low BG and ketones result in less available energy fuel for cellular function. However, the majority of new- borns remain asymptomatic during this period of these “physiological” low BG levels.
Epidemiology
Neonatal hypoglycemia is one of the most common diagnoses that require admission to the neonatal intensive
care unit. The true incidence of neonatal hypoglycemia varies significantly among different studies because differ- ent levels of BG were used to define hypoglycemia.16-18 Harris et al.19 reported incidence of 51% and 19% in infants with risk factors for hypoglycemia when the BG levels of <47 mg/dL and <36 mg/dL were used, respec- tively, for the diagnosis of hypoglycemia.
Glucose is the primary source of energy, and the BG level depends on demand and supply. Therefore, any interference with either a decrease in production/supply or increase in consumption can result in hypoglycemia, as shown in Table 1.20-24
Clinical Presentation
Clinical signs and symptoms of neonatal hypoglycemia are nonspecific and mimic many other conditions in neonates25,26 (Table 2). Therefore, it is essential to rule out other potentially severe or treatable conditions such as sepsis and asphyxia that can have manifestations similar to hypoglycemia or result in hypoglycemia.
Diagnosis
Blood glucose level testing is not required in healthy infants who lack the risk factors mentioned in Table 1. When deciding the glucose level for which interven- tions are required, it is essential to remember that the values obtained from the whole blood (point-of-care devices) are usually 15% lower than those obtained from plasma (central laboratory values).27-29 Another factor to consider that can affect the accuracy of glu- cose-level measurement is the method used to obtain these values. Glucose oxidase and peroxidase chromo- gen test strips (the most common method used in most nurseries) have been reported to have less accuracy, especially with the low values when compared with
875540 CPJXXX10.1177/0009922819875540Clinical PediatricsAlsaleem et al research-article2019
1The State University of New York, University at Buffalo, Buffalo, NY, USA 2UT Health San Antonio, San Antonio, TX, USA
Corresponding Author: Mahdi Alsaleem, Children’s Mercy Hospital, University of Kansas, 3600 E Harry St. Wichita, KS 67218, USA. Email: [email protected]
Neonatal Hypoglycemia: A Review
Mahdi Alsaleem, MD1 , Lina Saadeh, MD1, and Deepak Kamat, MD, PhD, FAAP2
2 Clinical Pediatrics 00(0)
the regular laboratory measurement using hexokinase- based method.30 For that reason, it is highly recom- mended to confirm the “significant glucose” levels obtained by the bedside chromogen test strip by labo- ratory methods before deciding whether to intervene based on that level. Recently, there has been an increasing interest in using “continuous glucose monitoring” (CGM) devices in the neonates. Multiple studies have shown that the use of CGM in both pre- term and near-term neonates is safe and practical with acceptable correlation with routine bedside BG mea- surement.31-34 Technological advancement in CGM sensors has resulted in more convenient nursing care35 and has shown a significant reduction of the proce- dural pain associated with the conventional methods of glucose monitoring.36 Despite these available data about safety and accuracy, well-designed randomized clinical trials are still required before the adoption of this method to become the standard of care for BG monitoring.
The timing of glucose screening in infants with risk factors, or those who exhibit symptoms, can be summa- rized as follows:
1. BG level should be obtained anytime infant is symptomatic.
2. For an infant who is asymptomatic but at risk for hypoglycemia, screening should be started after the first feed and continued at regular intervals before every feed for the first 24 hours.
3. For an infant who has a low BG level, bedside glucose monitoring should continue before feeds until BG levels can be maintained >60 mg/dL (3.3 mmol/L) for 24 hours.
Management
The goal of management of neonatal hypoglycemia is to prevent and treat acute symptomatic hypoglycemia, which can result in possible permanent brain damage and long-term adverse outcomes. A successful manage- ment plan should include identifying and treating the underlying etiology for hypoglycemia.
