Accepted Manuscript

Neurodevelopmental outcome of asymptomatic hypoglycemia in comparison to

symptomatic hypoglycemia and euglycemia in high risk neonates

Gagan Mahajan, MD, DM, Kanya Mukhopadhyay, MD, DM, Savita Attri, PhD,
Praveen Kumar, MD, DM

PII: S0887-8994(17)30282-5
DOI: 10.1016/j.pediatrneurol.2017.05.028
Reference: PNU 9169

To appear in: Pediatric Neurology

Received Date: 16 March 2017

Revised Date: 26 May 2017
Accepted Date: 29 May 2017

Please cite this article as: Mahajan G, Mukhopadhyay K, Attri S, Kumar P, Neurodevelopmental
outcome of asymptomatic hypoglycemia in comparison to symptomatic hypoglycemia and euglycemia in
high risk neonates, Pediatric Neurology (2017), doi: 10.1016/j.pediatrneurol.2017.05.028.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
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 ACCEPTED MANUSCRIPT

Title: Neurodevelopmental outcome of asymptomatic hypoglycemia in comparison to

symptomatic hypoglycemia and euglycemia in high risk neonates

Authors:

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1
Gagan Mahajan (MD, DM)

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1
Kanya Mukhopadhyay (MD, DM)

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Savita Attri (PhD)

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Praveen Kumar (MD, DM)

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Affiliations: 1Neonatal unit and 2Pediatric biochemistry unit, Dept. of Pediatrics, PGIMER,
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Chandigarh
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Corresponding author: Kanya Mukhopadhyay, Professor, Neonatal unit, Department of

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Pediatrics, PGIMER, Chandigarh, India 160012. Fax: 0172-2744401, Phone: 0172-2755316,18.

Email id: kanyapgi@gmail.com

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E-mail: drgaganmahajan@gmail.com,attrisavi@yahoo.co.in,drpkumarpgi@gmail.com
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Running title: Neurodevelopmental outcome of hypoglycemic neonates

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Funding: nil

Conflict of interests: none

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Contribution of authors:

GM: Prepared the protocol, collected and analyzed the data and drafted the manuscript

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KM: Conceptualized and designed the study, supervised data collection and analysis, and

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critically revised the manuscript

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SA: Conducted Biochemical analysis and reviewed the manuscript

PK: Reviewed data analysis and the manuscript

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ABSTRACT

Aims: To assess the neurodevelopmental outcome of asymptomatic neonatal hypoglycemia at 1

year and to compare it with symptomatic hypoglycemic and euglycemic neonates .

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Method: Seventy two hypoglycemic (plasma glucose <50 mg/dl) neonates, both symptomatic

(n=27) and asymptomatic (n=45) and 70 weight and gestation matched euglycemic neonates who

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were > 32 weeks gestation, enrolled during 1st week of life and assessed for neurodevelopmental

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outcome at corrected age (CA) 6 and 12 months ( n=67 and 62 in hypoglycemia group and 63

and 54 in euglycemia group, rest lost to follow up and death=1) .

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Results: At 1 year, 8% (5 of 62, 4 in symptomatic and 1 in asymptomatic group) hypoglycemic
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neonates developed Cerebral Palsy. Mean Motor and Mental DQ were significantly lower at
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CA 6 and 12 months in any hypoglycemia (p <0.001) and if blood glucose was < 40 mg/dl (p <

0.001) as compared to euglycemia. Symptomatic infants had lower MoDQ (p= 0.004 and 0.003)
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and MeDQ (p= 0.001 and 0.001) at CA 6 and 12 months than asymptomatic infants and
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asymptomatic infants had lower MoDQ (p= < 0.001and 0.004) and MeDQ (p= 0.001 and 0.004)

than euglycemic group at CA 6 and 12 months respectively. Blood glucose of < 40 mg/dl had
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high sensitivity (83% for MoDQ and 81% for MeDQ) for DQ scores of < 85.
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Conclusion: Hypoglycemia, both symptomatic and asymptomatic lead to adverse

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neurodevelopmental outcome as compared to euglycemia though it was worse in symptomatic

group and at blood glucose < 40 mg/dl.

