Outcomes of Neonatal Hypoglycaemia Judith Mary Ansell

296 Pages·2015·4.6 MB·English

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Children with Hypoglycaemia and their
Later Development
Outcomes of Neonatal Hypoglycaemia

Judith Mary Ansell

A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of
Philosophy, The University of Auckland, 2014.
Abstract
Neonatal hypoglycaemia is common and potentially impairs neurodevelopment. Uncertainty exists over
the blood glucose concentration that defines neonatal hypoglycaemia, neurodevelopmental outcomes of
at-risk children, and neurodevelopmental differences between at-risk children who do and do not
experience hypoglycaemia. We aimed to describe the neurodevelopmental outcomes of 2-year-olds born
at risk of neonatal hypoglycaemia, to test whether hypoglycaemia was associated with poorer outcomes,
and to examine relationships between neurodevelopmental outcome and other health and
sociodemographic variables.
Children born at risk of hypoglycaemia (infant of a diabetic mother, small (<10th centile or < 2500g), large
(>90th centile or > 4500g), late preterm (35 or 36 weeks’ gestation) or other) were assessed at 24 ±1
months’ corrected age. Assessments included Bayley III, executive function tasks, BRIEF-P and health
and sociodemographic information by parental questionnaire.
We assessed 404 (77%) children from the neonatal cohort. Children who had and had not experienced
neonatal hypoglycaemia had similar neurodevelopmental outcomes. However, children born small and to
diabetic mothers achieved worse Bayley-III, executive function and BRIEF-P scores than large or preterm
children. Girls and breastfed babies were more likely to experience hypoglycaemia but had better
outcomes. Socioeconomic status was strongly associated with 2-year neurodevelopmental outcome. We
found interactions between gender and risk factor, socioeconomic status and preschool attendance, with
boys, but not girls, of diabetic mothers and low socioeconomic groups achieving worse, and those who
attended preschool better, results than other groups, suggesting a greater vulnerability to environmental
factors for boys. Assessed executive functions were related but separable and only weakly associated
with parent-report but strongly related to language development.
Children born at risk of neonatal hypoglycaemia are at risk of adverse neurodevelopmental outcome
independent of whether or not they actually experience hypoglycaemia. This risk is higher in those born
small, to diabetic mothers, not breast fed, and to low socioeconomic status families, with boys more
vulnerable to poor outcome than girls. Executive function can be assessed at 2 years and appears to
comprise separate but related constructs, most strongly related to language development. This cohort
may benefit from continued monitoring, with early intervention service referrals where needed.

ii
Dedication

Dedicated to my parents, who made it all possible

iii
Acknowledgements
I have been privileged and extremely fortunate to have worked with exceptional and wonderful people during the
course of my PhD within the CHYLD Study. Neither the study, nor my part in it would, have been possible without the
vision, support and expertise of my supervisor, Distinguished Professor Jane Harding at Liggins Institute. Thank you
for your excellent teaching, guidance and patient supervision. Thank you too, to my co-supervisor Dr Trecia Wouldes
from the Department of Psychological Medicine, for your wealth of knowledge and friendly support.
The CHYLD study started with two of us and mushroomed to a team of over 30. Too many to name! However, I
would like to acknowledge the hard work and myriad contributions of all of those in this great team of talented people,
in particular the data team who worked with dedication and an eye for detail. My PhD experience would not have
been the same without the kindly expertise of and conversations with biostatistician Greg Gamble and statistician
Yannan Jiang. I would like to particularly acknowledge the friendship and experience of Coila Bevan, the queen of
follow-up studies, whose understanding of family meant every assessment was special and important; Jenny Rogers,
whose friendship, warmth and patient dedication to the value of tikanga Māori enhanced the study in many ways; and
not least Sandy Yu, my fellow PhD student, whose friendship, determination and good humour maintained for the
years it took, and beyond, and whose brilliant memory for a vast array of movie scripts, kept me awake through many
a long drive. May you all achieve your dreams!
Without the generosity of time and energy of more than 400 families this study could not have come into being. For
this willingness to support the study and to share your precious 2-year-olds: thank you all. The CHYLD Study also
received friendly, professional support from the staff at many clinics and hospitals including Tokoroa, Tauranga,
Taupo, New Plymouth, Te Kuiti, Whangarei and Patea. The neonatal team at Waikato not only recruited babies and
collected vast amounts of data, but gave us our first study ‘home’. Thank you all.
Within the wider community of Liggins Institute, I was inspired by and enjoyed coffee with many, and was happy to
have been befriended by the WDWD women, Anna, Jo and Barbara. Lorraine Nielsen from the Philson Library was
wonderful and generous in sharing her knowledge of Endnote, APA 6th and Word. I am fortunate, indeed, to have
many friends who encouraged me to start and continued to support me until I finished. Special thanks to Angela
Litterick-Biggs, who knows how to be there at just the right time; and Lou James, who provided adventures and the
essential marathon training.
I was supported by a University of Auckland doctoral scholarship, and latterly by a Liggins Institute doctoral
scholarship. I would like to gratefully acknowledge this support for my doctoral study.
I can’t imagine making it to the finish line without the unflagging support of my wonderful family: Melissa and Kallum,
thank you for the humour, the hugs and for making me the luckiest mother in the world; and Peter, 35 years later,
another Thorong La!
Truly, thank you all.