The most common etiology for neonatal hypoglyce- mia is the sudden cessation of glucose supply after the umbilical cord clamping, along with the transient eleva- tion of insulin level. Therefore, it is crucial to provide carbohydrate substrate source that can maintain physio- logic BG level to maintain cellular function and replen- ish the energy stores. A common management protocol in nurseries, with the recent use of dextrose gel, usually follows the approach shown in Figure 1. Refeeding with maternal breast milk and/or formula if feasible and not contraindicated should be the initial approach for man- agement of neonatal hypoglycemia.37,38 If low BG levels persist despite enteral feeds, then consideration should be given to provide more concentrated, rapidly absorb- able glucose source. Many studies have reported success rate with dextrose gel directly applied to the buccal mucosa.39-43 The use of dextrose gel has been shown to lower the incidence of neonatal intensive care unit admissions, lessen the disruption to parental bonding, and increase in cost saving. The use of dextrose gel as hypoglycemia preventive measure in infants at risk did not show a decrease in the incidence or the severity of neonatal hypoglycemia.44
Initiation of intravenous (IV) dextrose therapy should be considered if BG levels remain below the operational threshold after enteral feed and dextrose gel, or if the infant is unable to tolerate oral intake. As mentioned ear- lier, there is a lack of enough evidence and long-term outcome data on the specific numerical BG level at which one should initiate IV dextrose therapy. However, to help guide the clinicians, both AAP45 and PES46
Table 1. Risk Factors for Neonatal Hypoglycemia in Newborns.
Decrease in Glucose Supply
restrictiona Large for gestational age
Glycogen metabolism disordersa
Disorders of gluconeogenesisa
Polycythemia
Perinatal asphyxia or stressa
Hepatic dysfunction Congenital hyperinsulinemiaa
aConditions that can result in persistent hypoglycemia (low-blood glucose levels after 48 hours of life).
Table 2. Clinical Signs and Symptoms of Neonatal Hypoglycemia.
Symptoms Signs
Alsaleem et al 3
recommended operational threshold levels with time correlation with age in hours to intervene and to initiate IV dextrose, as shown in Figure 2.
Intravenous dextrose-containing fluid is initiated to provide a glucose infusion rate of 4 to 6 mg/kg/min in term infants and 6 to 8 mg/kg/min in preterm infants. Dextrose mini-boluses of 2 mL/kg of 10% dextrose solution can be considered.47 Close monitoring of BG levels is necessary to avoid the risk of rapid correction as this may lead to high BG levels, which can be associ- ated with adverse neurological outcomes.48,49 Central line access should be considered if requiring dextrose concentration above >12.5% to maintain euglycemia, due to the high risk of vessels injury.50
If neonates continue to have low BG levels requiring high GIR of >10 mg/kg/min after 48 hours to maintain average BG levels, then etiologies other than transient hyperinsulinemia should be considered.51 These include but not limited to persistent congenital hyperinsulinism, fatty acid oxidation defects, glycogen storage diseases, or hormonal abnormalities such as growth hormone and cortisol deficiencies.
Before discharge, the infant with neonatal hypoglyce- mia should be able to maintain pre-feed BG > 60 mg/dL (AAP recommendations) or > 70 mg/dL if persistent hypoglycemia is suspected (for conditions represented with superscript “a” in Table 1, PES recommendations).
This stability should be achieved with proper oral intake without the IV dextrose for at least 24 hours on an accept- able feeding schedule every 3 to 4 hours. Performing fasting test (performing BG check after skipping 1 feed) is recommended by PES, after achieving stable BG on a regular feeding schedule, to exclude the possibility of metabolic causes of hypoglycemia, which can manifest with prolonged fasting.
