Early Humun Development, 13 (1986) 97-105 Elsevier

97

EHD 00725

Controlled trial of new formulae for feeding low birth weight infants

Angela Bell, Henry Halliday, Garth McClure and Mark Reid Department of Child Health, Queen’s University, Belfast, and Royal Maternity

and Jubilee Maternity Hospitals, Beljast, Northern Ireland, U.K.

Accepted for publication 22 September 1985

Summary

Over a 13-month period 85 babies were randomly allocated to one of three groups at birth. Babies in Group A were fed SMA Low Birth Weight, Group B Prematalac and Group C Preaptamil. A fourth group, the control group was fed expressed breast milk (EBM). The babies were studied when they were on full enteral feeds until weight was > 2.0 kg.

Weight gain was greatest in Group B compared to the other three groups but there was no significant difference in gain of length or occipito-frontal cir- cumference. The babies in Group B had a lower volume of feeds and lower energy intake than the other groups but had a significantly higher sodium intake which was reflected in higher mean sodium levels. This may have accounted for the increased weight gain. There was no significant difference in serum calcium, osmolality, total protein or haematocrit.

low birth weight infant fomulae; expressed breast milk; growth; metabolic effects

Within the past 2 years new modified milk formulae have been prepared for the low birth weight infant with a higher protein, mineral and energy content than standard milk formulae. Growth of the preterm infant has been shown to be better with these new formulae when compared to expressed breast milk and standard milk formulae [2]. However, there are few studies comparing growth and biochemical measurements in low birth weight infants fed on different low birth weight formulae.

Address for correspondence: Dr. A. Bell, Jubilee Neonatal Unit. Belfast City Hospital, Belfast, Northern Ireland, U.K.

0378-3782/86/$03.50 0 1986 Elsevier Science Publishers B.V. (Biomedical Division)

Lisburn Road,

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We report a controlled trial of three new formulae compared to expressed breast milk.

Patients and Methods

85 babies were studied over a 13-month period from February 1983 to February 1984 inclusive in the newborn nurseries of Royal Maternity and Jubilee Maternity Hospitals, Belfast. At birth all babies > 1800 g birth weight were randomly allocated to one of three groups, Group A, B or C. All babies were well at the time of study and none had congenital malformations. Two babies were withdrawn from the study following development of severe necrotising enterocolitis. None died.

Babies in Group A were fed SMA Low Birth Weight Formula (Wyeth Laborato- ries, Taplow, Maidenhead, Berks.), in Group B Prematalac (Cow and Gate Limited, Trowbridge, Wiltshire) and Group C Preaptamil (Milupa Limited, Hillingdon, Great Britain). A fourth, Group D, fed expressed breast milk (EBM) was enrolled separately according to the availability of breast milk and mothers’ wishes.

Gestational age of the babies was assessed from the obstetric history and from clinical examination [6]. The babies received standard care [ll] and most had intravenous fluids with parenteral nutrition initially. Intragastric feeds were started as clinically indicated. Well babies were commenced on 60 ml milk/kg per day on day 1 gradually increasing the volume of feeds over 5 days to 150 ml milk/kg per day. Babies on parenteral nutrition were started on smaller volumes of milk which was increased as clinical state allowed. The study period commenced when the babies were established on full enteral feeds of 150 ml/kg per day and intravenous nutrition had cfased. The mean age of entering the study was 12 days. The study ended when each baby reached 2000 g.

Weight, length and occipito-frontal circumference were measured twice a week. Weight was measured on a beam balance to the nearest 5 g; crown heel length and occipito-frontal circumference were measured to the nearest 1 mm using a disposable paper tape measure. All measurements were made in triplicate by the same observer (A.B.). Complications such as vomiting, loose stools and necrotising enterocolitis were noted.

Compositions of the three formulae were taken from standard analyses produced by the three milk companies. Breast milk was analysed for energy content by bomb calorimetry [17] and protein content by the Kjeldahl method. The fat content of EBM was assayed using the creamatocrit method [14]. Mineral content was analysed by an automated technique (Beckman Astra 8 analyser).

