Maintenance of glucose homeostasis via initiation of glucose production is one of the critical physiological events that results in a smooth transition and adaptation to extrauterine life. A number of neonates have difficulty during transition to the extrauterine environment that result in altered glucose homeostasis and low plasma glucose concentrations. Although much progress has been made over the years in understanding the causes and mechanisms of altered neonatal glucose metabolism, the long-term consequences and the threshold values that may cause injury remain unknown. In 2000, Cornblath et al summarized the contemporary state of knowledge related to neonatal hypoglycemia by noting the following:
Unfortunately, untoward long-term outcomes in infants with one or two low blood glucose levels have become the grounds for litigation and for alleged malpractice, even though the causative relationship between the two is tenuous at best… The definition of clinically significant hypoglycemia remains one of the most confused and contentious issues in contemporary neonatology.1
There has been no substantial evidence-based progress in defining what constitutes clinically significant but transient neonatal hypoglycemia (as opposed to persistent hypoglycemia from hyperinsulinemia), particularly regarding how it relates to brain injury. Monitoring for and prevention and treatment of neonatal hypoglycemia remain largely empirical.
At present there is neither a rational basis nor sufficient evidence to identify a specific value or a range of plasma glucose concentrations that would define “hypoglycemia” as a pathologic entity. Nevertheless, many commentaries and opinions continue to recommend various plasma glucose concentrations that should be maintained in the neonatal period to prevent injury to the developing brain.2-9 Most published statements and opinions are based on low-level evidence, including small-scale human studies in select populations without control subjects or longer-term follow-up, case studies of neonates with a potpourri of diagnoses, or physiological or animal studies of limited relevance to human newborns. No definition of pathologic hypoglycemia or guideline for treatment of low plasma glucose concentrations in neonates has been validated in clinical practice or assessed in prospective follow-up studies.
Recognizing the common occurrence of low plasma glucose, usually noted as <40 to 45 mg/dL and occurring in as many as 5% to 15% of normal newborn infants,1,10 the potential for insufficient glucose supply to injure the developing brain, and a need to support research targeted at gaps in knowledge about neonatal “hypoglycemia” and its clinical implications, the Eunice Kennedy Shriver National Institute of Child Health and Human Development convened a workshop on Neonatal Hypoglycemia, held September 8-9, 2008. A diverse group of experts participated.
This report provides a summary of the workshop discussions. Because review articles have addressed specific hypoglycemic syndromes and several of the major themes addressed in this workshop,11-17 the following summary will focus on gaps in knowledge and suggested research. Unless otherwise stated, “hypoglycemia” refers to “neonatal hypoglycemia” and “blood glucose” concentrations to plasma values (or whole blood glucose concentrations corrected to plasma values), expressed in millimoles per liter with mg/dL in parenthesis. The workshop did not address the so-called persistent hypoglycemic syndromes caused by, for example, hyperinsulinemic hypoglycemia;18-25 hypoglycemia caused by fatty acid oxidation defects,26,27 and other inborn errors of metabolism, which been well characterized.28 Instead this review focuses on specific issues related to low plasma glucose concentrations in the first several hours or days after birth and their measurement, clinical monitoring, and long-term consequences.