Outcomes
The chances of brain damage as seen on magnetic reso- nance imaging and the adverse long-term neurodevelop- mental outcomes are higher in infants with symptomatic hypoglycemia.52-57 However, uncertainty exists about the BG level and the duration of hypoglycemia that can result in these consequences. The most severe immediate concern is seizure. The majority of neonates who developed seizures had persistent and severe hypoglycemia.58,59 The evidence is less clear about the association between asymptomatic hypoglycemia and adverse neurodevel- opmental outcome.60 A prospective study was conducted by McKinlay et al,61 which included infants born >32 weeks of gestation. They compared the outcomes at 2 years and again at 4.5 years of age between the groups who received treatment to maintain BG > 47 mg/dL versus those who did not require interventions. There
Dextrose gel (200mg/kg) to buccal mucosa
Confirmed BG < operational threshold after first feed.
(See figure 2 for operational threshold)
Start IV Dextrose fluid with GIR of 4-8 mg/kg/min ± Dextrose 10%
bolus Refeed ( MBM or formula)
A ble to feed?
H ypoglycem
ia resolved?
Regular newborn care, continue to check BG before each feed until stable (>60 mg/dl) for 24 hours.
H ypoglycem
ia resolved?
Figure 1. The management approach for neonatal hypoglycemia. GIR, glucose infusion rate; IV, intravenous; MBM, maternal breast milk. *Optional but recommended based on multiple recent studies.
4 Clinical Pediatrics 00(0)
was no difference at 2 years; however, those who required treatment had increased evidence of poor exec- utive as well as visual motor function at 4 to 5 years of age. In a more recent systemic review and meta-analysis that included 11 studies, which focused on outcomes following neonatal hypoglycemia,62 no association was found between neonatal hypoglycemia and neurodevel- opmental impairment in early childhood (2-5 years) period. However, visual and executive functions were affected. In older children (6-11 years), the risks for neu- rodevelopmental impairment as well as low literacy and numeracy were reported.62
Conclusion
The evidence is limited about the specific BG level that can result in permanent brain damage and adverse neuro- developmental outcome in healthy newborns; however, symptomatic infants with persistent or prolonged hypo- glycemia should be treated to restores glucose hemostasis. In persistent neonatal hypoglycemia, further evaluation should be performed to exclude other etiologies. Future use of CGM will provide a great opportunity to improve our knowledge regarding glucose hemostasis after birth.
Authors’ Note
Mahdi Alsaleem is also affiliated with Children’s Mercy Hospital and University of Kansas, Wichita, KS, USA.
Author Contributions
MA, LS and DK conceived and designed the review, and chose the research terms. MA and LS wrote the first draft of the manuscript. MA, LS and DK made substantial contribu- tions to the interpretation of articles found and were involved in drafting the manuscript and made critical revisions of the manuscript. All authors read and approved the version to be published.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD
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2. Miller HC, Hurwitz D, Kuder K. Fetal and neonatal mor- tality in pregnancies complicated by diabetes mellitus. JAMA. 1944;124:271-275.
3. Soderling B. Hazards of the infants of diabetic moth- ers during the neonatal period and views on treatment. Nordisk Medicin. 1940;8:2000-2002.
4. Cornblath M, Hawdon JM, Williams AF, et al. Controversies regarding definition of neonatal hypo- glycemia: suggested operational thresholds. Pediatrics. 2000;105:1141-1145.
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7. Rozance PJ, Hay WW, Jr. Neonatal hypoglycemia— answers, but more questions. J Pediatr. 2012;161:775- 776.
Figure 2. Operational threshold for blood glucose levels that require intervention according to both AAP and PES. *IV dextrose fluid is recommended at the lower threshold. +: <70 in infants with suspected persistent hypoglycemia. AAP, American Academy of Pediatrics; PES, Pediatric Endocrine Society.
8. Hay WW, Jr. Placental-fetal glucose exchange and fetal glucose metabolism. Trans Am Clin Climatol Assoc. 2006;117:321-340.
