Neurodevelopment of Hypoglycemic Neonates

Neurodevelopmental Outcome of Normoglycemic Versus Hypoglycemic Neonates at Risk for Hypoglycemia

The investigators propose to prospectively conduct a neurodevelopmental evaluation of SGA and late preterm neonates who underwent risk-based screening for hypoglycemia at newborn nursery during the first 24 hours of life based on AAP (American Academy of Pediatrics) hypoglycemia guidelines at 18 to 24 months of age. As per internal neonatal unit protocol (reflecting AAP guidelines), all neonates at risk of hypoglycemia (all preterm infants, term infants who are SGA or LGA and IDM) are routinely screened for hypoglycemia during the first 24 hours of life via bedside point of care glucose devices (see attached Weiler NICU (neonatal intensive care unit) hypoglycemia screening protocol). The investigators will compare neurodevelopmental outcomes of those who were and were not hypoglycemic in the newborn nursery based on electronic health record data.

Study Overview

• Status: Recruiting
• Conditions: Neurodevelopmental Disorders; Neonatal Hypoglycemia
• Intervention / Treatment: Diagnostic test: Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4)

Detailed Description

Neonatal hypoglycemia is the most common metabolic problem in neonates and a preventable cause of brain injury in infancy. Key risk factors for neonatal hypoglycemia include being born preterm, small for gestational age (SGA), large for gestational age (LGA), and being an infant of a diabetic mother (IDM) (1). Approximately 30% of all neonates are considered at risk, of whom approximately 50% develop hypoglycemia (2). Neonatal hypoglycemia is tightly related to adverse neurodevelopmental and brain injury outcomes, particularly among preterm infants who are SGA (3). Screening is recommended for babies with known risk factors (4). Glucose is an essential molecule that supplies energy for brain consumption. Neurons and glial cells in the brain are sensitive to hypoglycemia. Neonatal hypoglycemia has been recognized as a cause of long-term severe neurologic and neurodevelopmental morbidity due to damage to these cells (5). Neonatal hypoglycemia is a common finding associated with brain injury, neurodevelopmental delay, visual impairment, and behavioral problems.

Management of hypoglycemia in the newborn period is highly variable among institutions, and recommendations from different professional societies vary. In 2011, the American Academy of Pediatrics (AAP) Committee on Fetus and Newborn published a clinical report suggesting management guidelines for late-preterm and term infants with associated risk factors, targeting infants of IDM, LGA and SGA neonates (2). Of note, AAP clinical report provides guidelines only for the initial 24 hours of life and recommends screening of IDM and LGA infants for 12 hours and screening of SGA and late preterm infants for 24 hours. Canadian Paediatric Society in their updated position statement recommends a similar screening algorithm based on risk factors, stressing the importance of adequate feeding in SGA and late preterm infants. The Pediatric Endocrine Society (PES) issued the recommendations for evaluation and management of persistent hypoglycemia in neonates, infants and children beyond the initial 24 hours of life. The 2011 AAP guidelines define neonatal hypoglycemia as blood glucose <47 mg/dL and recommend maintaining blood glucose >40 mg/dL in the first 4 hours and >45 mg/dl between hours 4-24 (6). The PES has an even stricter threshold of >50 mg/dL. The AAP guidance, however, applies only to the first 24 hours of life, and the PES strategy focuses on infants beyond 48 hours of life with persistent hypoglycemia (7).

Due to poor correlation between blood glucose concentrations, clinical manifestations and controversial treatment thresholds, it is difficult to define a safe blood glucose level. Several studies have analyzed the effects of various ranges of hypoglycemia on neurodevelopmental outcome. However, variable results regarding the effect of hypoglycemia on the neurodevelopmental outcome have been reported without any clear conclusion (5,8-12).

In this study investigators propose to prospectively conduct a neurodevelopmental evaluation of SGA and late preterm neonates who underwent risk-based screening for hypoglycemia at newborn nursery during the first 24 hours of life based on AAP hypoglycemia guidelines at 18 to 24 months of age. As per neonatal unit protocol (reflecting AAP guidelines), all neonates at risk of hypoglycemia (all preterm infants, term infants who are SGA or LGA and IDM) are routinely screened for hypoglycemia during the first 24 hours of life via bedside point of care glucose devices (see attached Weiler NICU hypoglycemia screening protocol).

