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Blood Glucose Levels and Characteristics of Hypoglycemia in Low Birth Weight Neonates

Introduction: Low birth weight (LBW) neonates comprising of preterm and small for gestational age (SGA) are at risk of hypoglycemia. Hypoglycemia as such in LBW neonates is not well characterized. We aimed to study the blood glucose levels of these neonates and characterise the hypoglycemia. Methods: Blood glucose levels in singleton neonates with birth weight between 1500 gm and 2499 gm were studied prospectively. Glucose levels were assessed at six hour intervals in the first 48 hours of life and extended if indicated. Glucose level ≤ 45 mg/dL in the first 24 hours and < 50 mg/dL thereafter was considered hypoglycaemia. Results: A total of 320 among 3822 neonates satisfied inclusion criteria; 104 had at least one low glucose reading with an incidence of hypoglycaemia of 32.5%. Preterm neonates constituted 158 (49.4%) and SGA 76 (23.8%). Mean blood glucose values were lowest in the first hour of life (60.1 ± 17.2 mg/dL). Incidence of hypoglycemia was highest within one hour of life followed by day two of life (16.3% and 11.6% respectively). About 86 (82.6%) neonates were asymptomatic. Overall, 75% of neonates had a single episode of hypoglycemia and 25% had a recurrence. Hypoglycaemia was noted in 31.8% of neonates born to diabetic mothers, mostly in the first hour (57.1%). Other risk factors for hypoglycemia included intrapartum fluids, birth weight < 2000 g and polycythemia. Conclusions: About a third of LBW neonates had hypoglycemia; mostly on the first hour and day one of life. Asymptomatic nature of hypoglycaemia in the large majority and recurrent hypoglycemia in 25% cases warrants glucose monitoring in this subgroup.


INTRODUCTION
Most neonates maintain normal blood glucose levels by gluconeogenesis. However certain subgroups are relatively at higher risk for hypoglycemia. The important risk factors include prematurity, small for gestational age (SGA), large for gestational age (LGA), and maternal diabetes mellitus. A sudden metabolic transition from dependent to independent life at birth requires a coordinated and integrated change of hormones and enzymes. [1][2][3][4][5] The low birth weight (LBW) constitute a significant proportion of neonates and this proportion is much more in developing countries. The LBW neonates constitute preterm and intrauterine growth retardation neonates. Intrauterine growth retardation and prematurity impair nutrient reserves for mobilization, and thereby, impair the ability to maintain appropriate glucose concentration leading to hypoglycaemia. The glucose levels as such in LBW neonates are not well studied. Symptoms can also be due to neuroglycopenia. Persistent or recurrent hypoglycaemia can blunt the autonomic response and hence only the neuroglycopenic effects may manifest. 1,[5][6][7] Neonatal hypoglycemia is associated with adverse neurodevelopmental outcome. [6][7][8][9] The severity, duration as well as the number of episodes of hypoglycaemia may all have significant effects. R e c u r r e n t e p i s o d e s , a s w e l l a s s e v e r e hypoglycemia, is associated with a poor neurological outcome. Prompt recognition of risk factors, monitoring, prevention and management of hypoglycemia is important to reduce the risk of neurological sequel. In this context, we aimed to study the blood glucose levels and characteristics of hypoglycaemia in LBW neonates.

METHODS
A prospective study was conducted on singleton LBW neonates born in our hospital between February 2017 and May 2018. The LBW included neonates with birth weight between 1500 gm and 2499 gm. Outborn neonates, multiple gestations and those who succumbed within 48 hrs were excluded. Clearance was obtained from the ethics committee of the institution (IEC number: 90/2017). Baseline neonatal and maternal information, clinical features and examination findings of singleton LBW neonates were collected and documented in the proforma designed for the study. The blood glucose levels were assessed on a heel stick sample using a glucometer (Accuchek) within an hour and subsequently at six hour intervals in the first 48 hours of life. Extended blood glucose monitoring was carried out based on the physician's decision and such values were also recorded. The heel stick blood glucose was estimated as follows: the Accucheck strip was inserted into the glucometer; the heel of the neonate was cleaned with an alcohol-based skin disinfectant swab and allowed to dry for one minute; the lateral side of the heel was pricked with a heel lancet and the first drop was let out. The second drop of the blood was placed on the Accuchek strip for blood glucose estimation.