9. Pildes RS, Pyati SP. Hypoglycemia and hyperglycemia in tiny infants. Clin Perinatol. 1986;13:351-375.
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12. Marconi AM, Paolini C, Buscaglia M, Zerbe G, Battaglia FC, Pardi G. The impact of gestational age and fetal growth on the maternal-fetal glucose concentration differ- ence. Obstet Gynecol. 1996;87:937-942.
13. Bozzetti P, Ferrari MM, Marconi AM, et al. The rela- tionship of maternal and fetal glucose concentrations in the human from midgestation until term. Metabolism. 1988;37:358-363.
14. Hawdon JM, Weddell A, Aynsley-Green A, Platt MPW. Hormonal and metabolic response to hypoglycaemia in small for gestational age infants. Arch Dis Child. 1993;68(3 Spec No):269-273.
15. Hawdon JM, Ward Platt MP, Aynsley-Green A. Patterns of metabolic adaptation for preterm and term infants in the first neonatal week. Arch Dis Child. 1992;67(4 Spec No):357-365.
16. Pildes R, Forbes AE, O’Connor SM, Cornblath M. The incidence of neonatal hypoglycemia—a completed sur- vey. J Pediatr. 1967;70:76-80.
17. Lubchenco LO, Bard H. Incidence of hypoglycemia in newborn infants classified by birth weight and gestational age. Pediatrics. 1971;47:831-838.
18. Pildes RS, Cornblath M, Warren I, et al. A prospective controlled study of neonatal hypoglycemia. Pediatrics. 1974;54:5-14.
19. Harris DL, Weston PJ, Harding JE. Incidence of neona- tal hypoglycemia in babies identified as at risk. J Pediatr. 2012;161:787-791.
20. Schaefer-Graf UM, Rossi R, Bührer C, et al. Rate and risk factors of hypoglycemia in large-for-gestational-age newborn infants of nondiabetic mothers. Am J Obstet Gynecol. 2002;187:913-917.
21. Montassir H, Maegaki Y, Ogura K, et al. Associated fac- tors in neonatal hypoglycemic brain injury. Brain Dev. 2009;31:649-656.
22. Straussman S, Levitsky LL. Neonatal hypoglycemia. Curr Opin Endocrinol Diabetes Obes. 2010;17:20-24.
23. Stanley CA, Baker L. The causes of neonatal hypoglyce- mia. N Engl J Med. 1999;340:1200-1201.
24. Alsaleem M, Saadeh L, Misra A, Madani S. Neonatal iso- lated ACTH deficiency (IAD): a potentially life-threaten- ing but treatable cause of neonatal cholestasis. BMJ Case Rep. 2016;2016:bcr2016215032.
25. Cornblath M, Ichord R. Hypoglycemia in the neonate. Semin Perinatol. 2000;24:136-149.
26. Adamkin DH. Neonatal hypoglycemia. In: Martin G, Rosenfield W, eds. Common Problems in the Newborn Nursery. An Evidence and Case-Based Guide. Basel, Switzerland: Springer; 2019:99-108.
27. Kuwa K, Nakayama T, Hoshino T, Tominaga M. Relationships of glucose concentrations in capillary whole blood, venous whole blood and venous plasma. Clin Chim Acta. 2001;307:187-192.
28. Dillon RS. Importance of the hematocrit in interpretation of blood sugar. Diabetes. 1965;14:672-674.
29. D’Orazio P, Burnett RW, Fogh-Andersen N, et al. Approved IFCC recommendation on reporting results for blood glucose (abbreviated). Clin Chem. 2005;51:1573- 1576.
30. Rebel A, Rice MA, Fahy BG. Accuracy of point-of- care glucose measurements. J Diabetes Sci Technol. 2012;6:396-411.
31. Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, et al. Validation of the continuous glucose monitoring sensor in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2013;98:F136-F140.
32. Platas II, Lluch MT, Alminana NP, Palomo AM, Sanz MI, Vidal XK. Continuous glucose monitoring in infants of very low birth weight. Neonatology. 2009;95:217- 223.
