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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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CHAPTER 8
General discussion and directions for future research
The initial goal of this thesis was to investigate how to detect the influence of nutritional factors on neurological development of very low birth weight preterm infants. This goal transformed into two main aims described in this thesis, namely how to detect the effect of nutritional intake on growth/neurological development and how to distinguish normal vs. abnormal early neurological development.
To detect the effects of maternal milk we collected breastmilk from mothers willing and able to express their milk each week. Our study was unique for the amount of longitudinal data. Moreover, new data are reported on the changes in composition with postmenstrual or postconceptional age. It is generally accepted that maternal milk is the most appropriate nutrition for infants which is based on studies of fullterm infants. Less is known about nutritional needs of preterm infants or about nutritional values of breast milk of mothers delivering very premature infants (1-4). It has been reported that preterm infants grow better when given their mother's breastmilk instead of banked fullterm milk. In studies comparing the nutrient composition of term and preterm milk the most important difference was the amount of protein. This is consistent with a larger requirement for protein in preterms (5). Somewhat confusing is that this increase was not caused by a higher fraction of digestible proteins in milk (6-8). So how do preterm infants grow better on their mother's milk? Most studies have examined composition in relation to duration of lactation or postnatal age. Similar to fullterm babies, milk production for the preterm infant is initiated by the process of birth and the composition changes with postnatal age. If
breastmilk of mothers who deliver before term adapt to the nutritional needs of the preterm infant the differences in composition would be related to the gestational age of the infant at birth. Or another possibility is that milk compostion changes are related to postmenstrual or postconceptional age. In the third chapter of this thesis the nutritional values of such very preterm milk are reported. The macronutrient compositional changes were examined relative to postconceptional age. In our population of mothers of very preterm infants
(26-29 weeks gestation) longitudinal data shows that nutritional factors of human milk are mainly influenced by the postnatal age of the baby. It is interesting that breastmilk
composition changes with duration of lactation or postnatal age rather than postconceptional age. Whether this represents a nutritional adaptation for the postnatal advances in
physiology of the preterm infant is unclear and demands further investigation.
This randomized longitudinal study examined the physical and neurological development in preterm infants born before 30 weeks gestational age. The infants received standard formula (STF) or preterm formula (PTF) as their diet or as a supplement to maternal milk. The infants who are the subjects in this thesis were enrolled in a placebo controlled (double-blind), randomized trial on thyroxine supplementation. The clinical practice favored breast milk and thus a large percentage of mothers provided breast milk for their babies. This bias did not allow an analysis of breast vs. formula milk effects on growth of preterm infants. The additional thyroxine supplementation protocol resulted in even smaller groups for analyses. Nevertheless, preterm formula, even as a supplement to maternal milk, significantly increased growth. It was also interesting to find that additional
supplementation of the hormone thyroxine increased physical growth further. Longitudinal anthropometry (measuring 10 parameters) (chapter 4), enabled us to better illustrate the influence of nutrition on physical growth. Nutritional intake data for each infant were collected daily. Analysis was done on these data for seven postnatal weeks. The STF group started enteral feeding with STF and continued untill full enteral feeding volumes were reached at 3 to 4 weeks postnatally. That there was less growth when compared to the PTF group, even after Bonferroni correction, is interesting. Lucas also reported increased growth with PTF intake in the first few postnatal weeks (9). The role of thyroxine is relevant. The infants received an iso-caloric feeding. The explanation for the differences in growth rates is not simply due to caloric intake. It is known that thyroxine has a stimulating effect on maturational processes, e.g., development of gastro-intestinal tract (10-14). In studies which examine the effect of thyroxine supplementation on neurological outcome of (very) preterm infants, it is imperative to include short- and long-term side-effects of such supplementation (15,16). The increased growth seen in the thyroxine and PTF
