Early neurological delopment, growth and nutrition in very preterm infants - Chapter 1: General introduction

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Early neurological delopment, growth and nutrition in very preterm infants

Maas, Y.G.H.

Publication date

1999

Link to publication

Citation for published version (APA):

Maas, Y. G. H. (1999). Early neurological delopment, growth and nutrition in very preterm

infants.

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General introduction

1.5 Scope and general outline of the thesis 1.5.1 Aims

1.5.2 General outline

of inadequate prenatal and postnatal nutrition on the long term neurological outcome of infants (47,143,144). Extensive research on infant nutrition has been done in

underdeveloped countries. All of these studies had problems determining the relative impact and/or the interaction of social, psychological, physical and environmental factors on the outcome (142). Usually, no instrument was available to detect neurological damage in these young infants irrespective of these factors. A recent (1998) doctoral thesis by A.F. Hassan

'Visual and Brain Impairment in Childhood Malnutrition' from our department used visual evoked potential (VEP) measurements in a study of protein energy malnutrition in infants from Egypt (72). In this study VEP was useful as a measure for neural deficiency and impared visual maturation. Improvements in the Reversal (RvN70) latencies were seen following treatment. The importance of nutrition for immature and critically ill infants and the impact on clinical outcome and neurological development has become a concern for neonatologists since there has been a dramatic improvement in survival with availability of modern intensive care in the 1970s and 80s. Circumstantially, nutrition for infants prematurely born is not comparable to the term infant who has received placental nutritional support to term. Preterm infants at term corrected age are usually smaller than fullterm infants and as a group preterm infants have delayed development. When an infant is born preterm many of the maturational processes are delayed and others essential for survival e.g., lung development are advanced post delivery. Maturation of the nervous system takes time and continues even in fullterm infants postnatally. Therefore, preterm birth is a severe event to the developing fetus. Intensive care helps these infants survive, but more research is needed to improve longterm outcome. The development of diagnostic tools to identify (early i.e., at term conceptional age) infants at risk for long-term

neurological abnormalities would be an important clinical advance which may allow prevention and/or interventions to improve outcome.

Although progress has been made in attaining more knowledge about and insight into nutrition, metabolism and growth of the fetus and preterm infant, more research is needed to determine what is optimal for infants born before term.

Maturation of the nervous system may be less affected by extrinsic factors compared to adverse effects of inadequate nutrition (113). The "brain sparing" concept hypothesizes that

when nutrients are moderately insufficient, the brain is less affected compared to other systems . The development of a tool(s) to access the neurological "growth curve" and potential for later function would provide new clinical information not evident in the standard physical growth curve. This new tool would allow the evaluation of nutritional or other intervention strategies on the long term neurologic outcome of the prematurely born infant.

1.1 Nutrition

In ancient Greece Hippocrates frequently advised his patients about what foods they should eat. This has become a common practice by physicians all over the world who have used dietetics as part of their treatment. However, it was not recognized as an independent science until the twentieth century. In the Netherlands the science of Human Nutrition was introduced in 1969 at the Agricultural University of Wageningen. Usually, it was not part of the medical curriculum. "Clinical nutrition" in the 1980s has become an important and integrated part in the management of patients. The subject of malnutrition in

underdeveloped countries is covered under general and clinical nutrition science. Nutrition for preterm infants can be categorized under clinical nutrition to address the unique needs of critically ill preterm infants who require intensive care and under general nutrition to address their requirments for later growth and development. What is "appropriate" nutrition for the prematurely born infant may be very different than for the infant born at term. Nutritional issues may have had a lower clinical priority when survival was the main issue. However, now that techniques to support the critically ill preterm infant are markedly improved further studies on acute and long term nutrition are needed. Any feeding regimen for the preterm infant must take into consideration the limitation in function of the immature gastrointestinal tract. More information about the exact nutrient supply for the human fetal maternal placental unit would give valuable insight into the nutritional needs of the fetus. Imitating the in utero nutrition would seem ideal. However, the preterm baby is confronted with completely different circumstances and demands. A fetus does not thermoregulate its body temperature. Thermoregulation for the preterm baby will require more energy expenditure and fuel. Providing optimal nutrition early in life will be important to improve longterm development (12,17,58,88,103).

1.1.1 Human milk

There is a concensus that breast milk is the optimal nutrition for infants. The nutritional needs of term infants was determined through studies of human milk samples. Analyses of human milk samples taken at different postnatal ages, at different times of day from the same mother support that the composition of human milk is dynamic. These data support that the nutrient composition of human milk is adapted for nutritional needs of the growing and developing human infant (69,86,131).