Key words: Neurodevelopment; MoDQ; MeDQ; DASII score; hypoglycemia; blood glucose
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INTRODUCTION

Hypoglycemia in neonates has been recognized as a cause of serious long-term neuromorbidity

for over 50 years which causes damage to both neuronal and glial cells of the brain resulting in

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death or handicap (1, 2) . Due to poor correlation between blood glucose levels and clinical

manifestations and controversial treatment thresholds, it is difficult to define a safe blood

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glucose. American Academy of Pediatrics (AAP) in 2011 proposed a guideline of using

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intravenous (IV) fluids in late preterm, term small for gestational age (SGA) and infant of

diabetic mother (IDM)/large for gestational age (LGA) infants if blood glucose level is < 40

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mg/dl and in symptomatic cases. In asymptomatic infants, a trial of enteral feed is given if blood
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glucose is < 25 mg/dl within 1st 4 hours and at < 35 mg/dl between 4-24 hours of age. If no

improvement happens 1 hour after feed then IV glucose is recommended. In case of partial
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improvement, refeed/IV glucose as needed is recommended (3). Cornblath et al,proposed

operational thresholds of intervention at 36 mg/dl and to maintain a therapeutic level of more

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than 45 mg/dl in neonates (4). Several studies have looked into the effects of various ranges of
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hypoglycemia on their neurodevelopmental outcome (1-2,5-7) however the effect of

asymptomatic hypoglycemia has been reported with variable results on the neurodevelopmental
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outcome (1,5-6) without any clear conclusion. We planned this study to look at long term
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neurodevelopmental outcome in symptomatic and asymptomatic hypoglycemic neonates as

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compared to euglycemic neonates.

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METHODS

This prospective study was conducted in a level III neonatal unit and subsequently in neonatal

follow up clinic after discharge, from July 2010 to June 2012 in > 32 weeks gestation infants

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who developed hypoglycemia during first 7 days of life. As per our neonatal unit protocol, all

neonates at risk of hypoglycemia (all preterm infants, term infants who are SGA or LGA and

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IDM) are routinely screened for hypoglycemia during first 72 hours of life with 6 hourly blood

glucose monitoring. Neonates who developed hypoglycemia, as measured by glucose test strips

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(defined as blood glucose levels < 50 mg/dl, confirmed by lab glucose) were consecutively

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enrolled as cases after written informed consent from parents. Those who remained euglycemic
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were matched for weight and gestation and served as controls. In euglycemic group one lab

plasma glucose level was estimated within 1st 6 hours of life. If hypoglycemia was associated
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with lethargy, poor feeding, seizures, jitteriness and apnea, they were considered as symptomatic

hypoglycemia. Those with major congenital malformations, severe birth asphyxia, Rh iso-
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immunization and grade III or IV intraventricular haemorrhage (IVH) were excluded.

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After 72 hours if any baby became symptomatic due to any illness or developed any symptoms

suggestive of hypoglycemia , blood glucose was repeated and if found hypoglycemic were also
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planned to be enrolled as cases till day 7 of life.

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The initial blood glucose was done with Optium Xceed Glucometer, Abbott Diabetes Care Inc.
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Alameda, CA 94502 USA using Optium blood glucose test strips and if it was < 50 mg/dl,

plasma glucose level was done using hexokinase method on Clinical Chemistry Analyser. We

used oxalate and sodium fluoride containing vials for estimation of plasma glucose.

Infants with blood glucose < 40 mg/dl tested by glucose strips were started on IV fluids with

glucose infusion rate (GIR) of 6 mg/kg/min. Blood glucose was repeated every 15 minutes
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initially till stabilization, subsequently ½ hourly for 2 hours and then 6 hourly for next 72 hours.