General discussion and directions for future research 145
An important aim of this study was to identify a clinical instrument to monitor neurological maturation to distinguish normal from abnormal neurological development and to
prognosticate outcome of very low birth weight infants (< 30 weeks gestation). Although at 2 years of age neurodevelopmental tests such as Touwen and Bayley are used to identify normal and abnormal infants tests which can be applied at term conceptional age are not available. Spontaneously generated behaviours such as the behavioural states
(sleep-wakefulness) (17-20) and the quality of general movements are considered good indicators of normal vs. aberrant neurological development (21-33). Neither have been studied longitudinally in a large sample of very preterm infants. In chapter 5 more detail is provided on the developmental changes in sleep-wake organization. The behavioural states mature from the undifferentiated patterns at 30 weeks of age to more fully developed patterns by corrected term age in preterm infants. The amount of indeterminate state (IS), as a measure of organization, was significantly correlated with postmenstrual age. The amount of quiet sleep increased with postmenstrual age. The amount of active sleep initally increased then decreased after 36 weeks postmenstrual age. These findings corroborate previous reports (34-36) which use changes in the proportion of quiet to active sleep as a correlate of central nervous system maturation. Few preterm infants had wakefulness which limited analysis of the awake states. Time awake did increase with postmenstrual age. "Quiet" wakefulness was less frequent than "active". This may be parallel to quiet sleep developing after active wakefulness and REM- or active sleep. Some investigators (refs see below) recommend the examination of a full range of behavioural states i.e, both sleeping and waking states to fully understand behavioural states as a system (37,38). It is more difficult to study waking activity in preterm infants since they have little awake time. Examination of wakefulness at (corrected) term age may give additional information about maturation (39-41).
Interest in behavioural states as an indicator for normal neurological development had waned by the late 1980s and was replaced by the concept of spontaneous motor behaviour as a possible neurodiagnostic tool. Recently, many investigators have reported that the quality of spontaneously generated movements (GM) is a good indicator of normal development (42-49). This technique is useful to predict the risk for cerebral palsy at 2-4
months post term age however, the utility of this technique was never studied longitudinally in a large randomly selected population of preterm infants born at < 30 weeks gestational age. Contrary to our premise the quality of GM was not a useful method to follow in our infants who were studied from 30 to 40 weeks (corrected term) age (chapter 6). In this developmental age range the level of GM was comparable for neurologically normal vs. abnormal infants at two year corrected age. Our findings support Prechtl's view of the maturation of the human nervous system as described in 1984 and 1986 (50,51). Premature infants and fetuses of the same postmenstrual age have comparable movement patterns. However, this assessment at term postmenstrual age did not predict neurologic outcome at 2 years corrected age. The Ferrari Optimality score and global assessment were used to detemine the GM quality. The results from these two methods were highly correlated. Four percent of the single observations were scored as normal. The majority scored mildly abnormal (51%) or abnormal (45%) based on the categorization of Mijna Hadders-Algra (52). Descriptive subcategories (53-55) were not used. Future investigation using subcategories may find additional useful information about longitudinal changes for an infant. In a future study it would also be of interest to see if the results were the same using the Prechtl's original method of scoring. However, other investigators have concluded studies that preterm GM assessment does not have high predictive value for later neurological outcome (29,32,57-59). They report that preterm GM abnormalities may normalize by 2-4 months of age. However, if the abnormal GM persists at 2-6 months of age there is a greater risk that abnormal neurological outcomes will be seen at 2 years CA.