While there is general agreement among clinicians and other health workers and -organisations to advocate breastmilk for term infants this is less concensus for preterm infants. (11,14,31,50,51,93,111,127). Patricia B. Lawrence concludes in a review article on breastmilk published in 1994 that the growing positive attitude towards human milk of an infant's own mother, despite the fact that it is not considered to be ideal, "stems from a recognition that formula, although especially formulated for the preterm infant, is also less than ideal and may not be the optimal substitute for breast milk enriched with proteins and minerals". She also states that the breast milk of prematurely delivering mothers needs further study (93).

Some of the challenges in studying human lactation were noted by F.E. Hytten (77-81). The first and greatest difficulty is the collection of milk. Estimation of the quantity and composition of the milk received by an infant nursing at mother's breast is difficult. Milk expressed by the mother may not be the same as with her infant nursing. When a child is fed on demand the volume received may influence later milk production. Participation in human milk studies involves a commitment from the mother and inconvenience. Dedicated participants are imperative to get reliable results. This selection bias may affect the results. Other variables are: method of milk expression (137); changing composition during the course of the collection (48); diurnal variations in both volume and composition (52,92); changing composition with duration of lactation (2); varying composition between different individuals (2,6); effect of maternal diet on the composition (9,24,69).

These challenges surrounding human milk research are magnified for preterm milk. The mother may be ill at the time of the preterm birth and she may have received medications which may influence her milk production. The stress of the premature labor and birth affect her milk production and possibly her willingness to participate or to comply with the

protocol. These problems can be compounded when her infant is critically ill and the outcome is uncertian. Mothers of preterm infants may not produce sufficient volumes of milk and in these cases supplementation may be required (73,97). Moreover, the nutritional content of breast milk from mothers who deliver prematurely has greater variability compared to term milk. The breast milk composition also seems to depend on duration of gestation (95).

In the 1970s and 1980s extensive research was done which compared the composition of fullterm and preterm milk. The most striking difference was a higher protein content in preterm milk (7,9,10,26,35,36,57-59,86,89,90,92,101,123). In the 1990s further research work was done on fatty acid composition. Preterm milk has higher levels of easily absorbed medium-chain fatty acids and long-chain polyunsaturated fatty acids compared with term milk (17a,41,54,98).

These data have been interpreted to mean that preterm infants require more protein and higher levels of medium- and long-chain fatty acids. It is often concluded that preterm milk is especially adapted for the extro-uterine nutritional needs of prematurely born infants. Another interesting finding is that breast milk composition changes postnatally for term and preterm milk (7-10,26,57,77,78). Inspite of all research efforts to date the basis for these differences in nutrient composition are still unclear.

The duration of gestation is an obvious factor which could influence the composition of breastmilk (5,16,95). One hypothesis is that the postconceptional age changes in the breast milk of prematurly delivering mothers is an adaptation to the extro utero nutritional needs of the premature infant (49). To answer the question of specific suitability of preterm milk for preterm infants it is important to find out whether the differences found between milk produced by mothers of preterm and term infants are related to the different nutritional needs of these two groups of neonates.

1.1.2 Formula Feeding

Cow's milk was used as food for infants since the end of World War II. Its popularity decreased by the 1970s because of a resurgence of breastfeeding. With the evolution of modern neonatal intensive care at about the same time companies producing infant formula milk began focusing on the development and production of formulas for preterm infants.

Prior to the availablity of these special preterm formulas preterm infants were given banked human milk from mothers of term babies who were willing and able to donate breastmilk. Since the growth of these small infants on the banked milk was considered suboptimal by neonatologists, milk substitutes were sought. Although continuing research on the composition of term human milk provided relevant information for continuing adjustment of the formulas for term infants, these data did not advance the knowledge needed for the development of a preterm infant formula.

The first successful human milk substitutes were primarily based on cow's milk. The aim was to develop formulas that mimmiced the composition of term and preterm human milk. At this time the goal has changed to achieve the physiological growth effects seen in infants fed human milk (55,123). Current research has focused on the substances in human milk which facilitate the growth of the infant.

1.1.3 Nutrition optimality

Although the investigation of breast milk of the mother delivering before term is more challenging it can be argued that there is greater need for such information. What is the optimal nutrition for the prematurely born infant? In general, optimality of nutrition in infants is judged by following growth parameters (anthropometry). In the clinical practice adequacy of nutrition for preterm infants is asccessed from following the postnatal growth curves and by comparison with the in utero growth curves developed from fetal

measurements. Recommendations for daily intake are based on "expected growth" from the fetal growth curves (3). However, the question remains whether physical growth is the best criteriom to judge the quality of nutrition for preterm infants.