If blood glucose level remained below 40 mg/dl, than GIR was increased by 2 mg/kg/min till

blood glucose of 50 mg/dl or more was achieved. Those neonates having value > 40 mg/dl were

given oral feeds and monitored every ½ hr till blood glucose increased to 50 mg/dl. They were

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monitored for next 72 hours with 6 hourly blood glucose. In infants who were on IV fluids, oral

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feeds were started as soon as possible, initially at the rate of 20-30 ml/kg/day and advancement

of feed was done depending on tolerance and need for glucose infusion. After observing for 6

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more hours, if blood glucose remained in euglycemic range ( > 50 mg/dl) and the baby tolerated

feeds, then feeds were further increased and IV fluids tapered off. All blood glucose were done

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by optium glucose test strips. If the baby had intermittent hypoglycemia on subsequent days,
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everyday one sample for lab plasma glucose was sent during the episode of hypoglycemia. One

documented episode of hypoglycemia on each subsequent day was counted as one day and was
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added up for the total duration of hypoglycemia.

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At birth all infants were assessed by New Ballard Score (9) for accurate gestational assessment.
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Growth was categorized as AGA, SGA and LGA as per Lubchenco’s intrauterine growth chart

(10). After discharge infants were followed up at monthly intervals for 3 months for growth and
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feeding pattern and then at corrected ages (CA) of 6 and 12 months for neurodevelopmental

assessment. Neurological assessment was done by using Amiel Tison scale (11) and
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developmental assessment was done by using Developmental assessment score for Indian infants

(DASII) scoring system which is an Indian adaptation of Bayley Scale of Infant Development

(12). DASII scale was administered by the principal investigator (unblinded) who was trained by

a certified and experienced trainer. Mental and Motor development quotients (MeDQ and

MoDQ) were calculated as per the DASII instruction manual and a score of < 70 was considered
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as delay, between 70-85 borderline and > 85 average. Respiratory distress was defined as

tachypnea, retractions or grunt and need for oxygen or any form of respiratory support. We

included all cases of respiratory distress irrespective of causes. Sepsis included both culture

positive and culture negative with septic screen positivity alongwith symptoms. Polycythemia

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was defined as packed cell volume of > 65% sampled from a major vein. The study protocol was

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approved by Institute research ethics committee.

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SAMPLE SIZE

According to a previous study by Yamaguchi et al (13), DQ at 2 years was 103.8 ± 24.2 for cases

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of hypoglycemia and 116.8 ± 20.7 for controls. Based on this, to find out a difference of DQ of
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10, with a SD of 20 and alpha error of 5% and a power of 80%, 128 samples were required.

Anticipating 10% loss in follow up, we enrolled a total 142 (72 hypoglycemia and 70
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euglycemia) patients. We finally assessed 130 (67 in hypoglycemia and 63 in euglycemia group )
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at 6 months and 116 ( 62 in hypoglycemia and 54 in euglycemia group) at 1 year CA.

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We compared the outcome (DQ) in symptomatic and asymptomatic hypoglycemic infants as

well as compared them with euglycemic infants at CA 6 months and 1 year.

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STATISTICAL ANALYSIS
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Statistical analysis was done using SPSS version19. Quantitative variables are reported as mean
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(SD), median (IQR) and qualitative variables are reported as proportions. Comparison was made

by using student t test or chi square test, as appropriate.

A cut off of blood glucose level was established by constructing a receiver operating curve

(ROC) to define a normal DQ of > 85. A two tailed significance level of 0.05 was applied for all
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analysis. Multivariate regression analysis was performed to see the independent risk factors of

abnormal neurodevelopment other than low blood glucose levels.

RESULTS

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A total of 647 infants were screened who fulfilled eligibility criteria (Fig 1) and a final sample of

142 were enrolled (n=72, hypoglycemia and n=70, euglycemia). In the hypoglycemia group, 27

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(37.5%) were symptomatic (lethargy - 22, poor feeding – 15, seizures- 7, jitteriness- 5) and some

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infants had more than one symptoms .In the hypoglycemic group, 67 were followed up at 6

months and 62 at 12 months CA and in euglycemic group , 63 were followed up at 6 months and

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54 at 12 months CA. Baseline demographic profiles and morbidities of the 2 groups are given in
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Table1. Mean gestational age and proportion of SGA infants and morbidities (respiratory

distress, polycythemia, any sepsis) were significantly higher in hypoglycemic group than
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euglycemic group (Table1).