33. Perri A, Giordano L, Corsello M, et al. Continuous glucose monitoring (CGM) in very low birth weight newborns needing parenteral nutrition: validation and glycemic per- centiles. Ital J Pediatr. 2018;44:99.
34. Galderisi A, Facchinetti A, Steil GM, et al. Continuous glucose monitoring in very preterm infants: a randomized controlled trial. Pediatrics. 2017;140:e20171162.
35. Alsaleem M, AlMuhaisen FJ, Saadeh L. Use of Continuous Glucose Monitoring in Neonates. Can J Biomed Res & Tech. 2019;1(3).
36. Galderisi A, Lago P, Steil GM, et al. Procedural pain dur- ing insertion of a continuous glucose monitoring device in preterm infants. J Pediatr. 2018;200:261-264.
37. Sperling MA, Menon RK. Differential diagnosis and management of neonatal hypoglycemia. Pediatr Clin North Am. 2004;51:703-723.
38. Chertok I, Raz I, Shoham I, Haddad H, Wiznitzer A. Effects of early breastfeeding on neonatal glucose levels of term infants born to women with gestational diabetes. J Hum Nutr Diet. 2009;22:166-169.
39. Rawat M, Chandrasekharan P, Turkovich S, et al. Oral dex- trose gel reduces the need for intravenous dextrose therapy in neonatal hypoglycemia. Biomed Hub. 2016;1:448511.
40. Bennett C, Fagan E, Chaharbakhshi E, Zamfirova I, Flicker J. Implementing a protocol using glucose gel to treat neonatal hypoglycemia. Nurs Womens Health. 2016;20:64-74.
41. Hegarty JE., Harding JE., Gamble GD., Crowther CA., Edlin R., Alsweiler JM.. Prophylactic oral dextrose gel for newborn babies at risk of neonatal hypoglycaemia: a randomised controlled dose-finding trial (the Pre-hPOD Study). PLoS Med. 2016;13:e1002155.
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42. Ter M, Halibullah I, Leung L, Jacobs S. Implementation of dextrose gel in the management of neonatal hypogly- caemia. J Paediatr Child Health. 2017;53:408-411.
43. Palylyk-Colwell E, Campbell K. Oral Glucose Gel for Neonatal Hypoglycemia: A Review of Clinical Effectiveness, Cost-Effectiveness and Guidelines. Ottawa, Canada; Canadian Agency for Drugs and Technologies in Health; 2018.
44. Coors SM, Cousin JJ, Hagan JL, Kaiser JR. Prophylactic dextrose gel does not prevent neonatal hypoglycemia: a quasi-experimental pilot study. J Pediatr. 2018;198: 156-161.
45. Adamkin DH; Committee on Fetus and Newborn. Clinical report—postnatal glucose homeostasis in late-preterm and term infants. Pediatrics. 2011;127:575-579.
46. Thornton PS, Stanley CA, De Leon DD, et al. Recommendations from the Pediatric Endocrine Society for evaluation and management of persistent hypoglycemia in neonates, infants, and children. J Pediatr. 2015;167:238- 245.
47. Lilien LD, Pildes RS, Srinivasan G, Voora S, Yeh TF. Treatment of neonatal hypoglycemia with minibolus and intravenous glucose infusion. J Pediatr. 1980;97:295-298.
48. Suh SW, Gum ET, Hamby AM, Chan PH, Swanson RA. Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase. J Clin Invest. 2007;117:910-918.
