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Early neurological delopment, growth and nutrition in very preterm infants

Maas, Y.G.H.

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Citation for published version (APA):Maas, Y. G. H. (1999). Early neurological delopment, growth and nutrition in very preterm infants.

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Download date: 18 Aug 2019

CHAPTER 4

Physical development in very preterm infants: influence of early diet and thyroxine supplementation

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

4.1 Abstract

4.2 Introduction

4.3 Subjects and methods

4.3.1 Subjects

4.3.2 Diet

4.3.3 Administration of T4/placebo

4.3.4 Clinical data

4.3.5 Anthropometry

4.3.6 Statistical analysis

4.4 Results

4.4.1 Diet

4.4.2 Anthropometry

4.4.3 Statistical analysis

4.5 Discussion

4.6 Conclusions

4.7 References

Submitted

60 Chapter 4

61

Physical development in very preterm infants:

influence of early diet and thyroxine supplementation Yolanda G.H. Maas1, Jeanet Gerritsen1, Augustinus A.M. Hart2, Majid Mirmiran3, 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

4.1 Abstract

Background Few studies have systematically measured growth rate of very preterm infants

and studied the effects of diet and/or thyroxine. There are indications that these infants

benefit from special dietary regimens. Thyroxine might enhance this effect by promoting

the maturation of the gastrointestinal tract.

Methods We studied early postnatal growth in 109 very preterm infants (<30 weeks'

gestational age) by extensive anthropometry. Body weight, crown-heel and crown-rump

length, occipito-frontal head circumference, upper arm length, mid-upper arm

circumference and para-umbilical, subscapular, biceps and triceps skinfold thickness were

measured weekly during the first 7 postnatal weeks.

The infants were randomly allocated to start enteral feeding with maternal milk

supplemented with standard formula (STF) or preterm formula (PTF) to ensure a full

enteral intake of 125 kcal/kg/day. Each infant received a fixed dose of 8 /xg/kg/day of

thyroxine or placebo during the first six postnatal weeks. Statistical analysis was performed

using an unbalanced repeated measurement analysis of covariance with structured

covariance matrices for postnatal weeks 1 to 7.

Results When given as a supplement to maternal milk, PTF resulted in an increased overall

growth compared to STF. When thyroxine was added to PTF supplementation an additional

increase in growth, specifically for head circumference, subscapular and triceps skinfold

thickness (p<0.05), was found.

£2 Chapter 4

Conclusions Our data indicate that preterm physical growth in the first 7 weeks after birth

is not comparable to expected intra-uterine growth and that preterm formula is preferable to

standard formula as a supplement to maternal milk. Moreover administration of thyroxine

added to the preterm formula during the first weeks of life further increases the rate of

physical growth in very premature infants.

4.2 Introduction

Only few longitudinal studies have been performed on preterm growth and from these we

know that preterm infants do not show the same growth rates as they do intra-uterine (1,2).

As preterm delivery interrupts the intra-uterine growth processes it is difficult to state what

optimal growth is for these infants. Growth retardation relative to the intra-uterine growth

standards is commonly believed to indicate poorer overall outcome. Taking these intra­

uterine growth rates as reference, preterm infants and specifically the very preterm ones

require special nutritional care (3-10). Earlier studies have indicated that preterm infants

may indeed benefit from special dietary regimens, including formula feedings especially

made to meet their increased needs for specific nutrients (11-17).

We have initiated a large longitudinal study on physical and neurological development in

preterm infants born before 30 weeks gestational age. In this paper we studied the influence

of two randomly assigned dietary regimens (standard formula (STF) or preterm formula

(PTF) as a supplement to maternal milk) on growth. These infants were also enrolled in a

placebo controlled (double-blind), randomized trial on thyroxine supplementation, enabling

us to examine the effects of early feeding regimen and thyroxine supplementation on early

preterm growth.

4.3 Subjects and methods

4.3.1 Subjects

This study is based on 160 infants, born in 1991 and 1992, who participated in a

randomized, double-blind, placebo controlled trial of T4 administration (18). 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

Preterm growth, early diet and thyroxine 63

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 endocrinol­

ogical disease or was an illicit drug user. Of the 216 infants considered for inclusion,

nineteen infants died within 24 hours after birth, 8 were not included based on our

exclusion criteria, the parents of 16 infants refused informed consent and the parents of 13

infants were not asked informed consent for reasons like e.g. a language barrier.