These two methods were also used to analyse the effect of different nutritional regimens on maturation. First the combined effects of thyroxine and diet were assessed. Neither diet thyroxine or a combination had an effect on quality of GM. This result may not be surprising since the quality of GM is not discriminating for developmental differences in the ages we examined. The assessment of GM quality as applied in this study is not a useful tool to follow neurological development. The study of behavioural states was more helpful. A maturational change over time was seen (chapter 5). Infants who received standard formula as a supplement to maternal milk and thyroxine had less IS. These infants also had a greater decrease in IS (i.e., better sleep organization) compared to the other groups
General discussion and directions for fitture research 147
studied. Therefore, thyroxine and STF supplementation appeared to improve neurological maturation for the group. A stratified analysis of quiet and active sleep showed more QS and less AS in the group receiving PTF without thyroxine. The effect of diet may on sleep behavior in newborn infants was previously reported in 1973 (60). Butte et al. compared sleep patterns of breast-fed and formula-fed infants finding more quiet sleep and lower heart rates during sleep in the first group and more REM sleep with higher energy expenditure in the latter (61). Bhatia et al. found an effect of the protein/energy ratio in diets of preterm infants to have an effect on behavioural outcome (62). These results together with ours indicate an effect of composition of diet on sleep behaviour or other neurological outcome values. Moreover, Parmelee stated in 1970, based on Kleitman's concept of basic rest-activity cycles that because the lengthening of quiet sleep coincides with the development to sustain prolonged periods of sleep and wakefulness and visual attention, the quiet sleep component in an infant's sleep cycle could possibly allow us to predict capacity to sustain attention; a significant capacity to all learning (63,64). In our population this would mean that the infants supplemented with preterm formula would have better learning capacities. A striking difference in our results is a thyroxine effect on the maturation of the behavioural states producing structures, but not on the QS/AS ratio. With this explaination our findings are in accordance with the findings of Van Wassenaer et al., who did not find any positive effect of thyroxine supplementation in our very preterm population at 2 years corrected age (65). It is a pity that she did not analyse her data including diet randomization (66,67).
Reminiscent of our findings (chapter 4) on the relation between physical development and nutritional intake we see the interesting phenomenon of a relatively most increased physical growth in preterm formula suppleted infants and a relatively highest decrease of IS in standard formula suppleted infants both receiving additional thyroxine hormone suppletion. These results suggest that in combination with thyroxine hormone preterm formula promotes physical growth while standard formula promotes brain maturation. Promotion of maturational processes by suppletion of T4 could be expected knowing that this hormone has a maturational effect on both the digestive tract and the brain (10-14). We were not the first to find an effect of diet on growth or sleep organization. Earlier studies comparing
breast-fed and formula-fed infants have shown different growth patterns and differences in sleep organization and energy expenditure (4,9,60,61,68,69,70). However, we were the first to find that physical and neurological outcomes were not similarly related to diet. This finding may add to the existing uncertainties surrounding attempts to answer the question of how to feed the smallest among us, indicating that there is a possibility that nutrition composition can favour neurological maturation rather than physical development (growth) and vice versa. However, these findings support my suggestion to introduce a neurological "growth curve" in stead of a physical one to judge optimality of nutrition with. It needs no further explanation that before doing so, closer investigation is advisable. Moreover, the predictive capacities for long-term neurological outcome of the test used to assess each individual "neurological growth curve" needs to be examined. Because if there is no relation between the scores on the neurological growth curve in the pre-term period with later neurologically based capacities there is no surplus value to a physical growth curve. Future research may very well trip up the "bigger is better" policy now generally applied in neonatal wards. Moreover, a combination with head circumference growth curves could lead to a better understanding of the relation between head growth (even better relative head growth, using ratio's with e.g body weight, crown-heel length and/or mid-upper arm or chest circumference) and neurological maturation, enabling us to study the brainsparing from a new perspective.