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“Somewhere in the heart of experience there is an order and a coherence which we might surprise if we
were attentive enough, loving enough, or patient enough.”
- Lawrence Durrell

v
Table of Contents
Abstract .................................................................................................................................................. ii
Dedication .............................................................................................................................................. iii
Acknowledgements ................................................................................................................................ iv
List of Tables .......................................................................................................................................... xi
List of Figures ........................................................................................................................................ xiv
Glossary ................................................................................................................................................ xvi
Chapter 1. Literature review .................................................................................................................... 1
1.1. Introduction .................................................................................................................................. 1
1.2. History of neonatal hypoglycaemia research ................................................................................. 1
1.3. Neonatal and perinatal carbohydrate metabolism ........................................................................ 5
1.4. Measurement of blood glucose concentration .............................................................................. 8
1.5. Known developmental sequelae of neonatal hypoglycaemia......................................................... 9
1.6. At-risk groups of newborn babies................................................................................................ 12
1.7. Late preterm babies .................................................................................................................... 13
1.8. Socio-economic status and development .................................................................................... 15
1.9. Early childhood development ...................................................................................................... 19
1.10. Executive function .................................................................................................................... 22
1.11. Developmental assessment approaches at 2 years of age ......................................................... 25
1.12. The Waikato district and population ......................................................................................... 27
1.13. Summary .................................................................................................................................. 28
Chapter 2. Methods............................................................................................................................... 30
2.1. Introduction ................................................................................................................................ 30
2.1.1. Study hypothesis .................................................................................................................. 30
2.1.2. Specific aims ........................................................................................................................ 30
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2.2. Ethics .......................................................................................................................................... 30
2.3. CHYLD Study cohort – The neonatal studies ................................................................................ 30
2.4. The recruitment process ............................................................................................................. 31
2.5. CHYLD Study cohort – Exclusion criteria ...................................................................................... 32
2.6. The Assessment Process ............................................................................................................. 32
2.6.1. Assessor training .................................................................................................................. 32
2.6.2. Consent................................................................................................................................ 32
2.6.3. Video review ........................................................................................................................ 32
2.6.4. Assessment feedback ........................................................................................................... 33
2.6.5. Assessment locations ........................................................................................................... 33
2.7. Working with 2-year-olds ............................................................................................................ 33
2.8. The assessment schedule ............................................................................................................ 33
2.9. The Bayley Scales of Infant and Toddler Development – 3rd edition (Bayley III) ............................ 35
2.10. Executive Function .................................................................................................................... 35
2.10.1. Introduction ....................................................................................................................... 35
2.10.2. Snack Delay ........................................................................................................................ 37
2.10.3. Fruit Stroop ........................................................................................................................ 38
2.10.4. Reverse categorisation (Ducks) ........................................................................................... 39
2.10.5. Multisearch Multilocation (MSML) ..................................................................................... 40
2.10.6. Behaviour Rating Inventory of Executive Function – Preschool version (BRIEF-P) ................ 43
2.11. Vision Assessment .................................................................................................................... 45
2.12. The Home and Family Questionnaire ........................................................................................ 45
2.13. The Data ................................................................................................................................... 46
2.13.1. Data collection and scoring ................................................................................................ 46
2.13.2. Data checking ..................................................................................................................... 46