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Background
Attempt to define “significant hypoglycemia” was made by Hartmann et al in 1937.1 In the 1940s, reports described increased mortality among infants born to mothers with diabetes.2 Suggestions were made to treat these infants with sugar water or breastfeeding to prevent mortality.3 Important updates about the definition, clinical presenta- tion, and management of neonatal hypoglycemia have been reported since the middle of the 20th century. It remains one of the most controversial topics in the field of neonatology, especially regarding the numerical defini- tion of neonatal hypoglycemia, which may result in long- term neurological and developmental consequences.4-7 Therefore, the American Academy of Pediatrics (AAP) and the Pediatric Endocrine Society (PES) recommend using arbitrary glucose levels, for which interventions are needed to increase the “blood glucose” (BG) levels.8,9 The main goal of these recommendations is to reduce the potential adverse events associated with persistent, pro- longed, or symptomatic hypoglycemia.
In healthy pregnancies, maternal glucose is the pri- mary source of glucose supply to the fetus.8,10 During fetal life, glucose follows carrier-mediated transport pat- tern from the mother to the fetus. At birth, the newborn BG is about 70% of the maternal BG level.9 Previous studies have shown that there is a gradual physiological drop in the BG level in healthy infants during the first few hours after birth.11-13 Higher insulin levels after birth in infants at risk for hypoglycemia compared with children and adult augment this drop.14 Multiple theories have been proposed to explain the persistence of higher insulin levels. These include insulin transfer through the placenta from mother to the fetus, stress response at birth, and hypersensitivity of pancreatic B-cell. Associated with this higher insulin levels is the lower serum ketone levels.15 The low BG and ketones result in less available energy fuel for cellular function. However, the majority of new- borns remain asymptomatic during this period of these “physiological” low BG levels.
Epidemiology
Neonatal hypoglycemia is one of the most common diagnoses that require admission to the neonatal intensive
care unit. The true incidence of neonatal hypoglycemia varies significantly among different studies because differ- ent levels of BG were used to define hypoglycemia.16-18 Harris et al.19 reported incidence of 51% and 19% in infants with risk factors for hypoglycemia when the BG levels of <47 mg/dL and <36 mg/dL were used, respec- tively, for the diagnosis of hypoglycemia.
Glucose is the primary source of energy, and the BG level depends on demand and supply. Therefore, any interference with either a decrease in production/supply or increase in consumption can result in hypoglycemia, as shown in Table 1.20-24
Clinical Presentation
Clinical signs and symptoms of neonatal hypoglycemia are nonspecific and mimic many other conditions in neonates25,26 (Table 2). Therefore, it is essential to rule out other potentially severe or treatable conditions such as sepsis and asphyxia that can have manifestations similar to hypoglycemia or result in hypoglycemia.
Diagnosis
Blood glucose level testing is not required in healthy infants who lack the risk factors mentioned in Table 1. When deciding the glucose level for which interven- tions are required, it is essential to remember that the values obtained from the whole blood (point-of-care devices) are usually 15% lower than those obtained from plasma (central laboratory values).27-29 Another factor to consider that can affect the accuracy of glu- cose-level measurement is the method used to obtain these values. Glucose oxidase and peroxidase chromo- gen test strips (the most common method used in most nurseries) have been reported to have less accuracy, especially with the low values when compared with
875540 CPJXXX10.1177/0009922819875540Clinical PediatricsAlsaleem et al research-article2019
1The State University of New York, University at Buffalo, Buffalo, NY, USA 2UT Health San Antonio, San Antonio, TX, USA
Corresponding Author: Mahdi Alsaleem, Children’s Mercy Hospital, University of Kansas, 3600 E Harry St. Wichita, KS 67218, USA. Email: [email protected]
Neonatal Hypoglycemia: A Review
Mahdi Alsaleem, MD1 , Lina Saadeh, MD1, and Deepak Kamat, MD, PhD, FAAP2
2 Clinical Pediatrics 00(0)
the regular laboratory measurement using hexokinase- based method.30 For that reason, it is highly recom- mended to confirm the “significant glucose” levels obtained by the bedside chromogen test strip by labo- ratory methods before deciding whether to intervene based on that level. Recently, there has been an increasing interest in using “continuous glucose monitoring” (CGM) devices in the neonates. Multiple studies have shown that the use of CGM in both pre- term and near-term neonates is safe and practical with acceptable correlation with routine bedside BG mea- surement.31-34 Technological advancement in CGM sensors has resulted in more convenient nursing care35 and has shown a significant reduction of the proce- dural pain associated with the conventional methods of glucose monitoring.36 Despite these available data about safety and accuracy, well-designed randomized clinical trials are still required before the adoption of this method to become the standard of care for BG monitoring.