Any blood glucose level ≤ 45 mg/dL in the first 24 hours and < 50 mg/dL thereafter was considered as hypoglycaemia for study purpose. In cases of confirmed hypoglycaemia, if the neonate was on enteral feeds, glucose level was monitored within the next one hour. If the neonate was receiving intravenous fluids, 2 ml/kg of 10% dextrose bolus was given and the glucose infusion rate was increased by 2 mg/kg/min until normoglycaemia was achieved. If hypoglycaemia persisted even after 12 mg/kg/min of glucose infusion rate (GIR), a blood sample for serum cortisol and insulin was sent. A urine sample was sent to detect reducing substance and ketonuria. Dried blood spots for tandem mass spectroscopy, serum carnitine profile, aminoacidopathies and organic academia were also sent in cases of prolonged hypoglycaemia or hepatomegaly with jaundice.
Weight of unclothed neonate recorded within the first hour of life to the nearest of 5 gm with an electronic weighing machine was taken as birth weight. Gestational age was determined by maternal last menstrual period and / or antenatal sonography. Gestational age was further classified as preterm-gestational age < 37 completed weeks and term-gestational age of 37 to less than 42 completed weeks. Neonates were also classified as appropriate for gestational age (AGA)-birth weight between 90 th and 10 th percentile of gestational age, small for gestational age (SGA)-birth weight less than 10 th percentile for gestational age and large for gestational age (LGA)-birth weight above the 90th percentile of gestational age. 10 Gestational diabetes mellitus (GDM) was diagnosed based on International Association of Diabetes and Pregnancy Study Groups criteria, 11 as follows-At any time in pregnancy if one or more of the following criteria are met: fasting plasma glucose ≥ 93 mg/dL (5.1 mmol/L), 1-hour plasma glucose ≥ 180 mg/dL (10.0 mmol/L) following a 75 gm oral glucose load or two-hour plasma glucose ≥ 153 mg/ dL (8.5 mmol/L) following a 75 gm oral glucose load. The oral glucose tolerance test was obtained at 24 -28 weeks of gestation. The hypoglycemia was further classified as a single episode or recurrent hypoglycemia. Recurrent hypoglycemia included a second or subsequent episode. The duration of an episode was the time from the first glucose concentration less than the cutoff to the first measured glucose concentration more than the cutoff. Neonatal sepsis was considered if a neonate manifested by systemic signs of infection and isolation of a bacterial pathogen from the bloodstream. Mixed feeding was defined as feeding the infant both breast milk and the commercial infant formula. Polycythemia was defined as venous hematocrit of > 65%. Data were analyzed with SPSS 21 using descriptive statistics such as frequency, percentages and median with 25 th and 75 th Interquartile range (IQR). The association of risk factors with neonatal hypoglycemia was analyzed with a chi-square test. A p-value of < 0.05 was considered significant.

RESULTS
We studied the blood glucose levels in LBW neonates and the incidence of hypoglycaemia in them. Of 3822 neonates born in the hospital during the study period, 320 LBW neonates fulfilling the inclusion criteria were enrolled ( Figure 1). Of 320 newborns, 104 neonates were found to have at least one low glucose reading. The incidence of hypoglycaemia among LBW neonates was 32.5%.
Among 320 LBW neonates, there were 158 (49.4%) preterm and 162 (50.6%) term neonates ( Table 1). The male to female ratio was 1.02:1. In the present study, 104 out of 320 LBW neonates were found to have hypoglycemia on at least one In the present study, 86 (82.6%) LBW neonates had asymptomatic hypoglycaemia (Table 4). Among the symptomatic neonates, lethargy was noted to be the most common symptom and seven neonates had more than one symptoms. None had seizures.
In the present study, three (2.8%) neonates were found to have glucose values of < 21 mg/dL on day one (  More than one symptoms 7 (6.7)  Among 44 LBW neonates born to diabetic mothers, 28 were preterm, 16 were term, seven were SGA and 37 were AGA neonates ( Table 6). The incidence of hypoglycaemia in LBW neonates born to mothers with diabetes was 31.8%. Among the neonates born to mothers who received intrapartum fluids, 37.1% had hypoglycaemic events. Among neonates born to mothers who did not receive intrapartum fluids, 20.8% had hypoglycaemia. This difference was statistically significant.
