Factors Associated with Need for Intravenous Glucose Infusion for the Treatment of Early Neonatal Hypoglycemia in Late Preterm and Term infants

doi:10.21203/rs.3.rs-2010369/v1

Objective

To determine which late-preterm (35-36wk gestational age [GA]) and term neonates with early-onset hypoglycemia in the first 72h postnatal required a continuous glucose infusion in order to achieve and successfully maintain euglycemia.

Study Design:

Retrospective cohort study of late preterm and term neonates born in 2010–2014 and admitted to the Mother-Baby Unit at Parkland Hospital who had laboratory-proven blood glucose concentration < 40 mg/dL (2.2 mmol/L) during the first 72h of life. The cohort was randomly divided into a derivation cohort (n = 1288) and a validation cohort (n = 1298).

Result

In multivariate analysis, need for intravenous glucose infusion was associated with small size for GA, low initial glucose concentration, early-onset infection and other perinatal variables (e.g., fetal acidosis, hypoxic-ischemic encephalopathy) in both cohorts.

Conclusion

Need for intravenous glucose infusion was associated with small size for GA, low initial glucose concentration, early-onset infection and variables associated with prenatal hypoxia-asphyxia.

Hypoglycemia is the most common metabolic abnormality occurring in neonates. Some estimate a frequency of 1–5 per 1000 live births [1]. Others estimate this is higher, occurring in 5–15% of term neonates and as high as 30–50% in neonates considered to be high-risk [1–3]. However, the frequency of hypoglycemia varies with the use of different definitional thresholds for early-onset neonatal hypoglycemia.

Risk factors for early-onset neonatal hypoglycemia include preterm birth, large (LGA) or small (SGA) size for gestational age (GA), evidence of intrauterine growth restriction (IUGR), infants of diabetic mothers (IDM), early-onset sepsis, perinatal hypoxic-ischemic encephalopathy (HIE), polycythemia, inborn errors of metabolism and other endocrine defects [1, 3–5]. Neonates born preterm, SGA or with IUGR often lack sufficient stores of easily mobilized energy products, such as glycogen. On the other hand, IDMs who are LGA usually have high transient serum concentrations of insulin after birth [1, 4, 5]. This is due to high maternal blood glucose, which readily crosses the placenta, resulting in elevated intrauterine fetal blood glucose concentrations and enhanced fetal pancreatic insulin synthesis and release. After birth the neonate has persistent hyperinsulinemia, loss of transplacental glucose delivery, and limited ability to increase circulating glucose, resulting in hypoglycemia that requires medical intervention, i.e., initiation of an exogenous glucose supply until pancreatic function resets [1, 6].

Exogenous carbohydrate administration is available in many oral forms, including breastmilk, formula, sugar water [glucose solution in water at 5 g/dL (D5) or 10 g/dL (D10)], polymers of glucose or concentrated (40%) dextrose gel. Intake of breastmilk or formula has the advantage of providing not only carbohydrates, but also protein and fat, which tend to be metabolized at a slower rate, stimulate ketogenesis and reduce cellular uptake of glucose [1, 4]. Other exogenous forms of glucose include intravenous (IV) fluids containing varying concentrations of dextrose and total parenteral nutrition, which also provides amino acids and glycerol for gluconeogenesis.

In 2011, the American Academy of Pediatrics published treatment guidelines for early-onset hypoglycemia in late-preterm and term neonates [7]. For treatment of asymptomatic hypoglycemia, the guidelines recommend initiating oral feeds and rechecking blood glucose levels. If blood glucose concentrations remain between 25–40 mg/dL (1.4–2.2 mmol/L), they recommend another oral feed or the initiation of IV glucose in the form of a mini-bolus with 2mL/kg of D₁₀W and/or continuous glucose infusion rate of 5–8 mg · kg^− 1 · min^− 1 [8, 9] and total fluids of 80–100 mL· kg^− 1· day^− 1. If blood glucose concentrations remain < 25 mg/dL (1.4 mmol/L), it is recommended to forego oral feeds and start IV glucose as outlined above. Goal blood glucose concentrations are between 40–50 mg/dL (2.2–2.8 mmol/L) [7]. Based on this treatment strategy it is possible for neonates to have blood glucose values < 25 mg/dL for up to 4h and < 40 mg/dL for even longer time periods.