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Forty five (62.5%) neonates had asymptomatic and 27 (37.5%) had symptomatic hypoglycemia
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and the demographic characteristics were similar in these 2 groups (Table 2) except

polycythemia and sepsis which were significantly higher in symptomatic group. The mean
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lowest blood glucose level was significantly lower (p<0.001) in symptomatic hypoglycemia than

asymptomatic hypoglycemia group (20.4 + 8.2 vs. 30 + 8.4 mg/dl, p <0.001) respectively and
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these were significantly lower as compared to euglycemia group (59 + 4 mg/dl, p<0.001). In
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hypoglycemia group, there were 3 babies whose blood glucose was between 40-49 mg/dl and

they were all asymptomatic but rest 69 babies had blood glucose < 40 mg/dl of which 27 were

symptomatic and 42 were asymptomatic.

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Table 3 depicts the significant differences in MoDQ and MeDQ at CA 6 and 12 months among

symptomatic , asymptomatic hypoglycemic and euglycemic infants.

The mean MoDQ and MeDQ at 6 months ( 82 + 7 vs. 89 + 4, p<0.001 and 81 + 9 vs. 89 + 3,

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p <0.001) and at 12 months CA (82 + 9 vs. 89 + 3, p < 0.001 and 82 +10 vs. 90 + 2.5 , p <0.001)

were significantly lower in overall hypoglycemia group as compared to euglycemia group

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respectively.

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At 1 year, 8% (5 of 62) developed cerebral palsy in hypoglycemia group (4 in symptomatic and 1

in asymptomatic group). In the infants who had seizures 33.4% (2 of the 6) were abnormal as

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compared to 66.6% (4 out of 6, p=0.069) normal at CA 1 year. There was no difference in DQ
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scores at CA 6 and 12 months whether hypoglycemia persisted for < 48 hours vs. > 48 hours.

At 6 months CA, 28% (19 of 67) infants had MoDQ > 85 as compared to 75% (47 of 63 ) and
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MeDQ > 85 in 25% (17 of 67) as compared to 71% (45 of 63) infants ) in hypoglycemia and
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euglycemia group respectively (p<0.001). At 1 year CA, 53% (29 of 62) infants had MoDQ >
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85 as compared to 89% (48 of 54) and MeDQ > 85 in 45% (28 of 62) as compared to 93% (50

of 54) in hypoglycemia and euglycemia group respectively (p<0.001).

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Multivariate linear regression analysis by forward step wise method was carried out by using

MoDQ and MeDQ as dependent variable and factors found significant on univariate analysis like
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gestational age, birth weight, growth status, lowest blood glucose, respiratory distress,
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polycythemia, sepsis and IVH as independent variables. It was found that sepsis, birth weight

and lowest blood glucose were independent predictors of low MoDQ score and IVH and lowest

blood glucose for low MeDQ (Table 4).

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We prepared a ROC curve taking a cut off of MeDQ and MoDQ of < 85 at 6 months and lowest

blood glucose levels detected in hypoglycemic neonates. We found that a blood glucose cut-off

level of 40 mg/dl had sensitivity and specificity of 83% and 67% respectively for MoDQ and

81% and 70% for MeDQ. Area under curve was 0.806 (95% CI 0.72 to 0.88) for both MoDQ

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and MeDQ. Based on the ROC cut off, we divided hypoglycemic infants in 2 sub groups who

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had any episode of blood glucose < 40 mg/dl and > 40 mg/dl . DASII scores at CA 6 and 12

months were significantly lower in < 40 mg/dl group as compared to > 40 mg/dl group (p <

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0.001) (Fig2).

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DISCUSSION

This study shows that both symptomatic and asymptomatic hypoglycemia have worse outcomes

than euglycemic infants and a cut off of 40 mg/dl was associated with lower developmental

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score. We enrolled only > 32 weeks gestation neonates as co-morbidities would be less in this

gestation and hence less confounding factors for adverse neurodevelopmental outcome.