Assignment to thyroxine or placebo took place within the first 24 hours following birth,

additional assignment to an early diet within 72 hours postpartum. T4 randomization was

performed in blocks of 10 infants and diet randomization was done within the T4

randomization scheme in 4 blocks of 40 infants. An additional 11 infants died within 72

hours after birth leaving us with 149 infants to study. Extensive data were collected on

obstetric, fetal and neonatal variables.

Since it was not considered acceptable to influence a mother's choice as to whether or not

she wished to provide her own milk for her infant(s), all mothers were asked what they

preferred before diet randomization. Patients were stratified according to this preference

after randomization to thyroxine or placebo. If the mother decided not to express breast

milk, her infant was randomly allocated to start enteral feeding with either a 'standard'

formula or a 'preterm' formula (PTF), as sole diet. If she decided to feed her baby her own

milk, the infant was randomly allocated to start enteral feeding with the standard formula

(STF) or the preterm formula (PTF) as a supplement to maternal milk. Of the 149 infants

enrolled into this study, 120 entered into the "maternal milk 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. Since the number of infants available for anthropometry decreased

progressively in time (due to the transfer to other hospitals) we used the measurements

made before the eighth postnatal week in our statistical analysis. Out of the 120 infants 11

were not measured in the first 7 postnatal weeks because they died or because of the

g4 Chapter 4

severity of their illness. This resulted in a total of 109 infants, 53 in the thyroxine and 56 in

the placebo group. Fifty six infants were given standard formula and 53 preterm formula,

resulting in four groups (27 in the thyroxine/STF, 26 in the thyroxine/PTF, 29 in the

placebo/STF, 27 in the placebo/PTF group).

4.3.2 Diet

All 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. Sick infants were fed intravenously and

enteral feeding was started and gradually increased as tolerated, only after extubation. It

was assumed that 100 ml of human milk contained the same amount of energy as the

'standard' formula (STF), i.e. 66 kcal, whereas the 'preterm' formula (PTF) contained 80

kcal per 100ml. The macronutrient composition of standard and preterm formula is shown

in table 2.1 (for a more detailed description see manufacturer's data). We collected weekly

samples of maternal milk for analysis. With these data we were able to calculate energy

intake from maternal milk (19).

Till the start of this study our feeding regimen was to initiate acceptance of enteral feeding

with standard formula, based on our experience of an increased incidence of necrotizing

enterocolitis with the introduction of preterm formula. STF was replaced by PTF about one

week after accepting full enteral feeding (125 ± 15 kcal/kg/day). In this study we

compared this usual feeding regimen with one in which new preterm formula was used to

initiate acceptance of enteral feeding.

4.3.3 Administration of T4/placebo

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

T4 or placebo, was prepared. Thyroxine supplementation was started 12-24 hours after

birth in a daily, fixed dose of 8 ^g per kilogram birth weight. This dose was chosen on the

basis of results of a pilot study (20). Trial medication was given by an intravenous injection

as long as intravenous nutrition was given (mean period of 14 days) and enterally

thereafter. The treatment period lasted 6 weeks.

Preterm growth, early diet and thyroxine 65

4.3.4 Clinical data

Gestational age was determined by a reliable menstrual history. When maternal information

was inconclusive, an early ultrasound examination and/or the Dubowitz score (21) was

used. Data concerning clinical outcome within 24 hour after birth are shown in table 4.1.

Neonatal clinical data were collected until discharge (table 4.2). The clinical data include:

mortality, the incidence of respiratory distress syndrome, the need for supplemental oxygen

at 36 weeks postmenstrual age, the incidence of patent ductus arteriosus, the incidence of

necrotizing enterocolitis, the number of proven septicaemias and the incidence of cerebral

haemorrhage, ischaemic lesions, and ventriculomegaly.

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

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

(23). Classification of ventriculomegaly was performed according to Levene (24).

Assessment of overall cerebral ultrasound findings was done on all assessments made of the

infant during the entire stay in our neonatal unit and were classified 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.