While some neonates can achieve euglycemia solely with initiation of oral feeds, others require IV glucose infusion to achieve euglycemia. However, it remains unclear how these two groups can be distinguished soon after birth. In 2008 the Eunice Kennedy Shriver National Institute of Child Health and Development held a workshop on neonatal hypoglycemia and concluded that research was needed to determine the value of scoring systems [10]. Vanlhaltran et al. created a scoring system for determining which neonates born at ≥ 35wks GA and delivered of diabetic women should be directly admitted to the neonatal intensive care unit (NICU), based on the risk of having hypoglycemia and requiring IV glucose administration [11]. Proposed admission criteria to the NICU included either one of the following: clinically sick neonate and initial blood glucose < 36 mg/dL (2.0 mmol/L) or two of the following: preterm birth, pre-gestational diabetes type I, elevated maternal hemoglobin A1C level, macrosomia, and temperature instability [11]. However, this scoring system has not been validated in an independent cohort.

The current study was designed in 2013 to determine among late-preterm and term neonates admitted to the Mother-Baby Unit (MBU) at Parkland Hospital with laboratory documented and validated early-onset hypoglycemia what characteristics differentiate those who achieved euglycemia with oral feeds only from those who failed early feeds and required IV glucose administration for persistent hypoglycemia. We aimed to create and validate a risk calculator to help predict the likelihood of not requiring IV glucose in this patient population and thus to determine which patients are unlikely to need transfer to the NICU for IV infusion.

Design:

Retrospective cohort study

Inclusion and exclusion criteria:

We included late preterm (GA ≥ 35wks) and term neonates born from January 1, 2010 through December 31, 2014 and admitted to the MBU at Parkland Hospital who had one documented laboratory-proven glucose concentration < 40 mg/dL (2.2 mmol/L) during the first 72h of life.

We excluded the following:

patents receiving comfort care in the delivery room or upon admission to the newborn nursery or NICU
patients whose point-of-care (POC) estimated blood glucose concentration (EBG) < 40 mg/dL (2.2 mmol/L) was deemed to be erroneous by either direct documentation in the patient chart by the treatment team or with repeat POC EBG ≥ 40 mg/dL without intervention by the treatment team.
patients who received IV fluids for any indication other than hypoglycemia.

Definitions:

Hypoglycemia was defined as a blood glucose concentration < 40 mg/dL on POC that was confirmed in the hospital laboratory. POC used ACCU-CHEK Inform II® (modified quinoprotein glucose dehydrogenase method, Hoffman-Roche, Basel, Switzerland) POC glucose test strips for blood from heel sticks. This method has an average bias of 0.54 mg/dL (range − 14.4 mg/dL to + 31.7 mg/dL) [0.03 mmol/L (range − 0.80 to + 1.76 mmol/L)] and an average constant percentage bias of 1.15% (range − 21.8 to + 58.1%) [12]. Importantly, all POC glucose concentrations < 40 mg/dL were confirmed with the hospital laboratory Cobas glucose analyzer (hexokinase assay, Roche Diagnostics, Indianapolis, IN).

Preterm birth was defined as GA < 37wks 0 days. Late-preterm neonates were defined as those born between 35wks 0 days and 36wks 6 days GA. A birthweight < 10th centile or > 90th centile for GA and sex was used to define SGA and LGA, respectively [13]. Fetal growth restriction was defined either as a body mass index (BMI) < 10th centile for GA and sex [14] or a ponderal index < 10th centile for GA and sex [15]. Persistent hypoglycemia was defined as requiring a glucose infusion rate > 8 mg · kg^{− 1 ·} min^− 1 for > 48 h to achieve sustained euglycemia.

Setting:

Parkland Hospital has more than 10,000 deliveries per year. Stable neonates with birthweight ≥ 2100 g and ≥ 35wks’ gestation without pregestational diabetes are admitted to the MBU (Supplementary Table 1). Glucose concentration was routinely assessed serially by POC in neonates with birthweight > 3850 g and < 2500 g, IDMs and preterm newborns (Supplementary Fig. 1). Blood glucose concentration POC was measured hourly during the first three hours postnatal irrespective of feeding, followed by one measurement prior to each of the next 3 feeds, completing 6 measurements in approximately 12 hours.