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Various studies have used different cut off values (2-3 mmol/L) to define hypoglycemia (4, 6,

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14, 15 ). Generally a cut off of 47 mg/dl is considered to define hypoglycemia however scientific

evidence to adopt this policy is not robust and this level should be viewed with caution (14).

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Blood glucose levels which require active intervention is also controversial and American
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Academy of Pediatrics (AAP) in 2011 has suggested intravenous fluids only in symptomatic

infants with blood glucose < 40 mg/dl and in asymptomatic infants at blood glucose < 25 mg/dl
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within 1st 4 hours of life and < 35 mg/dl between 4-24 hours of life though the effects of
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asymptomatic hypoglycemia on neurodevelopmental outcome was not reviewed (3). Kalhan et al

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proposed a cut off value of 45 mg/dl in symptomatic infants and 36 mg/dl in asymptomatic

infants though the targeted therapeutic values are maintained in the range of 72-90 mg/dl (16).
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Wayenberg et al suggested active intervention at < 45 mg/dl as repeated mild hypoglycemia

could be detrimental to developing preterm brain (17). We used 50 mg/dl of plasma glucose as
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cut off for defining hypoglycemia and 40 mg/dl for active intervention in the form of intravenous
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fluids in our study population.

Various authors which conducted similar studies which included gestational age ranged between

28-43 weeks and birth weight between 1040-4850 grams ( 1,8,18,19,20,21,22) and in SGA

infants (20). Mean gestation and proportion of SGA infants in our hypoglycemia group was

significantly higher than euglycemia group though we wanted to match for this. Duvanel et al
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reported an incidence of 72.9% hypoglycemia in SGA infants ( hypoglycemia defined as <47

mg/dl) and found significantly lower head circumference and lower scores in psychometric tests

at 3.5 and 5 years of age (20) . Though we did not analyze DQ in SGA subcategories but overall

we had significantly high proportion of SGA infants in hypoglycemic group.

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Literature on neurodevelopmental outcome in asymptomatic hypoglycemia is very controversial.

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Koivisto et al found normal neurodevelopment at 1 – 4 yrs of age in all asymptomatic

hypoglycemic infants (n=66) except 4 having only abnormal ophthalmological findings (1),

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however we found neonates with even asymptomatic hypoglycemia had significantly lower

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MoDQ and MeDQ at 6 and 12 months CA when compared to euglycemic infants. Abnormal
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evoked potentials were recorded by Koh et al in 10 out of 11 children with blood glucose < 47

mg/dl and 5 of them were asymptomatic (5). Bland et al did not find any significant difference in
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developmental outcome in term euglycemic and mildly hypoglycemic infants at 4 years (18).

Griffiths et al (23) found normal neurodevelopment in all 12 asymptomatic hypoglycemic but 6

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of 29 symptomatic hypoglycemic were abnormal at 51 months follow up which is similar to

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our observation that symptomatic group had lower DQ than asymptomatic. Fluge et al reported 5

out 7 asymptomatic children to be normal at a mean of 3 and ½ years though only 1out of 9
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symptomatic infants was normal (24). Singh M et al reported mental and psychomotor

developmental index were significantly lower in infants with hypoglycemia and seizures as
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compared to hypoglycemia with other symptoms and in euglycemic infants (7). Koivisto et al

observed that outcome was worse in presence of seizures with hypoglycemia (1). In our study,

1/3rd were abnormal if they had seizure during hypoglycemia .

Though we did not find any significant difference in the DQ in the infants with hypoglycemia

persisting for < 48 hours vs ≥ 48 hrs, Singh et al found that the duration of hypoglycemia was
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directly related to mental developmental index ( r=-0.74, y=102.5-o.69x) and psychomotor

developmental index (r= -0.81, y = 105.6-0.86x) (7). The reason for our no difference could be

very small size in hypoglycemia lasting < 48 hours and our arbitrary cut off of 48 hours. It may

be repeated episodes of hypoglycemia within a particular time period which causes adverse

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outcome rather than duration alone. Fluge at al concluded that duration and severity influences

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the adverse neurological outcome (24). Lucas et al in 1988 reported a strong correlation with

duration of hypoglycemia and lower mental and motor developmental indices even after

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adjusting for other risk factors for hypoglycemia in a cohort of preterm infants (< 1850 grams).