As stated above it is of decisive importance to know if assessment of a preterm neurological growth curve has high predictive value for later outcome. It is more "easy" to catch-up on somatic growth than on neurological (mental) development. The time span in which the neurological system matures is up to 2 years postterm. Somatic growth continues up to puberty. The opportunity to make up for delays is much less for the neurological system. Information that can be obtained from a neurological growth curve in a neonatal unit, will therefore make the use of it preferable to that of a physical one, provided that its predictive value for long-term outcome is high. In chapter 7 we have examined the predictive values of two standard neurological tests, one used during the early neonatal period till term age (cranial ultrasounds), the other one at term age (Prechtl neurological test), and the two neurological tests studied in this thesis namely quality of spontaneous motility and of
sleep-General discussion and directions for future research 149
wake Organization at term, for final outcome at 2 years of age. We were able to relate our results to the outcome of standardized neurological examination (Touwen/Hempel;71,72) and psychodevelopmental examination (Bayley;73,74) at 2 years of corrected age. To our disappointment neither the level of behavioural states organization nor the quality of general movements during the prematurity period (30-40 weeks postmenstrual age) were able to predict the normal vs. abnormal neurological outcome at 2 years of age. However the Prechtl neurological examination at corrected term age could, independently of the other tests, predict Touwen and Bayley outcomes. Although overall cranial ultrasound scoring could not add to the predictive power of the Prechtl test, as a stand alone test it seemed comparable to the term Prechtl score for identification of clearly abnormal infants. These findings could have two possible explanations. First they can indicate that the assessment of behavioural states organization and/or GM quality are not appropriate methods for detecting lasting early neurological disorders. Second, measuring neurological and psychodevelopmental performance may not be able to detect all minor/major
developmental abnormalities originating from early neurological damage. It is common knowledge that every living organism, particularly human, has an amazing ability to compensate for perinatal insults to the CNS, especially at the functional level. However, while such neurological insults might be compensated for during later development, the neurological damage caused is likely to remain a weak spot making the individual more vulnerable. Both organization of behavioural states and GM quality could be expected to be better tests in search for other neurological insults not detectable by Touwen/Bayley tests.
In search of a test to detect the level of early neurological development in very young infants in relation to nutrition, we can conclude that studying behavioural states is more promising than assessing GM quality, especially before term age. If studying behavioural states in combination with anthropometry enables us to distinguish between physical and neurological development in relation to different nutritional intake (chapters 4 and 5), it is worthwhile to further examine the possibilities of applying assessment of behavioural states development as a method to detect degree of brain maturation in young infants suffering or having suffered from malnourishment. From our data we expect to find disturbances in nutrient composition in the perinatal period to influence behavioural states (brain)
organization and physical growth.
We studied early neurological development in relation to growth and nutrition within a (parent) study on thyroxine supplementation. While no positive effects were found on the 2 year neurological outcome by other members of the group (65,75,76), we found additional increase of growth rates and additional decrease of time spent in IS with thyroxine
supplementation. From an additional analyses of the "parent" population when divided into two GA categories ( < 27 weeks and > 27 weeks GA) it was found that thyroxine
administration in the infants of 25 and 26 weeks GA is associated with an improved mental developmental outcome, while in the 27-30 weeks G A infants indications of a harmful effect on mental outcome was found. Though thyroxine hormones are essential for early development and preterm infants show transient hypothyroxinemia not seen in term infants, caution is warranted if suppletion is considered (77). From animal studies it is known that thyroid hormones can hamper brain development. Too little is as yet known on the possible long-term effects of such treatments (16). Our parent study has shown that careful
investigation on dosage and time and duration of administration needs to be done in relation to long-term outcome. The translation of animal studies to clinical medicine needs to be treated with utmost care.
We have examined growth and different neurological assessment tests on a group level. We did not examine and therefore do not know whether our findings apply to individual infants. For tracing early neurological disorders it is important to be able to test on an individual level. Our study population was a randomly selected group of a gestational age
< 30 weeks. This means that both low and high risk infants were enrolled. Therefore we were not able to set standards for growth, behavioural states organization and GM quality. The large number of infants also made it impossible to see all infants on a weekly basis for behavioural observations.