Aims:

1. To compare cognitive and motor development assessed with the Bayley-4 scoring system between the normoglycemic and hypoglycemic at-risk SGA/late preterm neonates
2. To assess language development, social-emotional and adaptive behavior in the normoglycemic and hypoglycemic at-risk neonates
3. To compare Bayley-4 scores between the cohort of neonates needing intravenous (IV) dextrose administration/neonatal intensive care admission to those with hypoglycemia managed in the newborn nursery as well as to those neonates who remained normoglycemic

Hypothesis:

The investigators hypothesize that SGA and late preterm hypoglycemic neonates admitted to newborn nursery will have inferior neurodevelopmental outcome at 18 to 24 months age when compared to SGA and late preterm infants with normoglycemia.

• Study Type: Observational
• Enrollment (Estimated): 126

Contacts and Locations

• Study Contact: Name: Thomas Havranek, MD; Phone Number: 718-904-4105; Email: thavrane@montefiore.org
• Study Contact Backup: Name: Palanikumar Balasundaram, MD; Phone Number: 718-904-4105; Email: pbalasunda@montefiore.org

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10461
      • Recruiting
      • Montefiore Medical Center, Weiler Hospital
      • Contact: Thomas Havranek, MD; Phone Number: 718-904-4105; Email: thavrane@montefiore.org
      • Contact: Palanikumar Balasundaram, MD; Phone Number: 718-904-4105; Email: pbalasunda@montefiore.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 2 years (Child)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

This is a cross-sectional study evaluating neurodevelopmental outcome at 18 to 24 months of SGA/late preterm neonates who received risk-based screening for hypoglycemia and were found to be either normoglycemic or hypoglycemic during hospitalization. Eligible subjects will be identified via electronic health record search, and their hypoglycemia risk factors will be verified together with glycemia status. Parents of eligible subjects will be contacted via phone and invited for research participation; Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4) will be administered by one of the 2 blinded examiners who are unaware of neonatal glycemia status. Bayley-4 examines Cognitive, Language, Motor, Social-Emotional and Adaptive Behavior domains of development .

Description

Inclusion Criteria:

• Born at 35 weeks or more of gestation
• Birth weight of 2000 g or more
• Indication for routine screening for hypoglycemia: late preterm infants (gestational age from 35 weeks 0 days to 36 weeks 6 days) and newborns who were SGA (birth weight below the 10th percentile on the 2013 Fenton curve).

Exclusion Criteria:

• Neonates with indication for hypoglycemia screening - screening not properly done or missing
• Unable to reach the subject for neurodevelopmental assessment
• Non-English speaking subjects

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Hypoglycemic neonates; Preterm or small for gestational age neonates at risk for hypoglycemia who were found to be hypoglycemic during the screening for hypoglycemia	Diagnostic test: Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4); Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4) will be administered by one of the 2 blinded examiners who are unaware of neonatal glycemia status. Bayley-4 examines Cognitive, Language, Motor, Social-Emotional and Adaptive Behavior domains of development and may require up to 120 minutes to complete.
Normoglycemic neonates; Preterm or small for gestational age neonates who were found to be normoglycemic during the screening for hypoglycemia	Diagnostic test: Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4); Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4) will be administered by one of the 2 blinded examiners who are unaware of neonatal glycemia status. Bayley-4 examines Cognitive, Language, Motor, Social-Emotional and Adaptive Behavior domains of development and may require up to 120 minutes to complete.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of cognitive development using Bayley-4 scoring system	Compare cognitive development assessed with the Bayley-4 scoring system between the normoglycemic and hypoglycemic at-risk SGA/late preterm neonates	120 minutes
Comparison of motor development using Bayley-4 scoring system	Assess motor development between the normoglycemic and hypoglycemic at-risk neonates	120 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of language development using Bayley-4 scoring system	Compare language development using Bayley-4 scoring system between the normoglycemic and hypoglycemic at-risk neonates	120 minutes
Comparison of social-emotional behavior using Bayley-4 scoring system	Comparison of social-emotional behavior using Bayley-4 scoring system between the normoglycemic and hypoglycemic at-risk neonates	120 minutes
Comparison of adaptive behavior using Bayley-4 scoring system	Comparison of adaptive behavior using Bayley-4 scoring system between the normoglycemic and hypoglycemic at-risk neonates	120 minutes

Collaborators and Investigators

• Sponsor: Montefiore Medical Center
• Investigators: Principal Investigator: Thomas Havranek, MD, Montefiore Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): July 14, 2021
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): August 1, 2024

Study Registration Dates

• First Submitted: April 29, 2021
• First Submitted That Met QC Criteria: May 3, 2021
• First Posted (Actual): May 6, 2021

Study Record Updates

• Last Update Posted (Actual): February 12, 2024
• Last Update Submitted That Met QC Criteria: February 8, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Glucose Metabolism Disorders; Metabolic Diseases; Hypoglycemia; Neurodevelopmental Disorders
• Other Study ID Numbers: 2021-13030

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No