At 18 months corrected age MeDQ and MoDQ were reduced by 14 and 13 points respectively

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and incidence of neurodevelopmental impairment was increased by a factor of 3.5 ( 95% CI 1.3-
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9.4) if hypoglycemia was recorded on 5 or more separate days (8).
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We found that MoDQ and MeDQ were significantly lower in the group with blood glucose < 40

mg/dl as compared to > 40 mg/dl group. Pildes et al (19) showed that infants with asymptomatic
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hypoglycemia and blood glucose between 20 – 30 mg/dl did not have poor neurological
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abnormality while Singh et al showed that infants with blood glucose of 17.6 ± 4.4 mg/dl had

low mental and psychomotor developmental indices as compared to those with higher blood
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glucose (7). In a recent study reported by McKinlay et al concluded that maintaining blood

glucose above 47 mg/dl was not associated with adverse neurodevelopmental outcome at 2 years
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(25).

In our study in addition to lowest blood glucose, sepsis and birth weight were found to be

independent predictors of low MoDQ and IVH for low MeDQ however no such analysis were

done in previous studies except duration or number of episodes of hypoglycemia or lowest level
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of blood glucose ( 7,8,20). We also made a ROC curve to find the cut off level of lowest blood

glucose to predict low DQ scores (DQ <85).

The limitations of our study is absence of blinding due to limited man power. Primary

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investigator who enrolled cases conducted the development assessments. We monitored blood

glucose routinely till 72 hours of age in all infants hence some asymptomatic infants beyond 72

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hours may have been missed. This is also true that outcome at 6 months and 12 months may not

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correlate well with later cognitive outcomes, and may be more so if done in an unblinded set up.

These cases also require longer follow up beyond 1 year for better prediction of outcome.

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The strengths of our study are that we assessed neurodevelopmental outcome of asymptomatic
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group which is reported to have normal outcome in previous studies (1, 6) though a recent study

reported less proficient on fourth grade achievement in those who had transient early
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hypoglycemia as compared to normoglycemia (26). We also had adequate sample size, matched
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euglycemic controls and a good follow up rate till CA 1 year (86%). We used DASII scale which
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is an Indian adaptation of Bayley scale. We also developed a regression equation to calculate DQ

based on risk factors.

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In conclusion, symptomatic hypoglycemia had worst neurodevelopmental outcome however

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even asymptomatic hypoglycemia had a worse outcome as compared to euglycemic group and a
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cut off level of 40 mg/dl was associated with lower developmental scores. All high risk neonates

should be monitored adequately to prevent any kind of hypoglycemia.

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hypoglycaemia: a follow-up study of 151 children. Dev Med Child Neurol. 1972; 14:603-14.

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2. Fluge G: Clinical aspects of neonatal hypoglycaemia. Acta Paediatr Scand. 1974; 63:826-

32.

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3. Adamkin DH. Postnatal glucose homeostasis in Late -Preterm and Term infants. Committee

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on fetus and newborn. Americal Academy of Pediatrics. Pediatrics 2011; 127: 575-9.

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Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds.
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Pediatrics. 2000 ; 105:1141-5.

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Arch Dis Child. 1988; 63:1353-8.

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matched controls. Arch Dis Child. 1971; 46:819-27.

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7. Singh M, Singhal PK, Paul VK, Deorari AK, Sundaram KR, Ghorpade MD, Agadi A:

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11. Amiel-Tison C: Update of the Amiel-Tison neurologic assessment for the term neonate or

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13. Yamaguchi K, Mishina J, Mitsuishi C, Takamura T, Nishida H: Follow-up study of

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neonatal hypoglycemia. Acta Paediatr Jpn. 1997; 39 Suppl 1:S51-53

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14. Simmons R, Stanley C. Neonatal hypoglycemia studies — is there a sweet story of

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Srinivasan G, Pildes RS, Cattamanchi G, Voora S, Lilien LD: Plasma glucose values in
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normal neonates: a new look. J Pediatr. 1986;109:114-7.
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Pediatr. 2008 ; 15(2) : 153-6.

