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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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Development of behavioural states in very preterm infants
Yolanda G.H. Maas, Majid Mirmiran, Augustinus A.M. Hart, Janna G. Koppe and Henk Spekreijse
5.1 Abstract 5.2 Introduction 5.3 Subjects and methods
5.3.1 Subjects 5.3.2 Behavioural states 5.3.3 Statistical analysis
5.4 Results
5.4.1 Development of behavioural states 5.4.2 Covariates
5.4.3 Cerebral ultrasound
5.5 Discussion 5.6 References
Development of behavioural states in very preterm infants
1Yolanda G.H. Maas1, Majid Mirmiran3, Augustinus A.M. Hart2, Janna G. Koppe' and
Henk Spekreijse4
'Department of Neonatology and
department of Clinical Epidemiology and Biostatistics
Academical Medical Center, University of Amsterdam, Emma Childrens' Hospital ••Netherlands Institute for Brain Research
"The Netherlands Ophthalmic Research Institute and Laboratory of Medical Physics
1 Preliminary results of this study were presented in the SPR meeting and were published in
abstract form in Pediatric Res. 36 (1994) 25A.
5.1 Abstract
Background An early diagnostic tool to trace deviant neurological maturation related to the
risk of long-term neurological disorders in preterm babies and to test possible effects of new treatments is needed in neonatology. We wanted to examine whether longitudinal observation of behavioural states reflects preterm brain maturation when studied before corrected term age.
Methods The development of behavioural states (namely sleep and wakefulness) was studied
longitudinally in a group of 96 preterm infants born at < 30 weeks
gestational age. These infants were enrolled in a randomized trial studying early diet and thyroxine supplementation
Results 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. Both qualitative and quantitative aspects of behavioural states showed significant age effects during this very early neonatal period. We found some evidence of differences in the time course of behavioural states development as a function of early diet, thyroxine supplementation, birth weight and normal vs. abnormal cranial ultrasound.
Conclusions It was concluded that longitudinal assessment of behavioural states has the
potential to be a good method to detect deviations from a normal postnatal maturation process in preterm infants.
5.2 Introduction
The emergence of different behavioural states, i.e. quiet sleep, active (REM) sleep and wakefulness, is one of the most significant aspects of early brain maturation in infancy (1,2). These behavioural states are characterized by a number of state specific criteria which emerge coherently in time (3). A certain amount of brain maturation is required before the behavioural states can be classified. Earlier in ontogeny a large amount of time is spent in indeterminate sleep. It is hypothesized that the development of behavioural states is a good marker for the level of brain maturation based on fetal and neonatal (preterm infants) studies (4,5,6,7). However most of the earlier results were based on cross-sectional studies and showed large individual variabilities in behavioural states (8,9). We have initiated a large longitudinal study of behavioural states development in preterm infants born before 30 weeks gestational age. We wanted to test the hypothesis whether (brain) maturation of these infants is reflected in the development of behavioural states when studied longitudinally till corrected term age. These infants were also enrolled in a placebo controlled (double-blind), randomized trial on early diet and thyroxine supplementation effects on maturation of very preterm infants. Therefore we have examined the effects of thyroxine supplementation and early feeding regimen (standard formula (STF) or preterm formula (PTF)) on the development of behavioural states. Furthermore we have analysed the relation between behavioural state development and a number of covariables,
particularly with respect to repeated cranial ultrasound findings as an indirect method for measuring normal/deviant brain development.
5.3 Subjects and methods
5.3.1 Subjects
This study is based on 160 infants, born in 1991 and 1992, who participated in a
randomized, double-blind, placebo controlled trial of early diet and T4 administration (10). The study protocol was approved by the Medical Ethical Committee of the Academical Medical Center, Amsterdam. All infants born at a gestational age of less than 30 weeks, admitted to the Intensive Care Unit of the Academical Medical Center were entered into this trial if after full explanation informed consent from at least one parent was obtained
within 24 hours after birth. Babies were excluded if they had a major congenital abnormality known to influence growth or neurological development or when the mother had an endocrinological disease or was an illicit drug user. Of the 160 infants enrolled 11 infants died within 72 hours after birth leaving us with 149 infants to study (11). These infants were stratified (before diet randomization) according to mother's choice to breastfeed her infant(s). Of the 149 infants, 120 entered into the "maternal milk (MM) group" and 29 into the "only formula feeding (FF) group". The small number of mothers that chose not to express breast milk for their infant(s) resulted in a too small number of infants in the "only" formula feeding group" for reliable statistics. Therefore we further analyzed only the data of the maternal milk group. From these 120 infants 24 were never observed; 11 because they died within 3 weeks after birth; 4 (of which 3 died) because of the severity of their illness in the first 7 postnatal weeks, 1 because she was transferred to another hospital 6 days postpartum, 2 (twins) because the parents withdrew their informed consent and 6 because of absence of the researchers. This resulted in a total of 96 infants, 48 in the thyroxine and 48 in the placebo group. Fifty four infants were given standard formula and 42 preterm formula, resulting in four groups (26 in the thyroxine/STF, 22 in the thyroxine/PTF, 28 in the placebo/STF, 20 in the placebo/PTF group). Extensive data were collected on obstetric, fetal and neonatal variables.