2.13.3. Data entry .......................................................................................................................... 46
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2.14. Statistical Analysis ..................................................................................................................... 46
2.14.1. Statistics software .............................................................................................................. 46
2.14.2. Bayley Scales of Infant and Toddler Development III ........................................................... 46
2.14.3. Executive Function assessment .......................................................................................... 47
Chapter 3. The CHYLD Study cohort ....................................................................................................... 48
3.1. The CHYLD Study cohort ............................................................................................................. 48
3.2. CHYLD Study cohort description .................................................................................................. 50
3.3. CHYLD Study cohort 2 year follow up .......................................................................................... 52
3.4. CHYLD Study cohort socioeconomic status .................................................................................. 57
3.5. Family resources and health as a function of socioeconomic status............................................. 59
3.6. Discussion ................................................................................................................................... 62
3.6.1 Factors that influence follow-up rates ................................................................................... 62
3.6.2. The CHYLD cohort ................................................................................................................ 65
Chapter 4. Developmental assessment .................................................................................................. 67
4.1. Bayley III scores .......................................................................................................................... 67
4.2. Bayley III scores and socioeconomic status.................................................................................. 67
4.2.1. Bayley III scores and measures of socioeconomic status ....................................................... 67
4.2.2 Deriving a model for adjustment for socio-economic status .................................................. 77
4.3 Bayley III scores, breast feeding and ear infections....................................................................... 82
4.4: Bayley III scores, preschool education and language ................................................................... 82
4.4. Bayley III scores and family tobacco, alcohol and other drug use ................................................. 89
4.5. Discussion ................................................................................................................................. 101
Chapter 5. Executive function .............................................................................................................. 108
5.1. Executive function and risk factors ............................................................................................ 108
5.1.1. Snack Delay ........................................................................................................................ 108
5.1.2. Fruit Stroop ........................................................................................................................ 108
viii
5.1.3. Ducks ................................................................................................................................. 109
5.1.4. Multisearch Multilocation .................................................................................................. 109
5.1.5. EF total score ..................................................................................................................... 109
5.2. EF and SES ................................................................................................................................ 114
5.3. EF and breastfeeding, preschool attendance and home language ............................................. 117
5.4. EF and tobacco, alcohol and drugs ............................................................................................ 117
5.5. EF and behaviour ...................................................................................................................... 120
5.6. BRIEF-P scores .......................................................................................................................... 122
5.7. BRIEF-P scores and SES.............................................................................................................. 125
5.8. BRIEF-P and breastfeeding, preschool and language ................................................................. 129
5.9. BRIEF-P scores and family tobacco, alcohol and other drug use ................................................. 132
5.10. Clinically significant BRIEF-P results ......................................................................................... 136
5.11. Relationships between assessed EF measures ......................................................................... 139
5.12. Relationships between assessed EF task and BRIEF-P scores.................................................... 141
5.13. Discussion ............................................................................................................................... 144
5.13.1. Assessed executive function ............................................................................................. 144
5.13.2. BRIEF-P............................................................................................................................. 146
5.13.3. Correlations between assessed executive function measures and BRIEF-P ....................... 146
5.13.4. EF assessments as a unitary or composite construct ......................................................... 147
5.13.5. Risk Groups ...................................................................................................................... 148
5.13.6. Gender and EF .................................................................................................................. 149
5.13.7. SES and family effects on EF ............................................................................................. 151
5.13.8. Parental tobacco, alcohol and marijuana use.................................................................... 152
5.13.9. EF assessment in the future .............................................................................................. 153
Chapter 6. Executive function and developmental outcomes ............................................................... 155
6.1. Executive function and cognitive development ......................................................................... 155
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