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21. Montassir H, Maegaki Y, Ogura K, Kurozawa Y, Nagata I, Kanzaki S et al. Associated

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23. Griffiths AD, Bryant GM: Assessment of effects of neonatal hypoglycaemia. A study of

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41 cases with matched controls. Arch Dis Child. 1971; 46:819-827

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Scand. 1975; 64:629-34.

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based study.JAMA Pediatr 2015 ; 169(10) : 913-921.

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Table 1. Baseline characteristics and morbidities of Study subjects

Variables Hypoglycemia Euglycemia p value

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(n= 72) (n = 70)

^Gestation (weeks) 35.6 ± 2.2 34.8 ± 1.9 0.029*

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^Birth weight (grams) 1711 ± 433 1819 ± 383 0.119

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^OFC (cm) 30.5 ± 2.2 31.2 ± 1.6 0.022*

^Length (cm) 43.5 ± 3.6 44.4 ± 3.1 0.115

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#
Male 39 (54.2%) 38 (54.3%) 0.989
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#AGA 14 (19.4%) 29 (41.4%)

SGA 58 (80.6%) 41 (58.6%) 0.004*

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#
Maternal illness 52 (72%) 28 (40%) <0.001*
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$
Apgar Score 1 min 8 (7 - 8) 8 (8 – 8) 0.120
TE

$
Apgar Score 5 min 9 (9-10) 9 (9-10) 0.055
#
Respiratory distress 16(22%) 7(10%) 0.048*
EP

#
Polycythemia 26(36%) 1(1.4%) <0.001*
#
Any sepsis 21(29%) 2(3%) <0.001*
C

Values are expressed in #n (%), ^Mean ± SD, $ Median (IQR)

AC

*p < 0.05 considered significant

AGA- Appropriate for gestational age, SGA – Small for gestational age
 ACCEPTED MANUSCRIPT

Table2. Comparison of demographic characteristics of asymptomatic and symptomatic

hypoglycemic infants

Variables Asymptomatic Symptomatic p value

hypoglycemia hypoglycemia

PT
(n=45) (n=27)

^Gestation (weeks) 35.3 ± 2.3 36.0 ± 1.9 0.226

RI
^Birth weight (grams) 1680 ± 441 1761 ± 424 0.766

SC
^OFC (cm) 30.2 ± 2.2 30.8 ± 2.2 0.296

^Length (cm) 42.9 ± 3.4

U 44.6 ± 3.3 0.046*
AN
^Males 22 (48.9%) 17 (63%) 0.246
M

#AGA 10 (22.2%) 4 (14.8%)

SGA 35 (77.8%) 23 (85.2%) 0.442

D

#
Maternal illness 26 (54%) 12 (44%) 0.691
TE

$
Apgar Score 1 min 8 ( 7 - 8) 8 (7 - 8) 0.130
EP

$
Apgar Score 5 min 9 (9 -10) 9 ( 9 -10) 0.140
#
Respiratory distress 10(22%) 6(22%) 0.142
C

#
Polycythemia 15(33%) 11(41%) <0.001
AC

#
Any sepsis 7(16%) 14(52%) <.001
$
Duration of hospital stay 12.5 (5 – 60) 13.0 (5 – 56) 0.437

(days)

Values are expressed in #n (%), ^Mean ±SD, $Median (IQR),*p <0.05 considered significant
 ACCEPTED MANUSCRIPT

Table 3. Comparison of MoDQ and MeDQ at 12 months in various subgroups

DQ Euglycemia Asymptomatic Symptomatic p*

hypoglycemia hypoglycemia

6 months n=63 n=41 n=26

PT
MoDQ 89 + 4 84 + 6.5 79 + 7 <0.001

RI
MeDQ 89 + 3 84 +7 77 + 10 <0.001

SC
12 months n=54 n=36 n=26

MoDQ 89 + 3 85 + 7 79 + 10 <0.001

MeDQ 90 + 2.5 85 + 9
U 78 + 11 <0.001
AN
*Difference between groups by Bonferroni posthoc tests,
M

