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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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CHAPTER 6

Qualitative assessment of general movements in very preterm infants: relation to neonatal cranial ultrasound and neurological outcomes

Yolanda G.H. Maas, Majid Mirmiran, Augustinus A.M. Hart, Janna G. Koppe and Henk Spekreijse

6.1 Abstract

6.2 Introduction

6.3 Subjects and methods

6.3.1 Subjects

6.3.2 Overall cerebral ultrasound

6.3.3 Neurological examination at term

6.3.4 Spontaneous general movements

6.3.5 Statistical analysis

6.4 Results

6.5 Discussion

6.6 References

Submitted

106 Chapter 6

107

Qualitative assessment of general movements in very preterm infants: relation to neonatal cranial ultrasound and neurological outcome Yolanda 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

6.1 Abstract

Background An early diagnostic tool highly predictive of preterm babies at risk of long-

term neurological disorders is still needed in neonatology. We wanted to test the

applicability of a new method to detect early brain damage in newborn infants, based on the

observation of quality of spontaneous movements.

Methods We have examined longitudinally the quality of general movements (GMs) 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 Repeated measures of GM quality were stable over time and did not show

significant changes till corrected term age. No effects were found of early diet and/or

thyroxine supplementation. No significant differences in GM quality were found in infants

scored normal and abnormal based on repeated cranial ultrasound made before term age or

on neurological examination at term age.

Conclusions We conclude that the quality of GM is an easy and reliable measurement to be

carried out even in the neonatal intensive care unit in very preterm infants. Since it is stable

over time in the preterm period (from 30 to 40 weeks postconceptional age) one

observation would be sufficient for evaluation before term age. Diet and thyroxine

intervention effects were not found assessing preterm GM quality.

When applied before term age the agreement of this method with the results of preterm

108 Chapter 6

cranial ultrasound or conventional neurological outcome at corrected term age is very poor.

6.2 Introduction

In the United States alone approximately 50,000 infants are born yearly with a birth weight

< 1500g. Because of major advances in neonatal intensive care, 85% of these infants

survive (1,2). However 5-15% may develop major neurological abnormalities and an

additional 25-50% may exhibit minor neurodevelopmental disabilities (3). An early

diagnostic tool to identify babies at risk is needed. Prechtl and collaborators developed a

new and noninvasive assessment technique for the early detection of brain injury (4-8). This

new method is based on the observation of spontaneous motility assessing the quality of

general movement (GM) in preterm and term infants (4,9-14). This technique applied till 3-

4 months post term appears to have good predictive value for neurological dysfunction and

is superior to conventional neurological examination and cranial ultrasound (7,15-22). We

were interested to study the applicability of this test in our neonatal intensive care unit

(NICU) as an early diagnostic tool to detect neurological abnormalities in a group of 96

infants born before 30 weeks gestation. Each infant was examined longitudinally from 30

weeks postmenstrual age (PMA) till corrected term age. The reliability of this new method

was tested and its agreement with the results of repeated cranial ultrasound during the same

period and with those of conventional neonatal neurological examination at corrected term

age were validated. The infants were also enrolled in a randomized, double-blind, placebo

controlled trial on the early effects of diet and thyroxine supplementation on neurological

development.

6.3 Subjects and methods

6.3.1 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 (23).

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 and

admitted to the Intensive Care Unit of the Academical Medical Center, were entered into

General body movements in preterm infants 109

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 (24). 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 too small a number of

infants in the "only" formula feeding group" for reliable statistics. Therefore we further

analysed 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 and macronutrient composition of the standard and preterm formula used and of

our weekly collected maternal milk samples are described in detail and discussed in Maas et

al. submitted and Maas, et al, BJN (24,25).

For each infant entering the study a numbered 'blind' set of ampoules, containing 25 /xg/ml

T4 or placebo, was prepared. Thyroxine supplementation once a day was started 12-24

hours after birth, in a dose of 8 ng per kilogram birth weight. This dose was chosen on the

basis of results of a pilot study (26) 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.