In conclusion, there several interesting results from this research. The quality of human milk of very preterm infant mothers is largely influenced by postnatal processes rather than by postconceptional processes. Human milk combined with preterm formula yields highest
General discussion and directions for future research 151
growth rates in very low birth weight preterm infants. However when combined with standard formula it results in the best behavioural states organization. Addition of thyroxine supplementation and the formulas improves both outcomes although the possible side effects of this hormonal supplementation needs further study. Longitudinal anthropometry presents a good method for measuring physical growth of an infant in relation to the nutritional intake. The level of behavioural states organization (namely the emergence of sleep-wakefulness) on the other hand is a good measure for brain maturation in preterm infants when studied longitudinally. The introduction of a "neurological growth curve" accompanying the physical growth curve would improve the assessment of early nutrition. Sleep development and quality of GM did not predict the neurological outcome at 2 years CA. However, the Prechtl neurological examination at corrected term age could, independently of the other tests, predict Touwen and Bay ley outcomes.
Research using new quantitative brain imaging and functional techniques, including neuro-magnetic enchepalogram and functional neuro-magnetic resonance imaging (fMRI) are needed to improve our understanding of brain development and injury. Neuro-MEG and (f)MRI have shown to be able to localize brain damage where conventional EEG and ultrasound could not (78). Our suggestion for future research therefore is to combine assessment of
neurobehavioural tests with new quantitative imaging and functional techniques which may improve the ability to predict infants at greatest risk for an abnormal outcome.
Important insights about nutrition, maternal breast milk and brain development have been gained from this research however, much more investigation will be needed to develop a diagnostic tool which can be applied early in infancy to predict later neurological outcome.
References
1. Baum JD. Preterm milk (editorial). Early Hum Dev 1980;4:1-3.
2. Cunningham AS, Jelliffe DB, Jelliffe EFP. Breast-feeding and health in the 1980s: A global epidemiological review. J Pediatr 1991;118:659-666.
3. Lawrence PB. Breast milk. Best source of nutrition for term and preterm infants. Pediatr Clin North Am 1994;41:925-941.
NutrSci 1988;12:421-447.
5. American Academy of Pediatrics, Committee on Nutrition. Nutritional needs of low-birth-weight infants. Pediatr 1985;75:976-985.
6. Beijers RJW, Graaf FVD, Schaafsma A, Siemensma AD. Composition of premature breast-milk during lactation: constant digestible protein content (as in full term milk). Early Hum Dev 1992;29:351-356.
7. Britton JR. Milk protein quality in mothers delivering prematurely: implications for infants in the intensive care unit nursery setting. J Pediatr Gastroenterol Nutr 1986;5:116-121.
8. Hibberd CM, Brooke OG, Carter ND, Wood C. A comparison of protein
concentrations and energy in breast milk from preterm and term mothers. J Hum Nutr 1981;35:189-198.
9. Lucas A, Gore SM, Cole TJ, Bamford MF, Dossetor JFB, Barr I, Dicarlo L, Cork S, Lucas PL Multicentre trial on feeding low birthweight infants: effects of diet on early growth. Arch Dis Child 1984;59:722-730.
10. Fowden AL. Endocrine regulation of fetal growth. Reprod Fertil Dev 1995;7:354-356.
11. Jacobsen BB, Andersen HJ, Peitersen B, Dige-Petersen H, Hummer L. Serum levels of thyrotropin, thyroxine and triiodothyronine in fullterm, small-for-gestational age and preterm newborn babies. Acta Paediatr Scand 1977;66:681-687.
12. Lerman R, Koldovsky 0 . Growth and food intake of prematurely weaned rats: Effect of cortisone and thyroxine injection during the suckling period. J Nutr 1979; 109:916-923.
13. Symonds ME. Pregnancy, parturation and neonatal development: interactions between nutrition and thyroid hormones. Proc Nutr Soc 1995;54:329-343.
14. Timiras PS, Nzekwe EU. Thyroid hormones and nervous system development. Biol Neonate 1989;55:376-85.
15. Koldovsky O. Maturative effects of hormones on the developing mammalian gastro-intestinal tract. Acta Paediatr 1994;(Suppl 405):7-12.