Incidence of hypoglycaemia among low birth weight neonates born to mothers with diabetes (GDM and overt diabetes) was highest in the first six hours of life with an incidence of 57.1% at the first hour and 42.8% at six hrs of life (Table 7). There were seven preterm neonates and seven term neonates among the hypoglycaemia. Of 14 neonates, two were SGA and 12 were AGA.
In the present study, 34.8% of preterm neonates had hypoglycemia and 30.2% of term neonates had hypoglycemia (Table 8). A higher incidence of hypoglycemia was noted among LBW neonates with birth weight between 1500 -1999 gm than those with birth weight between 2000 -2499 gm (36.2% vs. 31%). There was no significant difference in the incidence of hypoglycemia noted among AGA and SGA categories. All neonates with polycythemia had hypoglycemia. Among eight neonates with sepsis one had hypoglycemia. This was preterm AGA neonate noted to have a single low blood glucose value at birth.

DISCUSSION
We studied the blood glucose values, the incidence of hypoglycaemia and characteristics of hypoglycemia in LBW neonates. Hypoglycaemia was studied in detail for many neonatal and m a t e r n a l v a r i a b l e s . T h e i n c i d e n c e o f hypoglycaemia among LBW neonates was 32.5%. The mean blood glucose values were lowest in the first hour of life. The hypoglycemic episodes decreased on day two of life. Most of the neonates with hypoglycaemia were asymptomatic. A higher incidence of hypoglycemia was noted among LBW neonates with birth weight between 1500 gm and 1999 gm than those with birth weight between 2000 gm and 2499 gm. About 25% found to have a recurrence of hypoglycemia. Maternal diabetes, The mean blood glucose values in LBW neonates were found to be lowest in the first hour of life and improved subsequently. Similar findings were reported in another study. 2 However, the authors reported much lower mean blood glucose values at the first hour of life in LBW neonates (41.0 ± 4.9 mg/dL). Following the birth of the normal newborn, the mean blood glucose levels dip within the first one to two hours, remain lower for two to three days and reach a normal, stable value of 70 to 100 mg/dL subsequently. In LBW neonates this dip is likely to be much more and may last for several weeks. [1][2][3][4][5] In the present study, the incidence of hypoglycemia was 32.5%. Incidence of hypoglycemia was noted to be highest within one hour of life followed by day two of life (16.3% and 11.6% respectively). Hypoglycemia beyond 48 hours was observed in 26 neonates and nine neonates had hypoglycaemia beyond third day. Faulty feeding, syndromic features, polycythemia, respiratory distress syndrome, LBW were the associated features with them. These are the other known risk factors for hypoglycemia beyond 24 hours in a neonate. A study of 187 SGA neonates in Montreal reported that 26% of the neonates had at least one episode of hypoglycemia. 12 Another Indian study found the incidence of hypoglycemia to be 32%, significantly greater in SGA and preterm neonates. 2 They reported maximum numbers of hypoglycemia within 24 hrs of life with a maximum incidence at six hrs of life, similar to the present study.