Infants started enteral feeding between 24 hours and several days after birth, depending on their clinical condition. Enteral feeding was increased thereafter till a full enteral intake of
125 + 15 kcal/kg/day had been achieved. Each infant was randomly assigned to STF or PTF. Diet protocol and the macronutrient composition of the standard and preterm formulas used and the macronutrient composition of our weekly collected maternal milk samples are described in more detail in chapters 2 and 4 (11) and 2 and 3 (12) respectively. For each infant entering the study a numbered 'blind' set of ampoules, containing 25 jug/ml T4 or placebo, was prepared. Thyroxine supplementation once a day was started 12-24 hours after birth, in a dose of 8 /ig per kilogram birth weight. This dose was chosen on the basis of results of a pilot study (13) and given via an intravenous injection as long as intravenous nutrition was given (mean period of 14 days) or enterally thereafter. The treatment lasted 6 weeks.
This was confirmed either by an ultrasound examination during early pregnancy or a maturational assessment of the preterm infant with the help of the Dubowitz score (14). Data concerning patient characteristics and clinical outcome within 24 hour after birth are shown in table 5.1. Neonatal clinical data were collected until discharge (table 5.2).
Table 5.1 Clinical characteristics of the infants within 24h after birth*
gestation (d), mean ± SD gestation below 189 days birth weight (g), mean + SD sex, male/female
ethnic origin: Caucasian Multiplets
Birth weight < 10th centile antenatal dexamethasone Caesarian section APGAR score at 5' intubation at birth
respiratory distress syndrome surfactant rescue therapy intrauterine infection" cerebral haemorrhage (day 1)
Thyroxine STF PTF (n=26) (n=22) Placebo STF PTF (n=28) (n=20) 194 ± 9 198 ± 8 196 ± 9 195 ± 9 6 4 7 5 1108 ± 247 1038 ± 213 1044 ± 189 1077 ± 274 11/15 15/7 11/17 8/12 19 13 21 17 6 13 14 8 1 4 3 2 18 17 15 17 2 6 6 2 8.5 ± 1.5 8.0 + 1.7 8.0 ± 1.7 8.6 + 2.2 5 9 13 4 12 13 1.3 12 8 9 7 6 2 2 1 2 7 4 6 3
* no statistically significant differences were found between the 4 study groups " proven by positive bacterial culture
Table 5.2 Clinical data until discharge* Thyroxine Placebo STF PTF STF PTF (n = 26) (n = 22) (n=28) (n = 20) Deaths 0 (0%) 1 (5%) 1 (4%) 0 (0%) Oxygen suppl. at 36 w 4(15%) 3 (14%) 3(11%) 6 (30%) Patent Ductus Arteriosus 8(31%) 1 (5%) 10 (36%) 7(35%) Necrotizing Enterocolitis 1 (4%) 0(0%) 1 (4%) 0(0%) Septicaemia 7 (27%) 4(18%) 8 (29%) 5(25%) Days of intubation 4 ± 4 5 + 5 5 + 7 6 + 7 Days of 02 therapy 27 ± 28 30 ± 33 32 + 46 33 + 33
Days of parenteral nutrition 16 ± 11 15 + 7 17 ± 11 15 + 6 PMA total enteral feeding (days) 211 ± 15 216 + 7 215 ± 14 211 + 10 PMA at discharge home (days) 269 ± 16 279 ± 21 275 ± 17 276 + 20 Cerebral ultrasound findings
Normal 12 (46%) 9(41%) 13 (46%) 8 (40%) Moderately abnormal 11 (42%) 9(41%) 15 (54%) 7(35%) Severely abnormal 3 (12%) 4(18%) 0 (0%) 5 (25%)
no statistically significant differences were found between the 4 study groups
Patent ductus arteriosus was diagnosed when clinical symptoms were confirmed by a cardiac ultrasound. Necrotizing enterocolitis was diagnosed by pneumatosis on an
abdominal radiograph and/or by findings during surgery. Cranial ultrasounds were carried out, using a 7.5 MHz transducer, within 24 h after birth and on days 5, 14, 28 and 42 or more often if clinically indicated. Classification of haemorrhage was done as described by Volpe (15). Haemorrhagic venous infarction followed by cysts were classified as
parenchymal haemorrhages. Ischaemic lesions were classified according to De Vries et al. (16). Classification of ventriculomegaly was performed according to Levene (17).