The timing of glucose screening in infants with risk factors, or those who exhibit symptoms, can be summa- rized as follows:
1. BG level should be obtained anytime infant is symptomatic.
2. For an infant who is asymptomatic but at risk for hypoglycemia, screening should be started after the first feed and continued at regular intervals before every feed for the first 24 hours.
3. For an infant who has a low BG level, bedside glucose monitoring should continue before feeds until BG levels can be maintained >60 mg/dL (3.3 mmol/L) for 24 hours.
Management
The goal of management of neonatal hypoglycemia is to prevent and treat acute symptomatic hypoglycemia, which can result in possible permanent brain damage and long-term adverse outcomes. A successful manage- ment plan should include identifying and treating the underlying etiology for hypoglycemia.
The most common etiology for neonatal hypoglyce- mia is the sudden cessation of glucose supply after the umbilical cord clamping, along with the transient eleva- tion of insulin level. Therefore, it is crucial to provide carbohydrate substrate source that can maintain physio- logic BG level to maintain cellular function and replen- ish the energy stores. A common management protocol in nurseries, with the recent use of dextrose gel, usually follows the approach shown in Figure 1. Refeeding with maternal breast milk and/or formula if feasible and not contraindicated should be the initial approach for man- agement of neonatal hypoglycemia.37,38 If low BG levels persist despite enteral feeds, then consideration should be given to provide more concentrated, rapidly absorb- able glucose source. Many studies have reported success rate with dextrose gel directly applied to the buccal mucosa.39-43 The use of dextrose gel has been shown to lower the incidence of neonatal intensive care unit admissions, lessen the disruption to parental bonding, and increase in cost saving. The use of dextrose gel as hypoglycemia preventive measure in infants at risk did not show a decrease in the incidence or the severity of neonatal hypoglycemia.44
Initiation of intravenous (IV) dextrose therapy should be considered if BG levels remain below the operational threshold after enteral feed and dextrose gel, or if the infant is unable to tolerate oral intake. As mentioned ear- lier, there is a lack of enough evidence and long-term outcome data on the specific numerical BG level at which one should initiate IV dextrose therapy. However, to help guide the clinicians, both AAP45 and PES46
Table 1. Risk Factors for Neonatal Hypoglycemia in Newborns.
Decrease in Glucose Supply
restrictiona Large for gestational age
Glycogen metabolism disordersa
Disorders of gluconeogenesisa
Polycythemia
Perinatal asphyxia or stressa
Hepatic dysfunction Congenital hyperinsulinemiaa
aConditions that can result in persistent hypoglycemia (low-blood glucose levels after 48 hours of life).
Table 2. Clinical Signs and Symptoms of Neonatal Hypoglycemia.
Symptoms Signs
Alsaleem et al 3
recommended operational threshold levels with time correlation with age in hours to intervene and to initiate IV dextrose, as shown in Figure 2.
Intravenous dextrose-containing fluid is initiated to provide a glucose infusion rate of 4 to 6 mg/kg/min in term infants and 6 to 8 mg/kg/min in preterm infants. Dextrose mini-boluses of 2 mL/kg of 10% dextrose solution can be considered.47 Close monitoring of BG levels is necessary to avoid the risk of rapid correction as this may lead to high BG levels, which can be associ- ated with adverse neurological outcomes.48,49 Central line access should be considered if requiring dextrose concentration above >12.5% to maintain euglycemia, due to the high risk of vessels injury.50
If neonates continue to have low BG levels requiring high GIR of >10 mg/kg/min after 48 hours to maintain average BG levels, then etiologies other than transient hyperinsulinemia should be considered.51 These include but not limited to persistent congenital hyperinsulinism, fatty acid oxidation defects, glycogen storage diseases, or hormonal abnormalities such as growth hormone and cortisol deficiencies.
