The Children with Hypoglycaemia and their Later Development

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Chapter 3.The Children with Hypoglycaemia and their Later Development (CHYLD) Study

This chapter provides an overview of the CHYLD study of which the research described in this thesis was part. Methodological details relating to the design of the CHYLD study are also provided.

Introduction

The CHYLD study was a large multidisciplinary prospective cohort study investigating the development of young children who were born at risk of developing neonatal hypoglycaemia. The cohort of 614 children was recruited as part of two studies: The Babies and Blood Sugar’s Influence on Electroencephalography Study (BABIES) (Harris et al., 2011) and the Sugar Babies Study both carried out at Waikato Hospital, Hamilton, New Zealand. The BABIES Study was primarily aimed at determining the relationship between brain function as measured with EEG and blood glucose level in children born at risk of neonatal hypoglycaemia (NH) (N=104). The Sugar Babies Study (Harris, Weston, Signal, Chase, & Harding, 2014) was a randomized clinical trial primarily aimed at evaluating the effect of 40% dextrose gel in reversing neonatal hypoglycaemia, which was detected by heel prick in the first 48 hours of life (N= 512). Two children were enrolled in both studies so the total number of participants in the CHYLD cohort was 614 (104+512-2). In addition to the standard heel-prick testing for blood glucose, the babies in the Sugar Babies study also wore interstitial glucose monitors, which provided continuous measurements of blood glucose for up to seven days after birth. The data from the continuous monitors were analysed after the trial was complete and demonstrated that many of these children experienced hypoglycaemic episodes that were not detected by standard heel-prick testing and, therefore, were not treated (McKinley et al., 2015). The CHYLD study team assessed cognitive and physical development, memory, vision and the general health of these children at 2 and 4.5 years of age and related these outcomes to the periods of hypoglycaemia that many of them experienced as newborns.
For the purpose of this thesis, only heel-prick blood glucose levels were considered for analysis, as this is the current standard clinical method. Glucose level of less than 2.6mmol/L (Cornblath et al., 2000) during the first week after birth was considered as neonatal hypoglycaemia. Any children who were detected as having neonatal hypoglycaemia underwent immediate treatment based on current clinical practice guidelines.

Objectives of the CHYLD study

The main objective of the CHYLD study was to observe neurodevelopment of children born at risk of having low blood sugar at birth and to relate the developmental outcomes with blood sugar levels in the neonatal period obtained via two measurement methods: the heel-prick method, and continuous blood glucose monitoring, a novel method not previously used in newborns.
It should be noted that these CHYLD study objectives are not the main objectives of this thesis. The objectives relevant to this thesis are explained in the earlier sections 1.2.1 and 1.2.2.

Study design

The CHYLD study was a longitudinal, investigator-masked observational study of children who were born at risk of having episodes of NH. As mentioned in section 3.1, these children were recruited at birth for two different studies and then followed-up until 4.5 years. The first neurodevelopmental follow-up was performed at the corrected age of 24 ±1 months. The second neurodevelopmental follow-up was conducted as the corrected age of 54 ± 2 months.
The age of 24 months for the first follow-up was chosen based on the consensus that children have developed cognitive and motor skills that are able to be evaluated via validated standard tools and by this age perinatal events still have influence on their development. The second follow-up at 54 months provided an opportunity to reassess physical, cognitive, motor and visual development directly, before the children had started school. Longitudinal assessments at a later age may become more complex once children have started school because specialized educational or health support may be made available to some children and not others. Also, by 54 months children develop independent behaviours that require a higher level of cognition, collectively known as executive functions.

Rationale for including visual assessment component in the CHYLD study

It is evident from Chapter 1 and Chapter 2 that children exposed to severe neonatal hypoglycaemia have a myriad of visual abnormalities such as strabismus, nystagmus. Furthermore, most of the imaging studies have come to a common ground that NH preferentially targets the occipito parietal region of the brain. This region of the brain represents the dorsal visual stream of human visual pathway. Hence, in order to explore the effect of NH on visual brain areas (particularly the function of the dorsal visual stream), global motion perception test, a test that has been shown to target the dorsal visual stream function was implemented. And to screen children for any vision disorders early in life, the common clinical vision tests were implemented.