The symptoms and signs of hypoglycaemia are the results of activation of the autonomic nervous system in response to a low glucose valueproducing neurogenic symptoms. [5][6][7][8] Symptoms can also be due to neuroglycopenia resulting in decreased cerebral glucose use. Neonatal hypoglycemia manifests as jitteriness, cyanosis, seizures, apneic episodes, tachypnea, weak or highpitched cry, floppiness or lethargy, prolonged sleep, poor feeding, and eye-rolling. [12][13][14][15] Persistent or recurrent hypoglycaemia may blunt the autonomic response resulting in manifestations of only the neuroglycopenic effects. In the present study, 82.6% LBW neonates with hypoglycaemia remained asymptomatic. Lethargy was the most common symptom and none had seizures. An Indian study earlier reported lethargy in 60% and jitteriness in 50% of hypoglycemic neonates. 15 The definition of neonatal hypoglycaemia and screening is controversial. Although continuous monitoring of glucose may be the best method to detect neonatal hypoglycemia, it may not be practical. 13,14 Estimation of both venous and capillary glucose levels are accepted modalities. Capillary glucose levels may differ from venous levels but the difference may not be physiologically significant. 14 Single low glucose value is unlikely to have any long term neurological sequelae. However, the need for monitoring of blood glucose in at-risk neonates and operational thresholds have been well stated by many studies and guidelines. [16][17][18][19] To determine or predict the neurological outcome, it becomes important to have information about the duration of hypoglycaemia as well as the number of episodes. Recurrent episodes of hypoglycaemia may lead to a poor neurological outcome. In the present study, 2.8% of neonates were found to have glucose values of < 21 mg/dL on day one. They required IV fluids and glucose values normalized   20 Authors reported blood glucose concentration ≤ 36 mg/dL in 19% and 37% having more than one episode. Ninety-eight neonates (19%) had recurrent episodes of hypoglycemia. 20 Hume et al reported that about 18% preterm infants were unable to maintain normal concentrations of blood glucose even though they are ready to be discharged. 21 Another study looked at long term neurological problems related to hypoglycaemia in SGA infants. 22 About 72.9% of SGA infants had hypoglycemia and those with repeated episodes of hypoglycemia had significantly reduced head circumference and lower scores in specific psychometric tests at 3.5 years of age. Further, they also had lower psychometric scores at five years of age. Infants with moderate recurrent hypoglycemia had lower scores at 3.5 and five years of age when compared with infants who had a single episode of hypoglycemic. The authors stressed the need for repetitive blood glucose monitoring for small-forgestational-age infants in the neonatal period.
Newborns from diabetic mothers with diabetes type 1 and 2 or gestational diabetes are at highest risk of developing symptomatic hypoglycemia in the first few hours after birth. [23][24][25] Among 44 LBW neonates born to diabetic mothers in the present study, the incidence of hypoglycaemia was 31.8%. Hypoglycaemia was highest in the first six hours of life -57.1% at the first hour and 42.8% at six hrs of life. A higher incidence of hypoglycaemia of 48% among neonates born to 199 diabetic mothers has been reported in another study. 20 Authors found 83% of hypoglycaemic episodes occurring within the first 24 hrs of life. A study from Sweden reported early neonatal hypoglycemia in infants of all types of diabetes in mothers whether they are insulin-treated, insulin-dependent or GDM. 24 They reported neonatal hypoglycemia in well-controlled pregnancies also. Compared to controls from nondiabetic mothers, the prevalence of hypoglycemic episodes in infants of diabetic mothers is as high as 40%. 3 Hence, neonatal hypoglycemia should always be anticipated and screened for in high-risk infants born to diabetic mothers, even in the absence of clinical symptoms, from the first hours of postnatal life itself. [25][26][27][28] If blood glucose is under 35 mg/dL at any point in time, initiation of IV glucose therapy is recommended. 25 This would avoid the immediate risk of convulsions, coma and even death as well as long term neurological consequences.
Among the neonates born to mothers who received intrapartum IV fluids, 37.1% had hypoglycaemic events whereas, among neonates born to mothers who did not receive intrapartum fluids, 20.8% had hypoglycaemia. Mothers receiving intrapartum glucose infusions need supervision. Previously a study reported that six out of 56 neonates born to mothers receiving intrapartum glucose infusions having hypoglycemia at one hour of life. 28 It is recommended that the normal parturient be given less than 20 gm/hour of IV glucose before delivery and have a blood glucose level less than 120 mg/dl at the time of delivery.
In the present study, 34.8% of preterm neonates had hypoglycemia and a higher incidence of hypoglycemia was noted among LBW neonates with birth weight between 1500 -1999 gm (36.2% vs. 31%) than those with birth weight between 2000 -2499 gm. This suggests the metabolic adaptation problem at birth in preterm and LBW neonates. Previously, hypoglycaemia of 77.7% among preterm neonates was reported by an Indian study. 2 Same study also found three times higher incidence of hypoglycaemia in SGA neonates compared to AGA neonates (64.2% vs.20.3%). Among breastfed neonates, 32.6% were found to be hypoglycaemia in the present study. Although early breastfeeding is protective against hypoglycemia in many infants monitoring is still needed. The incidence of hypoglycemia as high as 51% among neonates despite early and frequent breastfeeding was reported in one study. 20