Data extraction:

The patient population is a subset of the population described in a previous study [16]. Neonates were identified using electronically extracted data (EED) from EPIC™, our institutional electronic health record (EHR). Population for the current study only included neonates admitted first to the MBU. Data included variables observed during the stay in the MBU as well as variables after any transfer to the NICU.

We extracted information from the EHR, including maternal and pregnancy characteristics, infant characteristics, laboratory data and interventional data (including feeds, IV fluids, and medications used to treat hypoglycemia). For this purpose we used algorithms based on structured query language (SQL) that have been validated previously [16]. Information from neonates admitted to the NICU was extracted from the prospectively collected NICU Database, which has been validated on several occasions [17, 18]. The information was downloaded to a password-protected computer. Information was de-identified by assigning a unique study number for all further analysis. Individual chart reviews were performed in medical records on all identified cases.

Statistical analysis:

Statistical analyses were done with SPSS version 28 (IBM, Inc, Armonk, NY). All calculations used two-tailed tests and P < 0.05 as significant. The cohort (n = 3479) was randomly divided into two groups: a derivation cohort (n = 1288 with 81 needing IV glucose infusion) was used to create a prediction model for IV glucose administration and a validation cohort (n = 1298 with 98 needing IV glucose infusion) to test the model. Univariate analysis was done to compare variables associated with need for IV glucose infusion in the derivation cohort and the validation cohort. Values are presented as mean\(\pm\)SD or median (interquartile range). Continuous variables were analyzed using Student t-tests or Mann-Whitney tests depending on data distribution; nominal variables were compared by chi-square test or Fisher's exact tests followed by pairwise comparisons using Bonferroni correction. Multivariate analysis used a maximum of one variable per ten subjects with the variable of interest (IV glucose administration) [19]. Variables determined to have a clinically significant association with the need for IV glucose on bivariate analyses (Table 1) were first used in the derivation cohort. Several variables were then merged to run through a forward stepwise logistic regression model to determine adjusted odds ratio (OR) and its 95% confidence interval (CI) along with the C statistic. We eliminated variables with significant collinearity. We then used the same variables to establish a model in the validation cohort to confirm model accuracy. The predictive value from the model was computed for each individual in the derivation cohort and then different thresholds were used to predict the need for intravenous treatment of hypoglycemia. The different thresholds were compared using positive predictive value, negative predictive value, sensitivity, specificity and likelihood ratio of a positive test and of a negative test.