5.3.2 Behavioural States
Observations Procedure
Two-hour observations and polygraphic recordings were made as soon as the clinical condition of the infant was stabilized (usually 1 - 2 weeks after birth) and repeated every 2 weeks thereafter. The infants were studied until they left our neonatal unit (discharge home or transfer to another hospital) or reached term age. The number of infants available for observation decreased progressively (mainly due to transfer to other hospitals). If a baby left the hospital before 38 weeks of postmenstrual age we asked the parents whether we could see the child again at corrected term for a 2-hour observation.
All recordings were made in the hospital; generally between noon and 6 p.m., preferably between two feedings. Depending on age, feeding was either parenteral or via nasal tube or by bottle or (incidentally) breast. The infants were observed in the incubator or under a radiant warmer (Ohio Infant Warmer System, Ohmeda, BOC Group Inc., Columbia, USA). All infants were undressed before starting the observations, wearing only a diaper. They were then placed in the supine or semi-lateral position and allowed some time to adjust before recording in a well controlled thermal environment.
Polygraphic recordings were made of respiration and ECG via a HP neonatal monitor. In addition to this every minute the following state dependent criteria were written on the polygraph paper: a) eyes open or closed, b) eye movements present or absent, c) respiration regular or irregular, d) gross body movements present or absent, e) crying (vocalization), f) heart frequency (beats per minute), g) body temperature.
State analysis
A combination of behavioural observation and the polygraphic recording was used to determine the behavioural states. Five different "behavioural states" were scored OFF-line: 1. quiet sleep (QS), 2. active sleep (AS), 3. quiet wakefulness (QW), 4. active wakefulness (AW) and 5. crying, using a three-minutes moving window (table 5.3; (1,6)). The
remainder of each recording session in which state characteristic criteria were not fulfilled was assigned as "indeterminate sleep" (IS) (6,8,9).
Table 5.3 Definition of behavioural states quiet sleep active sleep quiet wakefulness active wakefulness crying
Eyes Eye Respiration Heart rate Gross body Vocali-open movement regular regular movements sation
+
+
+
+
+
+
+
+
We performed a total of 372 two hour observations of 96 infants. As the observations were mostly carried out once every two weeks, the data of the observations made at 30-31, 32-33, 34-35 and 36-37 weeks postmenstrual age were pooled for the repeated measurements analysis in addition to term (38-42 w PMA) observations (see table 5.4).
Table 5.4 Number of observations made of infants studied in four different treatment groups
Thyroxine Placebo postmenstrual age ALL STF PTF STF PTF
(weeks) (n=96) (n=26) (n = 22) (n=28) (n=20) 30-31 85 24 20 27 14 32-33 82 23 21 21 17 34-35 55 12 14 14 15 36-37 29 4 8 11 6 38-42 58 18 11 18 11
5.3.3 Statistical analysis
To evaluate the effect of the three main variables i.e. age, early diet and thyroxine administration on the development of behavioural states in our very premature infants population, unbalanced repeated measurement analysis of covariance with structured covari-ance matrices was performed using the statistical program BMDP 5V (18). This analysis allows for missing values which are estimated implicitly from the available data. Analysis was performed separately on the duration of quiet sleep, active sleep and indeterminate sleep. Although we recorded quiet (QW) and active (AW) wakefulness and crying, all three states occurred either not at all or only for a few minutes and only sporadically for longer episodes. This type of data doesn't lend itself readily for a statistical analysis and in any case the results of such an analysis would be difficult to interpret. Therefore we chose to ignore QW, AW and crying.