4.3.5 Anthropometry

The anthropometric measurements constituted of body weight, crown-heel and crown-rump

length, occipito-frontal head circumference, upper arm length, mid-upper arm

circumference and para-umbilical, subscapular, biceps and triceps skinfold thickness

measured in postnatal weeks 1 to 7 and at corrected term age. Body weight was determined

to 5g accuracy using an electronic digital scale (TEC Digital Scale, Tokyo Electric Co.,

LTD, Japan). Occipito-frontal head circumference and mid-upper arm circumference were

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68 Chapter 4

measured with a flexible, fibreglass tape, upper arm length by a slide-rule and crown-heel

and crown-rump length by use of a specially made measuring board with a fixed headboard

and a movable footboard. All these parameters were measured to the next succeeding

millimetre. All four skinfolds were measured with a skinfold calliper (Harpenden Calliper,

British Indicators Limited). All measurements, except for weight, were carried out weekly

in triplicate, usually by the first author (YGHM), blinded to the experimental condition of

the infants. Weight was determined daily by a member of the nursing staff. In 61 out of a

total of 671 measurement sessions in the first 7 postnatal weeks the measurements were

carried out by an assisting researcher after a 'run in' period to minimize interindividual

variation in measurements. Analysis of intra- and interindividual variation showed that for

occipito-frontal head circumference, mid-upper arm circumference, upper arm length,

crown-heel and crown-rump length all measurements could be used in our analysis,

contrary to the four skinfold thicknesses of which only the measurements of the first author

could be used due to the large interindividual variation.

4.3.6 Statistical analysis

To evaluate the effect of early diet and thyroxine administration on postnatal growth in our

very premature infants population, unbalanced repeated measurements analysis of covar-

iance with structured covariance matrices was performed using the statistical program

BMDP 5V (25). This analysis allows for missing values which are estimated implicitly

from the available data. Analysis was performed on relative changes of each growth

parameter by using the logarithmic transformation. The model contained the main effects of

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

grouping factor postnatal age (PNA) as well as all possible interactions between these 3

factors. In addition covariables (gestational age, sex, ln(birth weight), multiplets, APGAR

score at 5 minutes, surfactant therapy, intrauterine infection, weight < plO, cerebral

ultrasound findings) were included as well as their interactions with time (postnatal age in

weeks). 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

Preterm growth, early diet and thyroxine 69

of Thyroxine (yes/no), supplemented Formula (standard/preterm) and PNA or 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.

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

formed with the estimated values of the regression parameters resulting from the

unbalanced repeated measurements analysis. When indicated outliers were ommitted from

the analysis this led to the same conclusions. 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. Analysis of

covariance was performed on term follow-up data using the statistical program 2V of the

statistical package BMDP 7.0 (25).

P-values are generally unadjusted for multiple comparisons. However, in order to take into

account that we tested 10 morphometric measurements, Bonferroni's correction was

additionally applied as indicated in the text and tables.

4.4 Results

4.4.1 Diet

The intake of the trial diet depended on the mother's success in providing her milk and

maternal milk intake could vary from 0 to 100% on a daily basis. The average percentage

of energy intake from maternal milk per kg body weight, measured for the first 7 postnatal

weeks, was 39% ± 28% (median: 38%; lower and upper quartiles: 12%, 65%) (table 4.3),

with no differences between the four different treatment groups (Kruskall-Wallis p-value =

0.53). Neither did we find a difference in energy intake from parenteral (24% + 20%;

median: 17%;lower and upper quartiles: 12%, 30%) and total enteral nutrition (i.e.

maternal milk plus formula feeding) (76% ± 20%; median: 83%;lower and upper

quartiles: 70%, 88%) between the four groups (Kruskall-Wallis p-value = 0.66).

Replacement of STF by PTF in the infants assigned to STF, never took place before the

18th day after birth. The STF randomization group received 19% ± 16% of its total energy

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Preterm growth, early diet and thyroxine 71

intake from STF and 13% ± 16% from PTF in the first 7 postnatal weeks, while the PTF

randomization group received 1 % + 4% from STF and 39% ±28% from PTF.