Table 1

Demographics for the derivation cohort of neonates with a serum glucose < 40 mg/dL (2.2 mmol/L) within the first 72h after birth
	Oral feeds only (n = 1288)	Needed IV therapy (n = 81)	P-value
Estimated gestational age (wks)*	38.5 ± 1.7	38.1 ± 1.7	0.04
Male†	685 (53)	50 (62)	0.14
Birthweight (g)*	3573 ± 712	3277 ± 748	< 0.01
Birth length (cm)*	49.4 ± 3.1	48.3 ± 3.7	0.01
Head circumference (cm)*	34.4 ± 1.8	33.8 ± 1.9	< 0.01
Fetal growth
Ponderal index*	3.0 ± 1.8	2.9 ± 0.8	0.66
BMI (kg\(·\)m⁻²)*	15 ± 4	14 ± 3	0.12
Size for gestational age			< 0.01
Large for gestational age†	353 (27)	18 (22)
Appropriate for gestational age†	866 (67)	52 (64)
Small for gestational age†	69 (5)	11 (14)
Fetal growth restriction by ponderal index†	4 (< 1)	0 (0)	1.00
Fetal growth restriction by BMI†	25 (2)	3 (4)	0.23
Apgar scores
1-minute**	8 (8, 9)	8 (7, 8)	< 0.01
5-minute**	9 (9, 9)	9 (9, 9)	< 0.01
Multiple births†	139 (11)	4 (5)	0.10
Umbilical arterial blood gas Base excess* HCO₃⁻ (mmol/L)* pH_a* P_aCO₂ (mm Hg)* P_aO₂ (mm Hg)*	-5.6 ± 2.9 24.1 ± 2.3 7.25 ± 0.07 57.5 ± 11.4 27.8 ± 13.6	-7.3 ± 4.2 24.3 ± 2.8 7.20 ± 0.09 65.0 ± 12.4 22.2 ± 9.8	< 0.01 0.46 < 0.01 < 0.01 0.02
Neonatal complications†
Preterm birth	246 (19)	17 (21)	0.68
Infant of diabetic mother	306 (24)	21 (26)	0.66
Fetal acidosis	5 (< 1)	3 (4)	< 0.01
Hypoxic-ischemic encephalopathy	1 (< 1)	1 (1)	0.12
Early-onset sepsis	12 (1)	4 (5)	0.01
Congenital anomaly	12 (1)	6 (7)	< 0.01
Chromosomal anomaly	8 (< 1)	5 (6)	< 0.01
Congenital infection	20 (2)	7 (9)	< 0.01
Pulmonary hypertension	0 (0)	0 (0)	N/A
Persistent hypoglycemia†	1 (< 1)	10 (12)	< 0.01
Initial glucose (mg/dL)*	31 ± 7	25 ± 9	< 0.01
Second glucose (mg/dL)*	28 ± 8	26 ± 10	0.02
Change in glucose (mg/dL)*	-4.8 ± 8.5	-0.5 ± 11.9	< 0.01
First spun hematocrit*	58 ± 7	57 ± 8	0.19
Hematocrit > 65%†	183 (14)	10 (13)	0.66
Temperature (Fahrenheit)*	98 ± 1	98 ± 1	0.15
Data are means ± SD with T-test;*Data are medians (25th, 75th ) with Mann-Whitney U-test; †n (%) with Chi-square test or Fisher's exact test.
Abbreviations: BMI, body mass index

Approval:

The Institutional Review Board of the University of Texas Southwestern Medical Center and Parkland Health & Hospital System approved this study with a waiver of informed consent for the chart reviews at Parkland Hospital.

Univariate comparisons: Of the 51 973 neonates born at \(\ge\)35wks GA during the study period and admitted directly to the MBU, 3479 (6.7%) were identified as having early-onset neonatal hypoglycemia defined by a laboratory blood glucose <40 mg/dL (2.2 mmol/L) during the first 72 hours of life (Fig. 1). The derivation cohort included 1288 randomly chosen neonates of whom 81 (62.9/1000) required an IV glucose infusion, while the validation cohort consisted of 1298 neonates, 98 of whom (75.5/1000) required an IV glucose infusion, P = 0.21. In the derivation cohort, need for IV glucose was associated with several maternal variables, including high maternal body mass index (BMI), pre-eclampsia, and insulin-dependent diabetes mellitus (Table 2). In addition, the need for IV glucose was associated with several fetal-neonatal variables including: abnormal umbilical cord blood gas analyses, low GA, low birthweight, small length and head circumference, SGA, low Apgar scores at one and five minutes, congenital infection or the occurrence of early-onset sepsis during the first 72h, congenital anomaly, chromosomal anomaly, persistent hypoglycemia, low initial and second glucose concentrations and low change in glucose after feeding (Table 1). Data were similar in the validation cohort, except GA was not significant (Supplementary Tables 1 and 2).