16. Swaab DF, Mirmiran M. Possible mechanisms underlying the teratogenic effects of medicines on the developing brain. In: Joseph Yanai, editor. Neurobehavioral
General discussion and directions for future research 153
Teratology. Elsevier Science Publishers BV, Amsterdam, 1984.
17. Curzi Dascalova L and Mirmiran M, (eds). Manual of Methods for Recording and Analyzing Sleep-Wakefulness States in Preterm and Full-term Infants. INSERM, Paris, 1996.
18. Groome LJ, Swiber MJ, Atterbury JL, Bentz LS, Holland SB. Similarities and differences in behavioral state organization during sleep periods in the perinatal infant before and after birth. Child Dev 1997a;68:1-11.
19. Mirmiran M. The function of fetal/neonatal rapid eye movement sleep. Behav Brain Res 1995;69:13-22.
20. Thoman EB and Whitney MP. Sleep states of infants monitored in the home: individual differences, developmental trends, and origin of diurnal cyclicity. Infant Behav Dev 1989;12:59-75.
21. Bos AF. Analysis of movement quality in preterm infants. Eur J Obst Gynecol ReprodBiol 1998;76:117-119.
22. Bos AF, Martijn A, Van Asperen RM, Hadders-Algra M, Okken A, Prechtl HFR. Qualitative assessment of general movements in high-risk preterm infants with chronic lung disease requiring dexamethasone therapy. J Pediatr 1998;132:300-306.
23. Bos AF, Martijn A, Okken A, Prechtl HFR. Quality of general movements in preterm infants with periventricular echodensities. Acta Paediatr 1998;87:328-335.
24. Cioni G, Ferrari F, Einspieler C, Paolicelli PB, Barbani MT, Prechtl HFR. Comparison between observation of spontaneous movements and neurological examination in preterm infants. J Pediatr 1997;130:704-711.
25. Cioni G, Prechtl HFR. Preterm and early postterm motor behaviour in low-risk premature infants. Early Hum Dev 1990;23:159-191.
26. Einspieler C, Prechtl HFR, Ferrari F, Cioni G and Bos AF. The qualitative
assessment of general movements in preterm, term and young infants - review of the methodology. Early Hum Dev 1997;50:47-60.
27. Ferrari F, Cioni G, Prechtl HFR. Qualitative changes of general movements in preterm infants with brain lesions. Early Hum Dev 1990;23:193-231.
28. Hadders-Algra, M. The assessment of general movements is a valuable technique for the detection of brain dysfunction in young infants. A review. Acta Paediatr Suppl
1996;416:39-43.
29. Hadders-Algra, M, Klip-Van den Nieuwendijk AWJ, Martijn A, Van Eykern LA. Assessment of general movements: towards a better understanding of a sensitive method to evaluate brain function in young infants. Dev Med Child Neurol 1997;39:89-99.
30. Hadders-Algra M, Prechtl HFR. Developmental course of general movements in early infancy. I. Descriptive analysis of change in form. Early Hum Dev 1992;28:201-213. 31. Prechtl, HFR. Qualitative changes of spontaneous movements in fetus and preterm
infant are a marker of neurological dysfunction (Editorial). Early Hum Dev 1990;23:151-158.
32. Prechtl HFR, Einspieler C, Cioni G, Bos AF, Ferrari F, Sontheimer D. An early marker for neurological deficits after perinatal brain lesions. Lancet
1997;349:1361-1363.
33. Prechtl HFR, Nolte R. Motor behaviour of preterm infants. In: Prechtl HFR, editor. Continuity of neural functions from prenatal to postnatal life, Clinics in
Developmental Medicine No 94. Blackwell Scientific Publications Ltd. Oxford, UK, 1984:79-92.
34. Parmelee AH. Sleep cycles in infants. Dev Med Child Neurol 1969;11:794-795. 35. Prechtl HFR, Lenard HG. A study om eye movements in sleeping newborn infants.