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Methods used for the CHYLD study

The children enrolled for the CHYLD study had heel-prick and continuous blood glucose monitoring methods available, which provided glucose level data at the time of birth. The heel-prick blood glucose level was measured one hour after birth and then every 2 to 4 hours before feeding and up to 12 hours, and as required thereafter. Continuous glucose monitoring was conducted by inserting a sensor into the lateral aspect of the thigh. The sensor was kept there for a minimum of 48 hours and a maximum of up to 7 days.
At follow-up age, the children underwent a series of neurodevelopmental assessments, including vision. Details of the methods used for neurodevelopmental assessment for this study are presented in section 4.1.2 and 4.2.6.

Participants of the CHYLD study

Six hundred and fourteen infants from the BABIES and Sugar Babies studies were eligible to be enrolled in the CHYLD study. For the two “feeder” studies, mothers of the babies who were at risk of having NH were identified before the babies were born and were recruited for the study. Risk factors for having episodes of NH were:
 Small for gestational age (birth weight <10th percentile or < 2500g)
 Large for gestational age (birth weight >10th percentile or >4500g)
 Born to diabetic mothers
 Not feeding well
 Stressed: infants with congenital heart defects, respiratory distress, sepsis, haemolytic disease
 Born late preterm (≥32 weeks and ≤37 weeks of gestation).
Babies were not included if they had:
 Congenital malformations that were severe in nature
 Terminal illness
 Skin lesions that prevented application of the sensor used for continuous glucose monitoring.
If a child had more than one risk factor the primary risk factor was determined based on priority as follows: born to diabetic mothers, preterm, small for gestational age, large for gestational age and others.
Children who had acquired brain injury after the neonatal period were not included in the follow-up study.

Participants included in the analyses of this thesis

Out of 614 children eligible at the time of recruitment, 406 (77%) were followed up at 2 years. Out of the 406 assessed at 2 years, 95% (385) completed all the neurodevelopmental assessments, and 99% (405) completed vision assessments. Of the total 406 children assessed at age 2 years, 355 (87%) were assessed again at age 4.5 years. Hence, this thesis is based on the data of 355 children who were assessed both at age 2 years and age 4.5 years.

Ethics approval

The CHYLD study 2-year follow-up received ethics approval from the Northern Y Health and Disability Ethics Committee (NTY/10/03/021) of the Ministry of Health. To extend the study for the 4.5-year follow-up, an amendment was submitted, which was approved by the same ethics committee on the 24th of June 2011.

Consent process

During the recruitment processes for the BABIES and Sugar Babies neonatal studies, parents were informed about the possibility of following up these children in their later years. For the 2-year follow-up study, a set of documents that included an invitation to participate in the CHYLD study was sent to all families involved in the two earlier studies as their children approached two years of age. A further set of documents containing detailed information regarding the CHYLD study was provided to those families who agreed to take part. Finally, informed written consent was provided by the parent/caregiver on the date of the assessment. The same process used for the 2-year follow-up was done for the 4.5-year follow-up.

Venue of the assessments

Most of the 2-year follow-up assessments were conducted either at a local hospital or at a research house in Hamilton, Waikato, New Zealand. The research house was specifically established as a dedicated facility for assessing these children. In some cases, where the family was unable to attend any of these venues, assessments were conducted either in their own homes or at a community childhood centre (for example, Plunket) near to the family’s location. Most of the assessments at 4.5 years were carried out at the research house in Hamilton. However, as with some of the 2-year-olds, assessments at 4.5 years were carried out at different locations depending upon the location of the family.

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Child Assessors

Neurodevelopmental assessment was carried out either by registered New Zealand psychologists or research nurses. Vision assessments were carried out either by New Zealand registered optometrists or optometrically trained PhD students who were not registered in New Zealand but who were credentialed for the vision assessment procedures. The general health/paediatric assessment was carried out by qualified paediatricians or credentialed medical students. All assessors were provided with dedicated training specifically for the study. Good Clinical Practice training was completed by all of the assessors involved in the study. The tenets of the Declaration of Helsinki were followed while assessing the children.

