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 Table of Contents  
Year : 2017  |  Volume : 6  |  Issue : 3  |  Page : 163-167

Hypoglycemic relapse in term infants treated with glucose infusion

1 Medical Student, Faculty of Medicine, University of Geneva, Geneva, Switzerland
2 Neonatal Intensive Care Unit, Department of Pediatrics, Geneva University Hospital, Geneva, Switzerland
3 Pediatric Intensive Care Unit, Department of Pediatrics, Geneva University Hospital, Geneva, Switzerland; Division of Pediatric Critical Care Medicine, Children's Hospital of Richmond at VCU, Richmond, VA, USA

Date of Web Publication11-Jul-2017

Correspondence Address:
Oliver Karam
Division of Pediatric Critical Care Medicine, Children's Hospital of Richmond at VCU, 1250 E Marshall St, Richmond, VA 23219

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.JCN_10_17

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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.

Keywords: Hypoglycemia, newborns, relapse, risk factors

How to cite this article:
Sternberg J, Pfister RE, Karam O. Hypoglycemic relapse in term infants treated with glucose infusion. J Clin Neonatol 2017;6:163-7

How to cite this URL:
Sternberg J, Pfister RE, Karam O. Hypoglycemic relapse in term infants treated with glucose infusion. J Clin Neonatol [serial online] 2017 [cited 2018 Jan 20];6:163-7. Available from: http://www.jcnonweb.com/text.asp?2017/6/3/163/210128

  Introduction Top

Despite the high incidence (4%–20%[1],[2]) of neonatal hypoglycemia, its management is seldom based on evidence. Hypoglycemia is usually defined as a blood glucose concentration (BG) below 2.5 mmol/L.[3],[4],[5],[6],[7],[8] However, there has been considerable debate over what should be chosen as a safe lower limit for BG concentration in the neonatal period,[9] and no study has univocally been able to define it.[10],[11],[12] Different management strategies have been developed, depending on the severity of hypoglycemia.[13],[14] The American Academy of Pediatrics (AAP) recently stated that, although the “specific value or range of plasma glucose concentrations that potentially could result in brain injury” has not been determined, because “symptomatic hypoglycemia may result in neuronal injury, prompt intervention is necessary for infants who manifest clinical signs and symptoms.”[4],[15] Some experts recommend that severe hypoglycemia should be dealt with rapidly to limit associated neurological sequelae (severe mental retardation and/or spastic quadriplegia).[16] However, a meta-analysis failed to identify a valid estimate of the effect of neonatal hypoglycemia on neurodevelopment.[17] Nevertheless, some recent work suggested that neonatal hypoglycemia is not associated with an adverse neurologic outcome if adequately treated.[18]

According to the AAP, asymptomatic term infants should receive intravenous glucose only if BG values fall below 1.4 mmol/L (birth to 4 h of age) or 1.9 mmol/L (4–24 h of age).[15] Optimal monitoring after weaning from glucose infusion is debated. Most protocols suggest obtaining repeat measures of glucose, before consecutive meals after weaning from infusion.[18] For neonates who require glucose infusion, the Pediatric Endocrine Society suggested that a transition to normal feedings alone should be attempted after the glucose concentration is stabilized at >3.3 mmol/L.[19] However, the risk of hypoglycemic relapse (defined as blood glucose <2.5 mmol/L) after weaning from infusion remains unknown.

In this study, our primary objective was to determine whether measuring blood glucose levels 3, 6, and 9 h after weaning from glucose infusion is appropriate to detect hypoglycemic relapse. The secondary objective was to determine risk factors for hypoglycemic relapse.

  Methods Top

We conducted a single-centered retrospective study on all term newborns (≥37 0/7 weeks) who were admitted to our neonatal intensive care unit between January 1 2005 and December 31 2014 and who required glucose infusion for hypoglycemia. In our unit, term infants with BG values <1.5 mmol/L, prolonged values for more than 4 h, and symptomatic term infants with BG values <2.0 mmol/L (defined as severe hypoglycemia in our institution) are managed with glucose infusion in a thermo-neutral environment. Usually, treatment lasts at least 24 h after normalization of BG. Thereafter, slow weaning (stepwise decrease by 0.5–1 mg/kg/min every 3 h) of the infusion is monitored by glucose determinations prior to each decrease, while enteral feedings for every 3 h are pursued with a daily increase of 20 ml/kg or more if taken spontaneously by the newborn. After weaning is completed, and the newborn is on enteral feeding alone, we routinely measure BG levels before the next three meals (3, 6, and 9 h starting from the end of the glucose infusion).