110 Chapter 6

Gestational age was determined by the first day of the last menstrual period of the mother.

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 (27).

Data concerning patient characteristics and clinical outcome within 24 hour after birth are

shown in table 6.1. Neonatal clinical data were collected until discharge (table 6.2).

Table 6.1 Clinical characteristics of the infants within 24h after birth

Thyroxine Placebo STF PTF STF PTF

(n= 26) (n=22) (n=28) (n=20

gestation (days), mean ± SD 194 ± 9 198 ± 8 196 + 9 195 + 9

birth weight (g), mean + SD 1108 ± 247 1038 ± 213 1044 ± 189 1077 ± 274

sex, male/female 11/15 15/7 11/17 8/12

Multiplets n 6 13 14 8

Birth weight < 10th centile n 1 4 3 2

antenatal glucocorticoids n 18 17 15 17

Caesarian section n 2 6 6 2

APGAR score at 5', mean + 8.5 ± 1.5 8.0 ± 1.7 8.0 ± 1.7 8.6 ± 2.2

SD

intubation at birth n 5 9 13 4

respiratory distress syndrome n 12 13 13 12

surfactant rescue therapy n 8 9 7 6

intrauterine infection n 2 2 1 2

cerebral haemorrhage (day 1) n 7 4 6 3

General body movements in preterm infants 111

Table 6.2 Clinical data until discharge

Thyroxine Placebo

STF PTF STF PTF

(n = 26) (n = 22) (n = 28) (n = 20)

Deaths n 0 1 1 0

Oxygen suppl. at 36 w n 4 3 3 6

Patent Ductus Arteriosus n 8 1 10 7

Necrotising Enterocolitis n 1 0 1 0

Septicaemia n 7 4 8 5

Days of intubation, mean ± SD 4 ± 4 5 ± 5 5 ± 7 6 ± 7

Days of 02 therapy, mean ± 27 ± 28 30 ± 33 32 ± 46 33 ± 33

SD

PMA at discharge home (days), 269 ± 16 279 ± 21 275 ± 17 276 ± 20

mean + SD

Cerebral ultrasound findings

Normal n (%) 12(46%) 9(41%) 13 (46%) 8 (40%)

Moderately abnormal n (%) 11 (42%) 9(41%) 15 (54%) 7(35%)

Severely abnormal n (%) 3 (12%) 4(18%) 0(0%) 5(25%)

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 (28). Haemorrhagic venous infarction followed by cysts were classified as

parenchymal haemorrhages. Ischaemic lesions were classified according to De Vries et al.

(29). Classification of ventriculomegaly was performed according to Levene (30).

6.3.2 Overall cerebral ultrasound

An overall cranial ultrasound classification was made judged on the basis of all repeated

ultrasound scans made of each infant in our unit. For better comparison with GM quality

112 Chapter 6

and the Prechtl neonatal neurological test, ultrasound data were also divided into three

groups, namely normal, suspect and abnormal. Classification was made as follows:

Normal: no haemorrhage and no ischaemia and no ventricular dilatation; Moderately

abnormal: a grade 1 or 2 haemorrhage and/or a grade 1 ischaemia and or a grade 1

ventricular dilatation; Severely abnormal: a grade 3 or 4 haemorrhage and/or a grade 2 or 3

ischaemia and/or a grade 2 ventricular dilatation.

6.3.3 Neurologic examination at term

At term age neurodevelopment was assessed using the method described by Prechtl (31).

This test was scored as normal, suspect or abnormal, using the classification as described

by Jurgens-van der Zee et al. (32).