1.2 Growth

The intra-uterine growth curves are based on cross-sectional data from babies born at different gestational ages ranging from + 24 weeks G A to term age (85,87,96,136). For following the growth of a fetus in utero it is a reasonable reference curve for growth. For infants born premature such reference curves may be less appropriate since they are extra uterine and experiencing very different adaptations due to their premature birth. Is this growth trajectory optimal for the preterm infant?

Postnatal growth of premature babies is much more influenced by extrinsic factors such as the need for intensive care support and nutrition compared to term babies. This complicates generation of standards for "extra-uterine" preterm growth form longitudinal

anthropometric measurements of preterm infants of various gestational ages (37,43). A "healthy" preterm infant population measured under standard conditions would be required to establish such curves. These growth curves would be different from the postnatal growth curves of term infants at adjusted ages and may be different from the intra-uterine fetal growth curves (27).

1.3 Neurological development

1.3.1 Behavioural states

By the late 1950s the concept of behavioural states gradually emerged in infant research (115). Many review articles report on the research and significance of infant sleep (4,39,94,100,106,107,115,132). Through the development of polygraphic recording techniques it was possible to further the investigation of sleep research. Parmelee in 1970 (106) states that there was sufficient knowledge to allow the development of a predictive neurological assessment method for newborns. He emphasized the importance "of the study of sleep behavior in the newborn infant as a means of neurological assessment". The focus of infant sleep research was to use sleep characteristics as a measure of brain organization and development. By using these maturational changes a neurodiagnostic tool to assess the integrity of the central nervous system in newborn infants could be developed

(4,39,94,100,106,119,132).

Infant sleep has two distinctly different "behavioural" patterns. One which is characterized by eye movements, frequent small body movements and irregular respiration, rapid eye movement (REM), and paradoxical or active sleep. In the other state, called quiet sleep or non-rapid eye movements (NREM) sleep there are no eye movements, no body movements, except for occasional jerky body movements, and respiration is regular. Similar to adult sleep, infants show cyclic fluctuations between quiet and active sleep. The duration of sleep cycle was not found to be significantly increased with maturation from 35 weeks

but the most significant maturational change seen was a dramatic increase in the amount of quiet sleep relative to active sleep. This shift in proportion of quiet to active sleep with age was hypothesised to be an indicator of maturation of the nervous system

(30a, 105,119,132). While active sleep represents an anarchic primitive activity of the CNS, quiet sleep is a highly controlled state requiring complex feedback mechanisms. Sleep was less organized in preterm infants who had more undefinable state i.e., indeterminate sleep because of their more immature nervous systems. (39,107,117). Though Nijhuis in 1982 (102) states that organization of behavioural states, identical in fetus and premature infant of comparable age, is not developed before 36 weeks GA, in later years several

investigators found that state differentiation does exists long before term age intra- as well as extra-uterine (31,34,137). Therefore, changes in the development and amount of each behavioural state may be helpful in the assessment of neurological maturation, brain injury and to predict outcome in preterm infants (4,39,121,127).

Infant sleep research in infants has been hindered by a wide variety of criteria and state definitions between investigators (4,32,68,74,115,127,131). Harper et al. emphasizes that knowledge of normal development of sleep states is important for understanding early neurological maturation (68). Hoppenbrouwers in 1992 (74) gave the opinion that the use of sleep development was limited clinically due to differences in state definitions, data collection and analysis strategies. Curzi-Dascalova and Mirmiran recently reported a standardization of the method in their Manual of Methods for Recording and Analyzing Sleep-Wakefulness States in Preterm and Full-term Infants (33). However, the use of state analysis has been used primarily as a research method (81,99,122,130,138).

1.3.2 Spontaneous motility

The term spontaneous behaviour includes behavioural states and overt spontaneous motility occuring without manipulation in fetuses, preterm and fullterm newborns (38,112,117) In contrast to diminished interest in the last decade in behavioural states assessment as a method to evaluate brain function in newborns, assessment of general movements has been extensively explored for this application (1,18,28,47,52,65,82,83,88,139). In 1993 Julia J. Geerdink wrote her thesis on early motor development (51) and in 1997 Arie F. Bos noted

the scientific interest for the study of spontaneous activity in newborn infants in his thesis (19).