The role of the author in the CHYLD study

I am an optometrist with an overseas qualification. I was credentialed for vision assessment procedures by registered New Zealand optometrists who were my associate supervisors for this project. The methodology for the CHYLD 2-year-old study had already been designed by the CHYLD steering committee (a committee that represented neonatologists, vision scientists, optometrists and psychologists) before I enrolled into the PhD program. The CHYLD study was already recruiting 2-year-old participants and had completed data collection in almost 50% of the children.

Chapter 1. Introduction
1.1. General introduction
1.2. Research questions
1.2.1. Overall aims
1.2.2. Specific aims
1.3. Overview of the thesis
Chapter 2. Literature review
2.1. Visual development
2.2. Normal development of structures of the visual system
2.3. Visual processing in the human brain
2.4. Development of visual function
2.5. Stereopsis
2.6. Global motion perception (function of the dorsal visual stream)
2.7. Abnormal visual development
2.8 Summary of the literature review:
Chapter 3.The Children with Hypoglycaemia and their Later Development (CHYLD) Study
3.1. Introduction
3.2. Objectives of the CHYLD study
3.3. Study design
3.4 Rationale for including visual assessment component in the CHYLD study
3.5. Methods used for the CHYLD study
3.6. Participants of the CHYLD study
3.7. Participants included in the analyses of this thesis
3.8. Ethics approval
3.9. Consent process
3.10. Venue of the assessments
3.11. Child Assessors
3.12. The role of the author in the CHYLD study
Chapter 4. Methodology
4.1. Methods used for assessing 2-year-old children
4.2. Methods used for assessing 4.5-year-old children
4.3. Vision assessment in adults
4.4. Vision Assessor:
4.5. Data used in this thesis
4.6. Data analysis
4.7. Data normalisation
Chapter 5. Comparison of visual acuities measured using the Cardiff Acuity Cards, the Lea Symbols and the ETDRS chart in adults with normal vision
5.1. Introduction
5.2. Materials and methods
5.3. Data Analysis
5.4. Results
5.5. Discussion
5.6. Conclusion
Chapter 6. The development of visual acuity, stereopsis and global motion perception from 2 to 4.5 years of age
6.1. Summary of the raw data
6.2. Characteristics of the children assessed at both 2 and 4.5 years
6.3. Prevalence of eye and vision disorders at age 2 years and age 4.5 years
6.4. Development of binocular visual acuity from 2 years to 4.5 years
6.5. Development of stereopsis from age 2 years to age 4.5 years
6.6. Development of global motion perception from age 2 years to age 4.5 years
6.7. Summary of development of normalized visual function from age 2 years to age 4.5 years
6.8. Influence of gender on the development of normalized visual functions
6.9. The relationships between measures of visual function at age 2 years and at age 4.5 years.
Chapter 7. The effect of neonatal hypoglycaemia and its risk factors on the development of visual acuity, stereopsis and global motion perception
7.1. Effect of neonatal hypoglycaemia on the development of visual functions
7.2. Effect of individual risk factors on the development of visual function
7.3. Effects of multiple risk factors on the development of visual functions
7.4. Summary on the effect of NH and its risk factors on the development of visual functions
Chapter 8: Discussion
8.1. Comparison of visual acuities measured using the Cardiff Acuity Cards, Lea Symbols and ETDRS chart in adults with normal vision
8.2 The development visual acuity, stereopsis and global motion perception from 2 to 4.5 years of age
8.3. The effect of neonatal hypoglycaemia and its risk factors on the development of visual acuity, stereopsis and global motion perception
8.4. The effect of risk factors for NH on the development of visual acuity, stereopsis and global motion perception
8.5. Strengths and limitations of this study
8.6. Summary of the discussion
Chapter 9. Conclusion
9.1. Research contribution
9.2. Scope for future research
9.3. Take home messages of this study
Appendices:
Reference
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