6.3.4 Spontaneous General Movements

Observation and recording procedure

Two-hour video recordings were made of each infant. The recordings were started as soon

as the clinical condition of the infant was stabilized, usually at 1 - 2 weeks after birth and

continued every 2 weeks thereafter. The infants were studied until they left our neonatal

unit (discharged home or transferred to another hospital) or reached the expected date of

delivery (term age) in our unit. When infants left the hospital before 38 weeks of post-

menstrual age an additional video recording was made at term age (38 - 42 weeks' PMA).

All recordings were made in the hospital between noon and 6 p.m.. The infants were

recorded in the incubator or under a radiant warmer. All infants were undressed before the

start of each recording, wearing only a diaper, in the supine or semi-lateral position and

allowed some time to adjust. The video camera was positioned laterally, at an angle of 45°

degrees above the infant.

Assessment of the quality of general movements (GMs)

Video tapes were replayed and three representative general movements were selected from

each recording (total of about 10 minutes), excluding crying, fussing and sucking periods.

For each infant a collection of these selected GMs at different ages was then assembled and

stored on a separate tape, documenting the developmental trajectory of the GMs from birth

General body movements in preterm infants 113

to term age. The quality of the GM was assessed independently from these tapes by 2

observers (YGHM, MHA), both unaware of treatment and clinical and neurological

outcome of the infants.

The GMs were analysed according to Hadders et al. (1997) (8), a detailed method based on

the principles of Prechtl to assess the quality of GMs (4). This resulted in a classification of

normal, mildly abnormal or definitely abnormal GMs. Normal GMs consist of variable

movements of arms, legs, head and trunk. They wax and wane in intensity, speed and their

onset and offset are gradual. These movements are complex with many superimposed

rotations and with many changes in direction. This complexity and variability make the

movements fluent and elegant. Mildly abnormal GMs lack this fluency but are still

complex. Definitively abnormal GMs lack both fluency and complexity. Besides the global

assessment of GM quality, the Ferrari Optimality score was applied (5), judging 8 different

elements of movement this score distinguishes, such as movement character, sequence and

fluency. Inter-observer agreement was 100% for both scoring methods, based on the

independent assessment of GM quality of 24 recordings.

We have collected a total of 334 video recordings of 96 infants. The recordings were

divided per 2 weeks PMA and were divided over the four treatment groups (see table 6.3

and below).

Table 6.3 Number of observations made of the infants studied in the four different

treatment groups

Thyroxine Placebo

postmenstrual age ALL STF PTF STF PTF

(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 83 25 17 24 17

114 Chapter 6

6.3.5 Statistical analysis

To evaluate the effect of age, early diet and thyroxine administration on the development of

the quality of GM unbalanced repeated measurements analysis of covariance with structured

covariance matrices was performed on the optimality score of Ferrari (5) using program 5V

of the statistical package BMDP 7.0 (33). This technique allows for missing values which

are estimated implicitly from the available data. The model contained the main effects of

Thyroxine (yes/no), supplemented Formula (standard/preterm) and the within-infant grou­

ping 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 at birth) 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.

To test the assumptions of the model and to check on outliers, analysis of residuals was per­

formed from the unbalanced repeated measurements analysis. To adjust for the missing

values in the data all figures presented here are based on the estimated values of the

regression parameters resulting from the unbalanced repeated measurements analysis of

covariance. Additional analysis to find whether there was a relation between overall

preterm cerebral ultrasound findings and the developmental course of GM quality was

performed using ANOVA. Analysis of the agreement of global GM quality assessment at

corrected term age for neonatal neurological outcome examined at the same age was done

using the Pearson X2 test for 3x3 tables (BMDP program 4F (33)).

6.4 Results

In this study first a global assessment of GM quality was done, followed by a more detailed

analysis using the Ferrari optimality score. The findings of both scoring methods were

General body movements in preterm infants 115

highly correlated (p< 0.0001; Pearson X2). On statistical grounds the optimality score can

be expected to provide the higher power. Therefore only the results of the analysis of

optimality score data are described here. Abnormal GM (n= 148) corresponded with

scoring an optimality score of 8, mildly abnormal GM (n=168) corresponded with a score

of 10-11, while normal GM (n=13) had a score of 12-16.