Before discharge, the infant with neonatal hypoglyce- mia should be able to maintain pre-feed BG > 60 mg/dL (AAP recommendations) or > 70 mg/dL if persistent hypoglycemia is suspected (for conditions represented with superscript “a” in Table 1, PES recommendations).
This stability should be achieved with proper oral intake without the IV dextrose for at least 24 hours on an accept- able feeding schedule every 3 to 4 hours. Performing fasting test (performing BG check after skipping 1 feed) is recommended by PES, after achieving stable BG on a regular feeding schedule, to exclude the possibility of metabolic causes of hypoglycemia, which can manifest with prolonged fasting.
Outcomes
The chances of brain damage as seen on magnetic reso- nance imaging and the adverse long-term neurodevelop- mental outcomes are higher in infants with symptomatic hypoglycemia.52-57 However, uncertainty exists about the BG level and the duration of hypoglycemia that can result in these consequences. The most severe immediate concern is seizure. The majority of neonates who developed seizures had persistent and severe hypoglycemia.58,59 The evidence is less clear about the association between asymptomatic hypoglycemia and adverse neurodevel- opmental outcome.60 A prospective study was conducted by McKinlay et al,61 which included infants born >32 weeks of gestation. They compared the outcomes at 2 years and again at 4.5 years of age between the groups who received treatment to maintain BG > 47 mg/dL versus those who did not require interventions. There
Dextrose gel (200mg/kg) to buccal mucosa
Confirmed BG < operational threshold after first feed.
(See figure 2 for operational threshold)
Start IV Dextrose fluid with GIR of 4-8 mg/kg/min ± Dextrose 10%
bolus Refeed ( MBM or formula)
A ble to feed?
H ypoglycem
ia resolved?
Regular newborn care, continue to check BG before each feed until stable (>60 mg/dl) for 24 hours.
H ypoglycem
ia resolved?
Figure 1. The management approach for neonatal hypoglycemia. GIR, glucose infusion rate; IV, intravenous; MBM, maternal breast milk. *Optional but recommended based on multiple recent studies.
4 Clinical Pediatrics 00(0)
was no difference at 2 years; however, those who required treatment had increased evidence of poor exec- utive as well as visual motor function at 4 to 5 years of age. In a more recent systemic review and meta-analysis that included 11 studies, which focused on outcomes following neonatal hypoglycemia,62 no association was found between neonatal hypoglycemia and neurodevel- opmental impairment in early childhood (2-5 years) period. However, visual and executive functions were affected. In older children (6-11 years), the risks for neu- rodevelopmental impairment as well as low literacy and numeracy were reported.62
Conclusion
The evidence is limited about the specific BG level that can result in permanent brain damage and adverse neuro- developmental outcome in healthy newborns; however, symptomatic infants with persistent or prolonged hypo- glycemia should be treated to restores glucose hemostasis. In persistent neonatal hypoglycemia, further evaluation should be performed to exclude other etiologies. Future use of CGM will provide a great opportunity to improve our knowledge regarding glucose hemostasis after birth.
Authors’ Note
Mahdi Alsaleem is also affiliated with Children’s Mercy Hospital and University of Kansas, Wichita, KS, USA.
Author Contributions
MA, LS and DK conceived and designed the review, and chose the research terms. MA and LS wrote the first draft of the manuscript. MA, LS and DK made substantial contribu- tions to the interpretation of articles found and were involved in drafting the manuscript and made critical revisions of the manuscript. All authors read and approved the version to be published.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD
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