At 6 months , MoDQ, between euglycemia and asymptomatic hypoglycemia, p= < 0.001 and
D

between euglycemia and symptomatic hypoglycemia, p=<0.001 and between symptomatic and
asymptomatic hypoglycemia, p=0.004.
TE

At 6 months, MeDQ, between euglycemia and asymptomatic hypoglycemia, p=0.001 and

EP

between euglycemia and symptomatic hypoglycemia, p=<0.001 and between symptomatic and
asymptomatic hypoglycemia, p= <0.001.
C

At 12 months , MoDQ between euglycemia and asymptomatic hypoglycemia, p=0.004 and

between euglycemia and symptomatic hypoglycemia, p=<0.001 and between symptomatic and
AC

asymptomatic hypoglycemia, p=0.003.

At 12 months, MeDQ, between euglycemia and asymptomatic hypoglycemia, p=0.004 and

between euglycemia and symptomatic hypoglycemia, p=<0.001 and between symptomatic and
asymptomatic hypoglycemia, p=0.001.
 ACCEPTED MANUSCRIPT

Table 4. Regression equation for MoDQ and MeDQ based on risk factors

Variable Parameter Beta 95% CI p value

PT
Constant 70.4 61.5 – 79.2 <0.001*

RI
MoDQ Sepsis – 3.8 – 7.9 to – 0.38 0.03*

SC
Birth weight 0.005 0.001 – 0.008 0.02*

Lowest blood glucose 0.19 0.02 – 0.36 0.03*

U
AN
Constant 75.8 69.6 – 81.9 <0.001*

MeDQ IVH – 7.4 – 14.3 to – 0.57 0.03*

M

Lowest blood glucose 0.23 0.01 – 0.45 0.03*

D
TE

(MoDQ and MeDQ as dependent variable). CI - Confidence Interval, IVH- Intraventricular

haemorrhage
EP

*significant p value< 0.05

MoDQ = 70.4 + (0.005 x birth weight) + (0.19 x lowest blood sugar) -3.8, if sepsis is present and
C

70.4 + (0.005 x birth weight) + (0.19 x lowest blood sugar), if sepsis is not present
AC

MeDQ = 75.8 + (0.23 x lowest blood sugar) – 7.4 if IVH is present and
75.8 + (0.23 x lowest blood sugar) if IVH is not present
 ACCEPTED MANUSCRIPT

Fig. 1 - Flow of patients

n = 647
Total infants assessed> 32 wks gestation,
till 7 days age and all SGA, LGA, IDM or
preterm

PT
n= 109 n= 538
Hypoglycemia Euglycemia

RI
n= 70 (Euglycemia)
Excluded= 37

SC
Lab blood glucose not available – selected consecutively by
14, Investigator absent – 12, weight and gestation
Deaths – 5, declined follow up - 6 matching

U
AN
n = 72
Enrolled
M

n = 70
n= 45 n= 27 Enrolled
Asymptomatic Symptomatic
D

hypoglycemia hypoglycemia
TE

Lost to follow
up= 7
EP

Lost to follow
up= 4
Death = 1
n= 67 n= 63
C

Follow up till 6 months CA Follow up till 6 months CA

AC

Lost to follow
Lost to follow up= 9
up = 5

n= 62 n= 54
Follow up till 12 months Follow up till 12 months
CA CA
 ACCEPTED MANUSCRIPT

SGA – Small for gestational age, LGA – Large for gestational age, IDM – Infant of diabetic

mother

PT
RI
U SC
AN
M
D
TE
C EP
AC
 ACCEPTED MANUSCRIPT

Fig 2. Comparison of mean values of MoDQ and MeDQ in infants with blood glucose < 40

mg/dl with > = 40 mg/dl group at CA 6 months and 1 year

PT
92

90

RI
88

86

SC
84 <40 mg/dl
82 >=40 mg/dl

U
80

78
AN
76
MoDQ6 MeDQ 6 MoDQ 1 MeDQ 1
Mo Mo yr yr
M

All p values <0.001

D
TE
C EP
AC