Table 6.4 Estimated optimality score (+ SE) of Ferrari et al. (1990), of all infants studied, and of the Thyroxine and Placebo treatment groups per postmenstrual age group

postmenstrual All Thyroxine Placebo age n (n = 96) n (n=48) n (n=48)

30-31 83 9.5 ± 0.2 44 9.5 + 0.2 39 9.4 ± 0.2

32-33 79 9.5 ± 0.2 42 9.0 ± 0.2 37 9.8 ± 0.2

34-35 55 9.4 ± 0.2 26 9.5 + 0.2 29 9.4 ± 0.2

36-37 29 9.1 ± 0.3 12 9.4 ± 0.3 17 9.0 + 0.3

38-42 83 9.3 ± 0.2 42 9.3 ± 0.2 41 9.1 ± 0.2

The optimality score did not change between 30 weeks PMA and term age (table 6.4). We

found a difference in developmental trajectory for the infants receiving Thyroxine versus

Placebo (p = 0.0089), the main difference being found at 32-33 weeks PMA. When we

removed the T4xtime interaction from the analysis, no effects were found for diet

(p=0.45), thyroxine (p = 0.73) or time (p=0.070). Of the covariables we corrected for in

our analysis, gender and weight percentiles at birth showed evidence of an effect on GM

quality. The relation of gender and weightpercentiles at birth with the development

trajectory of the quality of GM are presented in figure 6.1 and 6.2. Except for 36-37 weeks

PMA, girls (n=51 (53%)) had a consistently higher optimality of GMs than boys (n=45

(47%)) (p = 0.0093). Infants who were growth retarded under the 10th weightpercentile

(SGA) (n= 10) had a different developmental trajectory from infants born with an

appropriate weight for their age (AGA) (n=86 (90%)) (p< 0.0001) with an initially poorer

GM quality but a clear improvement in time.

No relation was found between cerebral haemorrhage on postpartum day 1 and the

development of GM quality (p=0.45), nor could we find any significant relation between

116 Chapter 6

the overall cerebral ultrasound findings (based on all measurements done in our unit before

discharge) and development of GM quality (p=0.47) with low sensitivity and specificity of

50 and 51% respectively. No relation was found between global GM quality at corrected

term age and the outcome of the neonatal neurological examination (p=0.51) (table 6.5).

The low sensitivity and specificity were 60 and 52% respectively, while on the other hand

overall cranial ultrasound and neonatal neurological test were highly correlated(p = 0.0049).

Table 6.5 Results of GM quality assessment at corrected term age in 83 infants, per group of infants with a normal, suspect and abnormal overall cerebral ultrasound diagnoses, and per group of infants with a normal, suspect and abnormal outcome of the Prechtl neonatal neurological examination

Global GM quality score at corrected term age

normal suspect abnormal

normal (n=36)

(n=3) (n=39) (n = 41)

Overall normal (n=36) 1 (3%) 18 (50%) 17 (47%)

Cerebral suspect (n=37) 1 (3%) 17 (46%) 19(51%) Ultrasounds

abnormal (n=10) 1 (10%) 4 (40%) 5 (50%)

Prechtl normal (n = 54) 2 (4%) 25 (46%) 27 (50%)

score suspect (n=19) 0 (0%) 11 (58%) 8 (42%)

abnormal (n=10) 1 (10%) 3 (30%) 6(60%)

Legend to figures

Figure 6.1 Quality of General Movements (mean + SE) for girls (-Ö-) and boys (•••••) for

PMA week 30 to term age.

Figure 6.2 Quality of General Movements (mean ± SE) for infants with a birth weight <

plO (-O-) and infants with a birth weight > plO (•••••) for PMA week 30 to term age.