4.4.2 Anthropometry

For all ten anthropometric parameters measured estimated values (mean ± SE) are

presented for postnatal weeks 1 to 7 in two graphs, one for the thyroxine treated (right) and

one for the placebo treated (left) feeding groups (figure 4.1). An increase is seen for all

parameters in the first 7 postnatal weeks. In the placebo group we generally do not see a

different growth pattern for the PTF supplemented group compared to the STF

supplemented group, whereas in the thyroxine group a difference between the two feeding

groups is clear. This difference seems to develop mainly between postnatal weeks 1 and 2

leading to a lasting difference till at least the seventh postnatal week. However in both

placebo and thyroxine group we do see that the PTF supplementation curve is always above

the STF supplementation curve. The growth pattern of the T4/STF group (fig. 4. IB 1-10)

seems comparable to the growth pattern of both placebo groups (fig 4.1 A 1-10) for all

measurements, except for a (larger) reduction of mid-upper arm circumference (fig 4. IB 6)

and skinfolds (fig 4. IB 7-10) in the first postpartum weeks, causing a delay in regaining

their sizes at birth in comparison with the placebo groups.

Legend to figure

Figure 4.1 Changes of body weight (1), crown-heel (2) and crown-rump (3) length, occipito-frontal head circumference (4), upper arm length (5), mid-upper arm circumference (6), para-umbilical (7), subscapular (8), triceps (9) and biceps (10) skinfold thickness measurements on the logarithmic scale per randomization group (mean ± SE) for postnatal weeks 1 to 7. A) STF supplemented (•) and PTF supplemented (D) growth curves for the placebo group, B) STF supplemented (•) and PTF supplemented (D) growth curves for the thyroxine group.

72 Chapter 4

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Preterm growth, early diet and thyroxine

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74 Chapter 4

4.4.3 Statistical analysis

The results of the statistical analysis support our interpretation of figure 4.1 as described

above (table 4.4). Statistical differences between growth curves of the two feeding formulas

were found for weight, crown-heel length, and mid-upper arm in the total group. O-F head

circumference, subscapular and triceps skinfolds seem to have different growth curves for

the four treatment groups; T4 and the type of early feeding seem to modify each other's

effect on these growth parameters. Therefore a stratified analysis of both Thyroxine

supplementation (yes/no) and early feeding regimen (standard or preterm formula) was

performed for these growth parameters. From this analysis we found evidence of an effect

of early diet on subscapular (interaction Diet x time: p=0.0010) and triceps (interaction

Diet x time: p = 0.0002) skinfold development in the thyroxine group. Differences between

the growth curves of the Thyroxine and Placebo groups were found regarding O-F head

circumference (interaction T4 x time: p=0.0036) and triceps skinfolds (T4: p=0.0089)),

but only in the PTF group. Regarding the latter parameter, the Thyroxine group is

consistently higher than the Placebo group over the whole period. A quantitative

description of the differences found is given in table 4.5. So our statistical analysis

confirmed the differences in growth pattern in the first 7 postnatal weeks for the two

supplementary formula feedings, especially within the thyroxine group, as described above.

Moreover, a difference in growth for the T4 supplementation group with respect to the

placebo group within the PTF supplementary group was found, which is in agreement with

the interpretation (see above) that the T4/STF and both placebo groups have comparable

growth patterns, while the T4/PTF group is showing increased growth.

For all ten anthropometric parameters backtransformed estimated values (95 % CI) from our

measurements in the first postnatal week and at corrected term age are presented in table

4.6. From the analysis of covariance at corrected term age we did not find a significant

difference in any of the 10 growth parameters between the four treatment groups (p<0.05

after Bonferroni correction).

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4.5 Discussion

The aim of this paper was to study postnatal growth and the influence of two different

feeding regimes in very preterm infants. As these infants were also enrolled in a placebo

controlled (double-blind), randomized trial on thyroxine supplementation we also examined

the effect of thyroxine supplementation on early preterm growth.

We found that preterm formula (PTF) supplementation combined with the administration of

T4 gives a significant enhancement of growth compared with PTF supplementation without

T4 and standard formula (STF) supplementation with or without T4, especially for the

subscapular and triceps skinfolds and head circumference. Moreover we found that PTF

supplementation results in an increased overall growth as expressed by weight, length and

mid-upper arm circumference compared to STF supplementation. The latter finding is in

accordance with Lucas et al. (15). The proportion of maternal milk, while constituting

about 40% of the diet in our preterm infants (table 4.3), could have an influence on the

effects we found (12,14,26-28). We calculated daily intake and found that for all four

treatment groups maternal milk and formula feeding intake was comparable in the first 49

days after birth. Our feeding regimen was based on feeding isocalorically. When doing so

preterm formula supplied 0.5 g/100 ml more protein than standard formula and

carbohydrate in standard formula consisted almost exclusively of lactose while for 50 % in

preterm formula. For fat the most striking difference is that preterm formula contains twice

as much medium chain glycerides (MCT's) with a comparable quantity of long chain

glycerides (LCT's). This can possibly contribute to the different growth patterns we see for

the two feeding regimens.