The model contained the main effects of Thyroxine (yes/no), supplemented Formula (standard/preterm) and the within-infant grouping factor postmenstrual age (PMA) as well as all possible interactions between these 3 factors. In addition covariables (gestational age, gender, APGAR score at 5 minutes, surfactant rescue therapy, antenatal glucocorticoids, cerebral haemorrhage on day 1 postpartum, weightpercentiles) were included as well as their interactions with time (postmenstrual age in weeks). To adjust for differences in PMA within each category an additional covariable was introduced, defined by the difference between the actual PMA and the lowest (30,32,34,36) value or the midvalue (40) of the categories. In order to simplify the interpretation of the results we used a backward elimination of the three factors and their interactions, taking the hierarchical structure into account. This means that no main effect or interaction can be eliminated as long as it is included in a higher order interaction in the model. When an interaction between the three main effects Thyroxine (yes/no), supplemented Formula (standard/preterm) and PMA, or between two of the three main effects was found, we further analysed the relationship using a stratified analysis of the effect of the administration of Thyroxine or Placebo within the two supplemented Formula groups (standard/preterm) and/or the effect of the two types of early feeding regimens (supplemented Formula being standard or preterm) within the separate Thyroxine and Placebo groups.
per-formed from the unbalanced repeated measurements analysis. When indicated, a square root transformation was applied and the effect of outliers was analysed.
To adjust for the missing values in the data all figures on QS, AS and IS presented here are based on the estimated values of the regression parameters resulting from the unbalanced repeated measurements analysis of covariance.
5.4 Results
5.4.1 Development of Behavioural States
Quiet sleep
The amount of quiet sleep seems to increase with postmenstrual age (tables 5.5. 5.6 and fig. 5.1a).
However, there is some indication that this development differs between the four treatment groups and that T4 and the type of early feeding modify each other's effect on QS
(interaction T4 x Diet x time: p = 0.039). Therefore a stratified analysis of both Thyroxine supplementation (yes/no) and early feeding regimen (standard or preterm formula) was performed. From this analysis we found only some evidence of an effect of early diet (interaction Diet x time: p = 0.036) in the Placebo group, with more QS in the Preterm formula group.
Active sleep
There is not much evidence of a change in AS between 30 weeks PMA and term age (tables 5.5, 5.6 and fig. 5.1a). The effect of T4 on the amount of AS depends on the type of feeding and vice versa (p = 0.0022). From a stratified analysis we found only some evidence of an effect of early diet in the Placebo group (Diet x time: p=0.040; after elimination of interaction term, Diet: p = 0.025) with less AS in Preterm formula group.
Indeterminate sleep
The amount of indeterminate sleep decreased with postmenstrual age irrespective of diet or thyroxine (p = 0.0007) (tables 5.5, 5.6 and fig. 5.1a), demonstrating that sleep organization develops rapidly in the first weeks of life in very preterm infants. The effect of T4 on indeterminate sleep seems to depend on the type of early feeding (p = 0.046) and vice versa.
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w-i NO O eN en oo en r-en in Th O en ON in, oo Th, O N en en ON O N II a oo UI O CN CN Th CN Th en cn Th en Th en m N O cn Th NO en in Th Th N O en en CN en en en cn en CN Th en cn en in en en CN Th en en en in en t'-en CN Th O en CN en Th en N O en 00 en O en C N en Th cn en oo en O en CN cn Th cn N O en 00 en Cu 0) cog
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Cu O > T3 aTable 5.6 P-values1 from the repeated measurements ANOVA of the effect of age (time),
early diet (STF/PTF) and thyroxine administration (yes/no) on the development of behavioural states from postmenstrual week 30 till term. Results are adjusted for the covariables as mentioned in the text).
quiet sleep*' active sleep*' indeterminate sleep*' Time (PMA°) 0.018" 0.733) 0.000T] Diet 0.82" 0.015" 0.354) Thyroxine 0.93l) 0.26" 0.89"] Diet x Thyroxine 0.011" 0.00223' 0.0464' Diet x Time 0.56" 0.0463' 1.02) Thyroxine x Time 0.73" 0.332' 0.683'
Diet x Thyroxine x Time 0.039° 0.19" 0.39" *' Step in backward elimination process
11talized p-values indicate terms which are contained in other terms still in the model at
the last step. These should be interpreted with some caution. ° postmenstrual age
Legend to figures
Figure 5.1a Amount of quiet sleep ( - • - ) , active sleep (--*—) and indeterminate sleep (•••••) in minutes (mean, 95% CI) for 30 weeks postmenstrual age (PMA) to term corrected age.
Figure 5.1b Amount of wakefulness (i.e. quiet, active wakefulness and crying) in minutes (mean, 95% CI) for 30 weeks postmenstrual age (PMA) to term corrected age.
28 30 32 34 36 38 post menstrual age (w)
28 30 32 34 36 38 post menstrual age (w)
From a stratified analysis we found some evidence of an effect (p = 0.047) of T4 suppletion on the amount of indeterminate sleep between PMA week 30-31 and term age within the STF supplemented group; the T4 suppleted group showing less amount of IS compared to the Placebo group, indicating that the T4 suppleted group has a higher level of behavioural state organization than the Placebo group.