General body movements in preterm infants

Figure 6.1

117

28 30 32 34 36 36 postmenstrual age (weeks)

Figure 6.2

postmenstrual age (weeks)

118 Chapter 6

6.5 Discussion

The method of scoring quality of general movements (GMs) in the neonatal intensive care

unit which could even be carried out by video taping of infants inside the incubators, is

very practical and reliable. Our longitudinal study from 30 weeks till corrected term age of

96 very preterm infants ( < 30 w GA) indicates that scoring quality of GM is very stable

over time (table 6.4). The lack of change in quality of GM during early neonatal period

suggests that a single observation before term age is sufficient to assess the quality of GM

of an infant in the NICU. Apart from being very consistent, GM quality was rarely

(considered to be) normal before term age (4%). These results are in accordance with the

finding of others (7,8,10,34-37). Many preterm GM abnormalities may normalize by 2-4

months of age. The low gestational age (< 30 weeks) and the low percentage (< 10%) of

abnormal infants in our randomly selected population of very preterm infants based on the

2 years' neurological examination may explain why scoring GM quality appeared not to be

such a sensitive method to detect the abnormal infants in our group.

We were the first researchers using GM quality assessment to try to evaluate the effect of

diet and thyroxine treatment. But neither early diet nor thyroxine suppletion significantly

influenced the quality of GM. As this result is in accordance with other data of our group in

which neither neurological nor clinical outcomes of these children showed any significant

effect of thyroxine, diet or combination (23,38,39), it is difficult to judge assessment of

GM quality to be a sensitive method to distinguish between treatments before term age.

The slightly higher GM quality found in girls compared with boys in this study was

interesting. This is in accordance with sex differences in other neurological examinations of

preterm and term infants (40,41,42). At 36-37 weeks PMA boys had a higher GM quality

than girls. At this age however we observed only 29 infants, as most infants had been either

discharged home or transferred to other hospitals. Since infants that are very ill stay longest

in our neonatal department, the group studied at 36-37 weeks PMA is not representative of

the whole study population. Although our method of statistical analysis tries to adjust for

this phenomenon, there is no guarantee that this has been completely successful, especially

with such a high dropout.

Small for gestational age infants showed more variable GM quality over time compared

with appropriate for gestational age infants (15,17,35). Disregarding the outcome at 36-37

General body movements in preterm infants 119

weeks (see above) the SGA infants show an improvement of their GM quality from 30 to

40 weeks PMA. This result supports the findings of Amiel-Tison et al., reporting

accelerated neurological development in growth-retarded infants (43), but is in contrast with

the findings of Bos et al. (44). The number of SGA infants in our infant population was

very small (n= 10). A larger study of SGA infants is needed to follow on the significance of

this finding for detecting the neurological development of SGA babies. These infants are

neurodevelopmentally compromised and our finding of initially low GM quality is in

support of this notion.

One of the objectives of this study was to examine whether the developmental trajectory of

GM quality reflects differences between normal and abnormal infants based on repeated

cranial ultrasound in the NICU and neonatal neurological examination at corrected term

age. As is shown in table 6.5 no significant relationship was found between the quality of

GM and either cranial ultrasound or neurological examination. In contrast a significant

relation was present between the cranial ultrasound and neurological test in our infant

population. This finding can be at least partially attributed to the low gestational age of our

infants and the low percentage of infants (4%) scoring normal GM quality in contrast with

the percentages scoring normal for overall cerebral ultrasound (43%) and the Prechtl

neurological examination at term (65%). In conclusion, although the assessment of the

quality of GM is an easy and reliable method to perform in the NICU in very preterm

infants, we found its agreement during the prematurity period (i.e. before corrected term

age) with neurological outcome to be very poor.

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 Y.G.H. Maas to the exciting world of spontaneous movements in

young infants. Also the contribution of Dr. M. Hadders-Algra - analysis of all selections of

GMs on videotape - calls for special mention.

120 Chapter 6

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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124 Chapter 6