It is known from animal studies that thyroid hormones have an important role in fetal

growth and development (29-32). We also know that transient hypothyroxinemia after birth

is common in preterm infants (33,34,35,36). This could indicate that fat resorption in PTF

and T4 supplemented infants is restored faster, explaining the absence of a delay in

regaining sizes after birth as found in the other groups. Data from Jacobsen et al. (37)

already suggested that T4 may promote growth in premature and small-for-gestational-age

infants, which is in accordance with our data. One explanation for the mechanism of action

of T4 could be that it promotes maturation of the digestive tract resulting in a better

resorption of nutrients and that PTF has a more utilizable composition for the preterm

Preterm growth, early diet and thyroxine 79

intestine than STF (see table 2.1 and 38-41). Although both PTF and T4 appear to enhance

the effect on growth they also have independent effects.

In spite of the early postnatal differences found in our longitudinal analysis, none of these

were still found at corrected term age. However, such differences, when existing, are more

difficult to trace in a cross-sectional analysis as used for term age measurements than in a

longitudinal analysis. Therefore finding no differences in growth at term age does not mean

that infants do not benefit from special dietary regimens. Moreover, preventing huge losses

in weight and other body sizes and/or preventing a delay in regaining sizes at birth in the

first postnatal weeks can be very beneficial to the overall outcome of these infants.

Assuming that rapid growth is preferable in the early postnatal phase, our study indicates

that PTF supplementation is to be preferred to STF supplementation to start enteral feeding

of very preterm infants. Our results also suggest that supplementation of T4 in combination

with PTF results in better growth in very preterm infants. However caution is required

when T4 treatment is considered for clinical practice, because of the (possibly negative)

effects of the hormones on other than gastrointestinal functions of the infant (42).

4.6 Conclusions

Early postnatal growth is increased in very preterm babies when preterm formula (PTF) is

given as a supplement to maternal milk in stead of standard formula (STF). Moreover

administration of thyroxine in addition to PTF supplementation during the first weeks of

life further increases the rate of physical growth in very premature infants, reversing the

decrease in growth of especially skinfold thickness and the delay seen in regaining sizes at

birth in the first postnatal weeks.

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; to

D.A. van Tijn, M.D., and B. Wiedijk for guiding the combined T4 and formula feeding

supplement randomization, and to Dr. F.H.C. de Jongh for critically reading this

80 Chapter 4

manuscript.

Y.G.H. Maas and J. Gerritsen were 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.

4.7 References

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8 2 Chapter 4

26. Oberkotter LV, Pereira GR, Paul MH, Ling H, Sasanow S, Farber M. Effect of

breast-feeding vs formula-feeding on circulating thyroxine levels in premature infants.

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27. Hahn HB, Spiekerman M, Otto R, Hossalla DE. Thyroid function tests in neonates

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31. Timiras PS, Nzekwe EU. Thyroid hormones and nervous system development. Biol

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32. Lerman R, Koldovsky O. Growth and food intake of prematurely weaned rats: Effect

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33. Harkavy KL, Enecio CE. Free thyroxine levels in hospitalized newborns: depressed

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premature and sick neonates. Pediatr Clin North Am 1990;37:1297-1312.

35. Mercado M, Yu VYH, Francis I, Szymonwicz W, Gold H. Thyroid function in very

preterm infants. Early Hum Dev 1988;16:131-141.

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37. Jacobsen BB, Andersen HJ, Peitersen B, Dige-Petersen H, Hummer L. Serum levels

of thyrotropin, thyroxine and triiodothyronine in fullterm, small-for-gestational age

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38. Ehrenkranz RA, Ackerman BA, Nelli CM. Total lipid content and fatty acid

composition of preterm human milk. J Pediatr Gastroenterol Nutr 1984;3:755-758.

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Preterm growth, early diet and thyroxine 83

composition of breast milk from mothers of term and preterm infants. Am J Clin Nutr

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milk during early lactation from mothers giving birth prematurely and at term. Am J

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composition in milk from mothers of premature and full-term infants. Am J Clin Nutr

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84 Chapter 4