Brain Res 1967;5:477-493.
36. Stern E, Parmelee AH, Akiyama Y, Schultz MA, Wenner WH. Sleep cycle characteristics in infants. Pediatr 1969;43:65-70.
37. Becker PT, Thoman EB. 'Waking activity': the neglected state of infancy. Dev Brain Res 1982;4:395-400.
38. Thoman EB, Holditch Davis D, Denenberg VH. The sleeping and waking states of infants: correlations across time and person. Physiol Behav 1987;41:531-537. 39. Davis DH, Thoman EB. Behavioral states of premature infants: implications for
neural and behavioral development. Dev Psychobiol 1987;20:25-38.
40. Michaelis R, Parmelee AH, Stern E, Haber A. Activity states in premature and term infants. Dev Psychobiol 1973;6:209-215.
General discussion and directions for future research I55
throughout 24-h video recordings in preterm infants at term with good prognosis. Early Hum Dev 1989;19:183-190.
42. Albers S, Jorch G. Prognostic significance of spontaneous motility in very immature preterm infants under intensive care treatment. Biol Neonate 1994;66:182-187. 43. Bekedam DJ, Visser GHA, Vries JIP de, Prechtl HFR. Motor behaviour in the
growth retarded fetus. Early Hum Dev 1985;12:155-165.
44. Droit S, Boldrini A, Cioni G. Rhythmical leg movements in low-risk and brain-damaged preterm infants. Early Hum Dev 1996;44:201-213.
45. Einspieler C. Abnormal spontaneous movements in infants with repeated sleep apnoeas. Early Hum Dev 1994;36:31-48.
46. Einspieler C, Prechtl HFR, van Eykern L, de Roos B. Observation of movements during sleep in ALTE and apnoeic infants. Early Hum Dev 1994;40:39-50. 47. Geerdink JJ, Hopkins B. Qualitative changes in general movements and their
prognostic values in preterm infants. Eur J Paediatr 1993;152:362-367. 48. Prechtl HFR, Ferrari F, Cioni G. Predictive value of general movements in
asphyxiated fullterm infants. Early Hum Dev 1993;35:91-120.
49. Si val DA, Visser GHA, Prechtl HFR. The effect of intrauterine growth retardation on the quality of general movements in the human fetus. Early Hum Dev 1992;28:119-132.
50. Prechtl HFR (ed). Continuity of neural functions from prenatal to postnatal life. Clinics in Developmental Medicine no.94. Oxford: SIMP/Blackwell, 1984. 51. Prechtl HFR. New perspectives in early human development. Eur J Obstet Gynecol
ReprodBiol 1986;21:347-355.
52. Hadders-Algra, M, Klip-Van den Nieuwendijk AWJ, Martijn A, Van Eykern LA. Assessment of general movements: towards a better understanding of a sensitive method to evaluate brain function in young infants. Dev Med Child Neurol
1997;39:89-99.
53. Bos AF, Van Loon AJ, Hadders-Algra M, Martijn A, Okken A, Prechtl HFR. Spontaneous motility in preterm, small-for-gestational age infants. II Qualitative aspects. Early Hum Dev 1997;50:131-147.
preterm infants with brain lesions. Early Hum Dev 1990;23:193-231.
55. Prechtl HFR, Einspieler C, Cioni G, Bos AF, Ferrari F, Sontheimer D. An early marker for neurological deficits after perinatal brain lesions. Lancet
1997;349:1361-1363.
56. Geerdink JJ, Hopkins B. Effects of birthweight status and gestational age on the quality of general movements in preterm newborns. Biol Neonate 1993;63:215-224. 57. Kalkebeeke, TH, Siebenthal, KV, Largo, RH. Movement quality in preterm infants
prior to term. Biol Neonate 1998;73:145-154.
58. Van Kranen-Mastenbroek VHJM, Folmer KB, Kingma H, et al. The influence of head position and head position change on spontaneous body posture and motility of fullterm AGA and SGA newborn infants. Brain Dev 1997;19:104-110.