With the substantial improvements in perinatal care and increasing numbers of surviving preterm infants of early gestations, there is greater need for a reliable assessment technique to evaluate early neurological development and to predict outcome. Several studies in preterm infants concluded that qualitative and not quantative aspects of GMs have discriminative value for assessment of neurological development and outcome (20,21,47,120). Prechtl and co-workers have developed a method for the qualitative assessment of general movements as a diagnostic tool for early detection of brain dysfunction (47,64,113). By now general movements in preterms have been studied on a large scale, but never in large groups. Small groups of low-risk infants were studied and compared with small groups of infants potentially at risk for neurological dysfunction (22,23,40,42,43,47,53,118). By the nature of the assessment method GMs cannot easily be studied longitudinally at group level unless the Ferrari Optimality score is used (47). This semi-quantitative evaluation of GMs judges 8 distinguishable elements of movement. As a standard the method is now based on designing individual developmental trajectories using the global judgement of GM quality, i.e. normal or abnormal (47). Moreover, deviant movement quality can be scored using more descriptive categories (20,47,116). Most of the studies on spontaneous motilty in infants were done by or in collaboration with Prechtl and co-workers. Recently, another investigator made changes in the methods of assessment of GM quality which has lead to some disagreements about how the assessments should be used. Prechtl and his group have maintained the assessment technique as described in 1990 and reviewed in 1997 (44). Mijna Hadders-Algra endeavoured to improve this technique on the bases of a neurophysiologically accountable classification system (63,64). She introduced the category of mildly abnormal GMs in the global assessment and consequently developed different descriptive categories of deviant movement quality. Comparison of both scoring systems by independent researchers on the basis of long term data on neurological outcome should clarifiy whether the modification in methodology improves

1.4 Neurological outcome

Advances in technology and accessability of neonatal and perinatal care over the past decades have improved survival of preterm infants. Recently, it was reported in the United States that the incidence of prematurity is increasing due to delayed childbearing and the use of fertility drugs which has increased the incidence of multiple births (60). Preterm birth is accompanied by an increased risk of longterm (neurological) damage. This risk is inversely related to gestational age at birth. Though much progress has been made in treating (very) preterm infants the neurodevelopmental outcome for some of these infants is a concern (13,61,62,103,108,124,133). A clinical instrument to identify infants early (at term age) for later neurodevelopmental problems would be an important advance in neonatology. Such early identification may improve the chances of success of intervention and prevention.

1.5 Aims and general outline of the thesis

1.5.1 Aims

The aim of this thesis is twofold:

1. develop a clinical instrument to monitor neurological development and prognosticate outcome of very low birth weight infants ( < 30 weeks gestation)

2. investigate the applicability of this instrument to judge optimality of nutrition

1.5.2 General outline

In chapter 2 the infant population, protocol procedures and methods are described. The limitations for the present investigation as part of a parent study which examined thyroxine supplementation are briefly mentioned. Chapter 3 describes the macronutrient composition of very preterm human milk and analyzes whether there is a (functional) relation between the macronutrient composition of very preterm human milk and gestational age, postnatal or developmental (i.e. postmenstrual) age of the preterm infant. Chapter 4 describes relative growth of very preterm infants until term age using anthropometric measurements of 10 different parameters. The effects of different feeding regimes on this relative preterm growth within the randomized, placebo controlled (double-blind) trial on thyroxine

supplementation are reported. In chapter 5 development of behavioural states in very preterm infants was studied to determine whether longitudinal assessment of behavioural states is a good method for early detection of neurological deviations in very preterm infants. And chapter 6 documents the development of quality of spontaneous motility in very preterm infants in order to determine whether longitudinal assessment of quality of general movements provides a good method for early detection of neurological deviations in very preterm infants. Chapter 7 evaluates the predictive value of preterm cranial

ultrasound, the Prechtl neurological test at term and our newly introduced methods of studying the development of behavioural states and the quality of spontaneous motility at term age in preterm infants based on their neurodevelopmental outcomes at two years corrected age. The 5 sub-study sections are followed by a general discussion in chapter 8. This discussion addresses the question whether this research has developed an instrument to monitor neurological development in very preterm infants and predict the risk of

neurodevelopmental abnormalities. A comparison of the effects found of different feeding regimes on growth (physical development) and neurological development is made, and the applicability of the studied methods for investigation of optimality of nutrition in very young infants is discussed. The limitations of the study as described in this thesis are discussed. Directions for additional/ futher research are addressed. Chapters 9 and 10, finally, summarize the main results and conclusions of this thesis in English and Dutch respectively

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