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Early neurological delopment, growth and nutrition in very preterm infants
Maas, Y.G.H.
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Citation for published version (APA):
Maas, Y. G. H. (1999). Early neurological delopment, growth and nutrition in very preterm infants
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Download date: 18 Jun 2017
CHAPTER 9
Summary
Millions of babies and young infants throughout the world suffer from malnutrition. It is
still the most important public health problem in underdeveloped countries. In the early
years of life - from gestation onwards - the brain is developing rapidly. During this so
called brain growth spurt the neurological system is particularly vulnerable to any growthrestricting events. Malnutrition - surely in its severe form - must cause lasting effects on the
developing neurological system, impairing irreversibly full development of the natural
abilities and talents of so many infants, provided that they survive. Until now research in
this field - relating nutrient depletion and its effects on neurological development in early
life - reached a deadlock because of social, psychological, physical and environmental
interference with the outcome. The importance of nutrition for immature and critically ill
infants and the impact on clinical outcome and neurological development also became a
concern for neonatologists in the Western World with the availability of neonatal intensive
care units in the 1970s. Consequently, the need for diagnostic tools to assess neurological
development of young infants at risk for long-term neurological abnormalities was
reinforced. This research aimed at the discovery of such (a) test(s). Moreover, the effect of
nutritional intake on growth and neurological development in very preterm infants were
studied and compared. To conclude, the predictive value of the two neurological assessment
methods studied in this thesis were compared with the predictive value of two standard
neurological tests used in neonatology based on neurodevelopmental outcome at 2 years of
corrected age.
In chapter 1 some background information is given on how this thesis came about. Then
the state of the art on the three areas studied and combined in this thesis, viz. nutrition,
growth and neurological development in very preterm infants (< 30 weeks' gestational
age) is presented. The aim of the research is twofold: 1. development of a (clinical)
instrument to monitor neurological development and predict long-term outcome of very
preterm infants and 2. to test this instrument for its suitability to judge optimality of
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nutrition. The contents of the chapters 2 to 8 are reviewed.
The study design, the study population and the methods used are described in chapter 2.
The framework of the study and the restrictive conditions of an interfering randomized
thyroxine supplementation trail are briefly mentioned. Of the methods applied in more than
two of the chapters 3 to 7 a detailed description is given. For ease of survey a flowchart of
the babies participating in the various parts of the research protocol is included in this
chapter.
Chapter 3 describes the macronutrient composition of longitudinally collected human milk
samples of very preterm infant mothers and deals with the question whether the changes in
composition found in these samples are related to the postnatal or postconceptional age of
the infant or to the duration of gestation. The 24-hour milk volume was used as a timevarying covariate in the statistical analysis. Postnatal age was clearly related with total
nitrogen and lactose content in very preterm milk. While total nitrogen concentration
decreased with postnatal age, lactose concentration increased. Only for carbohydrate
concentration a gestational age related difference was found: the concentration decreased
with an increasing gestational age. No evidence was found for a 'teleological' basis for the
patterns of changes in composition for any of the nutrients studied, meaning that the
macronutrient composition of human milk is not determined by endogenously generated
maturational processes from conception onwards. No relation was found between the
amount of 24-hour milk produced and postnatal or gestational age.
Chapter 4 deals with the issue of nutrition and physical development (growth). Early
postnatal growth of very preterm infants ( < 30 weeks gestation) was studied on a
longitudinal basis using extensive anthropometry (10 parameters). The infants studied were
randomly assigned to start enteral feeding with maternal milk supplemented with standard
formula (STF) or preterm formula (PTF) on an isocaloric basis. They were also enrolled in
a placebo controlled (double-blind), randomized trial on thyroxine supplementation. Data of
postnatal week 1 to 7 were analysed. Preterm formula given as a supplement to maternal
milk resulted in an increased overall physical development compared to standard formula
supplementation. Additional increase in growth was seen when thyroxine was added to
preterm formula supplementation, specifically for head circumference, subscapular and
triceps skinfold thickness. Provided that rapid growth is most desirable for very preterm
Summary
161
infants in the early postnatal phase, this study indicates that these infants do benefit from
special, adapted formula feeding. Moreover supplementation of thyroxine in combination
with preterm formula in the first weeks of life seemed to further increase physical growth.