Table 2

Maternal characteristics for the derivation cohort of neonates with a serum glucose < 40 mg/dL (2.2 mmol/L) within the first 72h after birth.
Characteristics	Oral Feeds Only (n = 1250)	Needed IV therapy (n = 78)	P-value
Age* (hours after birth)	30 ± 6	28 ± 7	0.11
Race and ethnicity† White Hispanic Hispanic Black Asian Other	47 (4) 1036 (83) 134 (11) 31 (3) 2 (< 1)	4 (5) 66 (85) 7 (9) 1 (1) 0 (0)	0.89
Gravidity*	3 ± 2	3 ± 2	0.45
Maternal anthropometrics
Admission height (cm)*	159 ± 7	159 ± 7	0.72
Weight 9 months before delivery (kg)*	74 ± 18	78 ± 21	0.08
Hospital admission weight (kg)*	84 ± 20	90 ± 21	0.06
BMI (kg\(·\)m⁻²)*	33 ± 7	36 ± 9	0.01
Weight change during pregnancy (kg)*	8 ± 7	8 ± 8	0.60
Obesity†	142 (11)	12 (15)	0.28
Pregnancy complications†
Gestational diabetes	276 (22)	18 (23)	0.84
Pre-gestational diabetes	13 (1)	3 (4)	0.06
Chronic hypertension	68 (5)	7 (9)	0.20
Pre-eclampsia	117 (9)	13 (17)	0.04
Eclampsia	0 (0)	0 (0)	N/A
Chorioamnionitis	0 (0)	0 (0)	N/A
Placental Abruption	3 (< 1)	1 (1)	0.22
Diabetes
Random glucose during pregnancy (mg/dL)*	90 ± 26	96 ± 39	0.19
Glucose tolerance test (mg/dL)*	188 ± 33	174 ± 38	0.13
Insulin ordered within 9 months prior†	122 (10)	13 (17)	0.05
EBG before birth (mg/dL)*	103 ± 25	106 ± 26	0.49
Data are means ± SD with T-test;*Data are medians (25th, 75th ) with Mann-Whitney U-test; †n (%) with Chi-square test or Fisher's exact test.
Abbreviations: BMI, body mass index; N/A, not applicable; EBG, estimated blood glucose

Multivariate analyses

Variables used in multivariate analysis for the derivation cohort included size for GA [i.e., appropriate for GA (AGA), SGA, LGA], initial glucose concentration, infection (congenital or early-onset) and perinatal complication (hypoxic-ischemic encephalopathy, fetal acidosis, cord gas base excess 10 mmol/L) (Table 3a). The model in the validation cohort did not differ (Table 3b). Notably, the derivation cohort had a c statistic of 0.76. In the validation cohort the c statistic was 0.72.

Table 3. Factors associated with need for intravenous glucose administration.

Table 3a

Derivation cohort, n = 1369.
Variable	Odds ratio (95% confidence interval)	P-Value
Size for age and sex AGA LGA SGA	Reference 0.75 (0.42, 1.34) 3.11 (1.48, 6.57)	0.003 - 0.33 0.003
Initial blood glucose concentration (mg/dL)	0.90 (0.87, 0.92)	< 0.001
Early-onset infection	7.15 (3.17, 16.15)	< 0.001
Perinatal complication(s)	2.48 (1.28, 4.80)	0.007

Table 3b

Validation cohort, n = 1389.
Variable	Odds ratio (95% confidence interval)	P-Value
Size for age and sex AGA LGA SGA	Reference 0.63 (0.37, 1.09) 2.64 (1.29, 5.42)	0.003 - 0.10 0.008
Initial blood glucose concentration (mg/dL)	0.93 (0.90, 0.95)	< 0.001
Early-onset infection	6.02 (2.69, 13.49)	< 0.001
Perinatal complication(s)	1.91 (1.04, 3.49)	0.04
Abbreviations: AGA, appropriate for gestational age; SGA, small for gestational age; LGA, large for gestational age
Infection: congenital or early-onset neonatal
Perinatal complication: hypoxic-ischemic encephalopathy, fetal acidosis, or cord gas base excess \(\ge\)10 mmol/L

Using a threshold of 0.4–0.6, the model from the derivation cohort had an excellent negative predictive value of needing intravenous glucose infusion close to 95% (Table 4).

Table 4

Prediction of need for intravenous glucose infusion after failed oral glucose treatment based on different thresholds in the derivation cohort.
Threshold	Positive predictive value	Negative predictive value	Sensitivity	Specificity	Likelihood ratio of a positive test	Likelihood ratio of a negative test
0.4	64.3%	94.7%	11.1%	99.6%	27.8	0.89
0.5	70.0%	94.6%	8.6%	99.8%	43.0	0.92
0.6	66.7%	94.2%	2.5%	99.9%	25.0	0.98
Abbreviations: MBU, Mother-Baby Unit; NICU, neonatal intensive care unit

In this cohort of neonates admitted to the MBU and with early-onset neonatal hypoglycemia, need for IV glucose infusion was associated with small size for gestational age, low initial glucose concentration, infection and perinatal variables associated with hypoxia-asphyxia, both in a derivation cohort and a validation cohort. Multivariate analysis using these variables allowed us to predict which neonates were very unlikely (~ 5% likelihood) to need intravenous glucose infusion and thus could be considered eligible to stay in the MBU.