For this study, we collected the following data: neonatal sex, birth weight (BW), gestational age, delivery method, presence of gestational diabetes, multiple pregnancy, perinatal hypoxia (umbilical pH <7.0 and/or 5-min Apgar ≤3), small for gestational age (SGA) (BW <10th percentile), macrosomia (BW >90th percentile)[20] or respiratory distress syndrome, start and end times of glucose infusion, infusion rate, maximum glucose concentration, time, and value of the three preprandial BG measurements 3, 6, and 9 h after weaning from infusion, and in the case of hypoglycemic relapse, time when glucose infusion was reinitiated.

Our protocol was approved by the Local Ethics Committee.

Results were described as the mean ± standard deviation for variables with normal distribution, or as the median and interquartile range (IQR) for variables with nonnormal distribution. Proportions and 95% confidence intervals (95% CIs) were also reported. Risk factors for hypoglycemic relapse were identified by univariate analysis, using Mann–Whitney U-test to compare dichotomous variables and Fisher's exact test for continuous values. We measured the significance of the association between hypoglycemic relapse and BW with a logistic regression model. We also determined the area under the receiver operating characteristic curve (AUC) of BW and presence of hypoglycemic relapse. Statistical analyses were performed with SPSS software version 22.0 for Mac (IBM inc, Armonk, NY, USA). The result was considered statistically significant if P ≤ 0.05.

  Results Top

During the 10 years of the study, about 40,000 children were born at our center. Of the approximately 36,000 term neonates, 129 (3.6%) had severe neonatal hypoglycemia requiring glucose infusion. The mean gestational age of this group was 38 4/7 weeks (IQR 37 6/7; 40 0/7 weeks). There were 59 (46%) vaginal births and 70 (54%) cesarean sections [Table 1]. Median weight at birth was 2950 g (IQR 2530; 3480 g). Median head circumference was 34 cm (IQR 33; 35 cm). There were 37 infants (29%) with SGA and 10 infants (7%) with macrosomia. Twelve infants (9%) were born of diabetic mothers, five infants (4%) were born after a twin pregnancy, and three infants (2%) presented with perinatal hypoxia. Median duration of glucose infusion was 36 h (IQR 24; 56 h).
Table 1: Population demographics, according to the presence or absence of hypoglycemic relapse after weaning from glucose infusion

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Of the 129 patients, eight (6.2%, 95% CI: 3.2%–11.8%) had hypoglycemic relapse. No newborn (0%, 95% CI: 0%–2.9%) had a recurrence of hypoglycemia immediately before the first feed (3 h after weaning from infusion). Five infants (3.9%, 95% CI: 1.7%–8.8%) had hypoglycemic relapse before the second feed (6 h after weaning), and three infants (2.3%, 95% CI: 0.8%–6.6%) had hypoglycemic relapse before the third feed (9 h after weaning). All hypoglycemic relapses were of mild severity (BG: 2.0–2.5 mmol/L).

SGA and BW bellow 2550 g were associated with an increased risk of hypoglycemic relapse (odds ratio: 8.9, P = 0.003 and 0.008, respectively), [Table 1] and [Figure 1]. The AUC of BW relative to hypoglycemic relapse was 0.83 (95% CI: 0.75–0.91), [Figure 2]. For BW below 2550 g, the sensitivity and specificity were 77% and 88%, respectively, with a negative predictive value of 98.8% (95% CI: 94.2%–100%) and positive predictive value of 20% (95% CI: 8.4%–36.9%).
Figure 1: Boxplot of birth weight according to the presence or absence of hypoglycemic relapses after weaning from glucose infusion. Dashed line represents birth weight of 2550 g

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Figure 2: Receiver operating characteristic curve of birth weight relative to the presence of hypoglycemic relapse. Area under the curve was 0.83 (95% confidence interval: 0.75–0.91). Diagonal segments are produced by ties

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  Discussion Top

In our population, 6% of term infants who required glucose infusion to treat severe hypoglycemia presented with hypoglycemic relapse after weaning from the infusion. SGA and low BW were the main risk factors for hypoglycemic relapse.

Interpretations and implications

No early hypoglycemic relapse was observed at the first monitoring point, which is in support of the proposed slow weaning process. In addition, the short interval between cessation of the infusion and the first glucose check at 3 h may have been insufficient in some cases for the completed transition to a new balance, from infused glucose to a storage-based metabolism. Transitional neonatal hypoglycemia in normal newborns is a hypoketotic form of hypoglycemia, with a nadir in the first few hours of life.[10] We hypothesize that, in the current practice, the first sample after weaning is superfluous and may be omitted to reduce painful blood sampling and distress for the infant and parents.