59. Vies, J., Kingma, H, Caberg, H, Duniels, H, Casaer, P. Posture and motility of lowrisk preterm infants: a study from 32-36 weeks of postconceptional age. Dev Med Child Neurol 1989;31:191-195.
60. Yogman MW, Zeisel SH. Diet and sleep patterns in newborn infants. N Engl J Med 1983;309:1147-1149.
61. Butte NF, Jensen CL, Moon JK, Glaze DG, Frost Jr JD. Sleep organization and energy expenditure of breast-fed and formula-fed infants. Pediatr Res 1992;32:514-519.
62. Bhatia J, Rassin DK, Cerreto MC, Bee DE. Effect of protein/energy ratio on growth and behaviour of premature infants: preliminary findings. J Pediatr 1991 ; 119:103-110.
63. Parmelee AH. Sleep cycles in infants. Dev Med Child Neurol 1969;11:794-795. 64. Parmelee AH. Sleep studies for the neurological assessment of the newborn.
Neuropädiatrie 1970;1:351-353.
65. Van Wassenaer AG, Kok JH, de Vijlder JJM, Briet JM, Smit BJ, Tamminga P, Van Baar AL, Dekker FW, Vulsma T. Effects of thyroxine supplementation on
neurological development in infants born at less than 30 weeks gestation. N Engl J Med 1997;336:21-26.
66. Morley R, Lucas A. Influence of early diet on outcome in preterm infants. Acta Paediatr Suppl 1994;405:123-126.
General discussion and directions for future research 157
67. Lewis DS, McMahan, Mott GE. Breast feeding and formula feeding affect differently plasma thyroid hormone conventrations in infant baboons. Biol Neonate 1993;327-335.
68. Bell A, Halliday H, McClure G, Reid M. Controlled trial of new formulae for feeding low birth weight infants. Early Hum Dev 1986;13:97-105.
69. Brooke OG, Wood C, Barley J. Energy balance, nitrogen balance, and growth in preterm infants fed expressed breast milk, a premature infant formula, and two low-solute adapted formulae. Arch Dis Child 1982;57:898-904.
70. Dewey KG, Heinig MJ, Nommsen LA, Peerson JM, Lönnerdal B. Breast-fed infants are leaner than formula-fed infants at 1 y of age: the DARLING study. Am J Clin Nutr 1993;57:140-145.
71. Hempel MS. The neurological examination for toddler-age. Thesis, University of Groningen, the Netherlands, 1993.
72. Touwen BCL, Hempel MS, Westra LC. The development of crawling between 18 months and four years. Dev Med Child Neurol 1992;34:410-416.
73. Meulen BF van der, Smrkovsky M. De Bayley Ontwikkelings-schalen (BOS 2-30). Lisse: Swets and Zeitlinger, 1983.
74. Meulen BF van der, Smrkovsky M. De Bayley Ontwikkelings-schalen (BOS 2-30), Niet-Verbale versie. Lisse: Swets and Zeitlinger, 1987.
75. Smit BJ, Kok HJ, de Vries LS, van Wassenaer AG, Dekker FW, Ongerboer de Visser BW. Motor nerve conduction velocity in very preterm infants in relation to L-thyroxine supplementation. J Pediatr 1998;132:64-69.
76. Smit BJ, Kok HJ, de Vries LS, van Wassenaer AG, Dekker FW, Ongerboer de Visser BW. Somatosensory evoked potentials in very preterm infants in relation to L-thyroxine supplementation. Pediatr 1998;101:865-869.
77. Free thyroxine levels in hospitalized newborns: depressed levels in critical, nonthyroidal illness. J Perinatol 1991;11:117-121.
78. Born P, Leth H, Miranda MJ, et al. Visual activation in infants and young children studied by functional magnetic resonance imaging. Pediatr Res 1998;44:578-583.