Wakefulness
From our data we can see that the amount of "wakefulness" (i.e. quiet and active wakefulness and crying) during our 2-hour observations increased from an average 5.8 (3.4-8.2, 95%CI) minutes at PMA week 30-31 to an average of 26.5 (19.1-33.9, 95%CI) minutes at term age (fig. 5.1b).
5.4.2 Covariates
The development of QS differs between boys and girls (p = 0.0007). Boys have more QS than girls, except for 36-37 weeks PMA probably due to a lower number of observations made in this group. No evidence for a gender difference was found regarding the other sleep states.
Infants that are growth retarded under the 10th weightpercentile (SGA) (n=10) had on average 33% more QS compared with the AGA (n=86) infants (p=0.0018) between 32 and 37 weeks of age with no significant differences at term.
No evidence was found of a relation between weight and the other sleep states, nor of a relation between the other covariables and any of the behavioural states analysed.
5.4.3 Cerebral ultrasound
A separate analysis was performed to see whether a relation between overall cerebral ultrasound findings and behavioural states development could be found.
Some evidence of a difference regarding both QS (p = 0.045) and AS (p=0.031), and IS (p=0.077) for the infants with an abnormal outcome (n= 12) compared with the infants with a normal (n=42) cerebral ultrasound outcome, between 30 and 40 weeks PMA, was found. In contrast to controls "abnormal" infants did not show the gradual steady increase in quiet sleep from 30 weeks till corrected term age. However, they consistently showed
more IS between PMA week 30-31 and term age.
5.5 Discussion
In accordance with our hypothesis postnatal brain maturation in preterm infants born < 30 weeks gestational age as measured by behavioural states development showed a significant time (age) effect. Preterm infants spent more than 50% of the recording time in an indeterminate state at 30-31 w PMA which decreased to less than 20% at corrected term age. This was mainly due to the development of quiet sleep and wakefulness. This developmental change and pattern of sleep-wake by term age found in this longitudinal study in preterm infants was reminiscent of observations in fetal and neonatal studies (1,5,7,19,20,21,22,23). The developmental change towards more organized behavioural states as found in the reduction in amount of time spent in indeterminate state was more remarkable around 32-34 w PMA supporting the earlier cross sectional studies in preterm infants by Curzi et al. 1988,1993 (8,9). At present we can only speculate that at this age a certain brain area/network is developing that is responsible for better and tighter
organization of behavioural states from a more random chaotic pattern to well defined states of sleep and wakefulness.
Although not to a substantial degree, some evidence was found regarding differences in the pattern of behavioural states development among normal, mildly abnormal and abnormal (based on cranial ultrasound) infants. Particularly quiet sleep in the abnormal group did not show the normal continuous increase as a function of age. This effect was significant at the 5% level. Of course the normal and abnormal group were not comparable in number (42 vs. 12).
Both diet and thyroxine had a significant effect on behavioural states in our very preterm infants. Some evidence of interactions between diet or thyroxine and age were found for quiet sleep, active sleep and indeterminate sleep. By and large the pattern of behavioural states development as measured by decreased indeterminate sleep, increased quiet sleep and wakefulness from 30-31 w PMA to term, was not affected by these supplementations. From this study we cannot conclude that either preterm diet or thyroxine or both substantially influence the developmental course of state time in very preterm infants, which is in accordance with the lack of beneficial effects found by others of our group studying the
same preterm infant population examined for neurological maturity at term and 2 years of age (10,24,25). However, considering the small groups and the relatively small differences in treatment, it is hopefull to find some effects on behavioural states' development patterns before term age for future employment of this method to trace deviant preterm neurological maturation. A larger study including more high risk preterm infants is required to test the significance of using behavioural states as a clinical measure to determine normal/abnormal brain development in neonatology.
Acknowledgements
We would like to thank all participating infants and their parents for their cooperation. We are grateful to all medical and nursing staff of our neonatal department for their share in carrying out the study protocol; to Dr. J.H. Kok, Dr. A.G. van Wassenaer, Dr. B.J. Smit and Dr. P. Tamminga for their share in the execution of the combined research protocol. Special thanks should go to Dr. H.F.R. Prechtl, who has spent a considerable amount of his time to introduce me to the exciting world of "behavioural states" in young infants. Y.G.H. Maas was financially supported by Nutricia, The Netherlands.
This report is part of a study in fulfilment of the Degree in Philosophy in Science for Y.G.H. Maas.
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