Furthermore, all recorded hypoglycemia relapses were of mild severity with value >2.0 mmol/L.[3] The distinction between mild, moderate, and severe hypoglycemia was established for newborns immediately following birth,[3],[10] but however, this distinction may not be appropriate for a few-days-old infants, when gluconeogenesis is more mature and the brain possibly is more tolerant to lower glucose values as able to use alternative substrates.[21] Thus, one might hypothesize that the clinical significance of mild hypoglycemia may be even less at these later time points.

SGA and low BW were associated with an increased risk of hypoglycemic relapse. Neonatal hypoglycemic etiologies are commonly divided into three pathophysiological categories: (1) depleted glycogen stores, found in newborns with a low BW or SGA and often associated with microcephaly if growth restriction occurred early and was severe; (2) glucose overconsumption, such as in neonates with perinatal hypoxia and asphyxia, hypothermia, and neonatal or congenital infection; and (3) hyperinsulinic infants with macrosomia, such as in infants from diabetic mothers, from mothers undergoing glucose infusion, as well as neonatal hemolysis.[16] In our cohort, the only category of patients at risk of recurrence was the first type of newborns with low glucose stocks. The negative predictive value of a relapse of term infants with a BW over 2550 g was 99%. Therefore, future research should evaluate the risk of monitoring for hypoglycemic relapse after weaning from glucose infusion in term infants only to those with low BW (<2500 g or SGA).

Strengths and limitations

Our study was conducted over 10 years and included all consecutive term infants in a tertiary neonatal unit, allowing a good generalizability of the results. However, its limitations must be acknowledged. First, our retrospective design may have led to selection bias. We believe that this bias should be minimal because all cases of severe hypoglycemia requiring glucose infusion were systematically reported due to Swiss insurance policies. Furthermore, there should not be any recall bias, as the outcome is objective. However, the relatively low number of macrocosmic infants suggests an obstetric practice of “anticipated” pregnancy termination. Second, our study was done in only one center, and our management of hypoglycemia may have influenced the results. On the other hand, the local algorithm is very similar to other protocols such as the one recommended by the AAP.[22] Third, we were unable to determine retrospectively the dose of glucose infusion in mg/kg/min. However, these limitations should not influence the primary outcome. Fourth, the low proportion of hypoglycemic relapse might be due to our glucose infusion weaning protocol, wherein glucose levels were measured after each decrease in the perfusion rate. Faster weaning protocols may result in higher relapse rates. Fifth, our study does not consider hypoglycemic relapses that could eventually occur later than 9 h after weaning of the perfusion. However, considering the observation during the weaning process and then the surveillance for hypoglycemic relapse, the likelihood of such events seems very small. Finally, despite the long inclusion period, we enrolled only 129 term patients, of which only eight had the primary outcome, excluding the possibility of a multivariate analysis. This low inclusion rate might result from our algorithm that favors oral feeding to prevent and treat nonsevere hypoglycemia. An extension to late preterm neonates would increase the inclusion rate, but might also concern to a very different physiopathology and outcome pattern.

  Conclusions Top

In a population of term newborns presenting with severe hypoglycemia requiring glucose infusion, only a small proportion presented with mild hypoglycemic relapse after slow weaning from infusion.

Future research directions

As SGA and low BW were the main risk factors for hypoglycemic relapse, future research should assess whether it is sufficient to screen only SGA and low BW infants for hypoglycemic relapse. Studies should also address whether the first sample point (3 h after weaning) can be dropped allowing to screen only at 6 and 9 h after weaning of the glucose infusion, therefore decreasing unnecessary and distressing sampling.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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Rozance PJ, Hay WW. Hypoglycemia in newborn infants: Features associated with adverse outcomes. Biol Neonate 2006;90:74-86.  Back to cited text no. 11
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Holtrop PC. The frequency of hypoglycemia in full-term large and small for gestational age newborns. Am J Perinatol 1993;10:150-4.  Back to cited text no. 13
Canadian Paediatric Society. Screening guidelines for newborns at risk for low blood glucose. Paediatr Child Health 2004;9:723-40.  Back to cited text no. 14
American Academy of Pediatrics Committee on Fetus and Newborn. Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics 2011;127:575-9.  Back to cited text no. 15
Rennie J, Roberton N. Disorders of glucose homeostasis. A Manual of Neonatal Intensive Care. 4th ed. London: Arnold; 2002. p. 283-92.  Back to cited text no. 16
Boluyt N, van Kempen A, Offringa M. Neurodevelopment after neonatal hypoglycemia: A systematic review and design of an optimal future study. Pediatrics 2006;117:2231-43.  Back to cited text no. 17
McKinlay CJ, Alsweiler JM, Ansell JM, Anstice NS, Chase JG, Gamble GD, et al. Neonatal glycemia and neurodevelopmental outcomes at 2 years. N Engl J Med 2015;373:1507-18.  Back to cited text no. 18
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  [Figure 1], [Figure 2]

  [Table 1]


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