The chapters 5 and 6 study neurological development in very preterm infants (gestation <
30 weeks) in search of an early diagnostic tool to identify babies at risk for longterm
neurological disorders. Moreover, both chapters address the subject of a possible relation of
nutrition and early neurological development. The infants studied were enrolled in a
randomized trial on diet and thyroxine supplementation. Data on the development of
behavioural states (e.i. sleep and wakefulness) are presented in chapter 5. The amount of
time spent in quiet sleep increased significantly at the expense of the amount of
indeterminate state from 30 to 40 weeks postmenstrual age. This finding confirmed our
hypothesis that brain maturation in very preterm infants is reflected in the development of
behavioural states when studied postnatally till corrected term age. Based on the covariate
analysis indications were found that behavioural states patterns differ amongst normal,
mildly abnormal and abnormal (based on cranial ultrasound) infants. Indications were also
found for an effect of gender on the development and of weight at birth on the amount of
quiet sleep. Both diet and thyroxine supplementation had a significant (interaction) effect on
the developmental patterns of behavioural states. However, from stratified analyses we
could conclude that neither preterm diet nor thyroxine substantially influence the
developmental course of the amount of time spent in the different behavioural states before
term age.
Data on the development of spontaneous motility are provided in chapter 6. The
developmental course of the quality of general movements (GMs) was studied from 30 till
40 weeks (corrected term) age. To this new method has been ascribed high predictive value
for assessing neurological outcome when used till 3-4 months post term. That was why we
were interested to test its applicability in very preterm infants born before 30 weeks
gestation. Quality of GMs was very stable, that is strikingly low, over time before
(corrected) term age. No developmental changes in GM quality were seen as a function of
postmenstrual age. Moreover, unlike our expectations, the sensitivity and specificity of the
GM quality assessment method in relation to outcomes of repeated cranial ultrasound and
neurological examination at (corrected) term age are very poor. Indeed recent other studies
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also concluded that assessment of preterm GMs is not highly predictive of later neurological
outcome. No effects were found of early diet and/or thyroxine supplementation. From our
covariate analysis indications were found for an effect of gender and weight at birth on GM
quality.
Though a reliable and easy method to perform, even in a neonatal IC environment, we
found assessment of GM quality during the prematurity period (i.e. before corrected term
age) to be an unfit method for detecting early neurological disorders or to predict
neurological outcome at term age.
Chapter 7 reports on the predictive value of several neurobehavioural tests easily
applicable in a neonatal ICU setting. These tests included: cranial ultrasound, Prechtl
neurological test at term, quality of spontaneous general movements and quality of
sleep-wake organization. They were tested for their ability to predict the
neurodevelopmental outcome at 2 years of (corrected) age of preterm infants born at a
gestational age < 30 weeks. Data on the early neurobehavioural tests were related to the
outcome of standardized neurological (Touwen) and psychodevelopmental (Bayley)
examination at 2 years of corrected age. The Prechtl neurological test at corrected term age
appeared to be the only test able to predict neurological and psychodevelopmental outcomes
at 2 years of age independently of the other tests. Cranial ultrasound could not add to the
predictive power of the term Prechtl test, however as a stand-alone test it seemed to identify
the clearly abnormal infants as well as the Prechtl score. Neurobehavioural tests like
repeated cranial ultrasound, quality of general movements and development of sleep are of
disappointingly limited value for the prediction of neurodevelopmental abnormality at 2
years' corrected age of preterm infants.
In chapter 8 the results of chapters 3 to 7 are combined in a general discussion.
Applicability of the studied methods for research on possible relations between
undernourishment and neurological development in very young infants is deliberated.
Implications of our findings for new studies are reviewed and a suggestion for future
research is given.
In summary our main conclusions are that macronutrient composition of very preterm
human milk is not related to the developmental stage of the prematurely born infant, but
Summary
163
rather to the duration of lactation. Physical development or growth reflects dietary intake
very well and differences in dietary intake are traceable using longitudinal anthropometry.
Longitudinal scoring of behavioural states in preterm infants till corrected term age
provides us with a method for measuring brain maturation as opposed to longitudinal
scoring of the quality of general movements. The introduction of a "neurological growth
curve" accompanying the physical growth curve would improve the assessment of early
nutrition. Neither the level of behavioural states organization nor the quality of general
movements nor repeated cranial ultrasound when applied till term age yield very reliable
tests for prediction of neurological and psychodevelopmental outcomes (at 2 years corrected
age) of very preterm infants. We believe that it is likely that the neurological and
psychodevelopmental tests used here do not capture all neurological abnormalities.
Organization of behavioural states and quality of general movements both represent basic
functions of the brain and therefore they can be expected to be better tests when searching
for damage to the CNS. New techniques, like (fjMRI, can be of help in discovering their
applicability as predictive tests.
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