Strengths of this study include using a birth cohort, AAP guidelines for diagnosing and treating neonatal hypoglycemia [7], a validated method for EED [16], and random split of the study population to design and validate a weighted algorithm to predict need for IV glucose infusion.

This study has several limitations. Since this is an observational study, it can only show associations and not causality. Neonates born to mothers with pregestational diabetes mellitus, who were admitted directly to the NICU were excluded from the study. Glucose concentration was not measured by glucose oxidase methodology, which is the current gold standard [20]. No information was collected on timing and volume of milk intake. This study was designed 8 years ago on neonates born 7–10 years ago; time lag between delivery and submission for publication resulted from the need to first design and validate methods for EED and to publish these findings [16]. Birthweight criteria for glucose POC were based on Lubchenco's growth curves, which had been obtained at high altitude [21]. Since these criteria led to underestimate SGA infants [22], the study population may have missed some SGA infants with hypoglycemia.

The definition of neonatal hypoglycemia used in this study [7] is not based on risk for neurodevelopmental outcome. Neonatal hypoglycemia may have long-term consequences that may not be detected until school age [22–25]. There is considerable heterogeneity across studies about which level of hypoglycemia is associated with long-term consequences; controversy may not be resolved until school age outcomes are available for the randomized trial by van Kempen et al [26]. Neonates in this cohort would currently be eligible to either a validated bundle of care [24] or glucose gel [27], which have been shown to reduce the risk of hypoglycemia in at-risk neonates. Variables used in this model should be tested again in the current setting using glucose gel, which may reduce the need for IV glucose administration and admission to the NICU and may increase the percentage of exclusive breastfeeding at discharge [28–31]. Whether administration of glucose gel in at-risk neonates may improve neurodevelopmental outcome is controversial [31, 32].

Summary: In this large cohort of neonates admitted to the MBU and with early-onset neonatal hypoglycemia, the need for IV glucose infusion was associated with small size for age, low initial glucose concentration, infection and perinatal variables associated with prenatal hypoxia-asphyxia.

AGA Appropriate for gestational age

BMI Body mass index

CI 95% confidence interval

D5W Glucose solution in water at 5 g/dL

D10W Glucose solution in water at 10 g/dL

EGG Estimated blood glucose

EED Electronically extracted data

EHR Electronic health record

GA Gestational age

HIE Hypoxic-ischemic encephalopathy

IDM Infant of diabetic mother

IUGR Intrauterine growth restriction

IV Intravenous

LGA Large for gestational age

MBU Mother-Baby Unit

NICU Neonatal Intensive Care Unit

OR Odds ratio

POC Point of Care

SGA Large for gestational age

SQL Structured query language

Disclosures

There are no conflicts of interest to disclose. This study was funded by the George L. MacGregor Professorship of the University of Texas Southwestern Medical Center awarded to Dr. Rosenfeld.

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Author contributions

All authors reviewed, edited and approved the manuscript as written. Drs. Scheid and Rosenfeld designed the study. Dr. Brion wrote the first version of the manuscript. Mr. Brown conducted statistical analyses.

Acknowledgements

We acknowledge the contribution of Christopher Clark, who designed the algorithm for EED that was used to find neonates with hypoglycemia and several variables used in this study [16].

Financial Disclosure

No financial relationships relevant to this article to disclose.

Funding Source

This study was funded by the George L. MacGregor Professorship (CR Rosenfeld)

Conflict of Interest

No potential conflicts of interest to disclose.

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There is NO conflict of interest to disclose.

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Factors Associated with Need for Intravenous Glucose Infusion for the Treatment of Early Neonatal Hypoglycemia in Late Preterm and Term infants

Status:

Version 1

Abstract

Objective

Study Design:

Result

Conclusion

Figures

Introduction

Methods

Design:

Inclusion and exclusion criteria:

Definitions:

Setting:

Data extraction:

Statistical analysis:

Approval:

Results

Discussion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1