Serum urea and electrolytes, calcium and osmolality were measured weekly using a Beckman Astra 8 analyser. Plasma aminograms were performed 2 weeks after starting the study on samples taken 2 h after a feed. 18 amino acids were studied, aspartic acid, threonine, serine/glutamine, glutamic acid, proline, glycine, alanine, valine, cystine, methionine, isoleucine, leucine, tyrosine, phenylalanine, ornithine, lysine, histidine and arginine (LKB 4101 Amino Acid Analyser).

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Amino acid molar ratio was calculated from total branch chain and total aromatic amino acids [8]. Haematocrit was measured by centrifugation of venous blood. When plasma constituents were measured weekly the mean of the measure- ments for each baby was calculated.

Statistical analysis Groups were compared using the x2 test for categorical variables and one way

analysis of variance for continuous variables. Continuous variables which had a skew distribution were log transformed before analysis. In the analysis of variance the three artificially fed groups were compared with the EBM group using the method of contrasts. Comparisons within the three artificially fed groups were made using Duncan’s multiple range test. In a small number of tests where the homogene- ity of variance assumption for the analysis of variance failed, non-parametric tests were used.

Results

Table I shows the typical analysis of the formulae and breast milk. 85 infants were studied, 25 fed on SMA-LBW (Group A), 25 Prematalac (Group B), 25 Preaptamil (Group C) and 10 expressed breast milk (Group D) (Table II). There were no significant differences among the 4 groups with regards to gestational age, birth weight and weight at entry to the study. There was no difference among the groups in sex distribution, birth order or those who were small for gestational age. The intake of milk, growth and biochemical measurements are shown in Table III.

Milk in take There was no significant difference in volumes of milk taken. Energy intake were

greater in Group A compared to Group B and Group C (P < 0.05). Protein intake and sodium intake were greater in Group B compared to Group A (P < 0.01) and

TABLE I

Typical analysis per 100 ml

SMA-LBW Prematalac Preaptamil EBM

Energy (kcal) Fat (g) Protein (g) Carbohydrate (g) Sodium (mg) Calcium (mg) Phosphorus (mg) Osmolality (mosmol/kg)

* Lactose/maltodextrin. ** Davies, 1977 [ll].

80 79 14 70 4.4 5.0 3.6 2.9 2.0 2.4 2.1 1.5 8.6 * 6.6 8.7 1.3 **

32 60 35 29 75 6-l 60 28 40 53 40 12

268 342 350

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TABLE II

Comparison of group characteristics at entry to the study

SMA-LBW (n = 25) Prematalac (n = 25) Preaptamil (n = 25) EBM (n = 10)

Gestation (wk) * 30.8 * 2.5 31.3 k 2.5 31.Ok2.9 30.3 f 2.4 Birth weight(g) * 1503 + 282 1510*306 1471 f 246 1322 + 220 M:F 11:14 14:ll 10:15 5:5 SGA 4 (16%) 3 (12%) 4 (16%) 1 (10%) Weight at entry (g) * 1544 f 201 1580*192 1573 f 193 1459 * 194

* Mean * S.D.

Group C (P < 0.001). Group D had a much lower protein intake than the 3 formulae groups but statistical analysis was not possible due to the difference already shown among the formulae groups.

Growth Weight gain was lowest in Group C compared to Group A and Group B

(P < 0.01). Weight gain was greatest in Group B but the difference from other groups was not statistically significant. The increased weight gain was not associated with increased gain in length or in occipito-frontal circumference.

Biochemistry and haematology Mean sodium concentration was higher in Group B compared to Group A and

Group C (P < 0.01). No cases of hypernatraemia (serum sodium > 150 mmol/l) were recorded. Three babies had hyponatraemia (serum sodium < 130 mmol/l), 2 in Group A and 1 Group C.

Serum urea was lowest in Group A compared to Group B and Group C (P < 0.001) but there were no significant differences among groups in mean serum total protein concentration. Serum osmolality was lower in Group D than the three formulae groups. Mean serum calcium showed no significant difference between groups. Four cases of hypocalcaemia (serum calcium < 1.8 mmol/l) were recorded, 1 in Group B and 3 in Group C.

There was no difference in the mean packed cell volume or the incidence of anaemia.

Plasma amino acid concentrations in the different feeding groups is shown in Table IV. Threonine, proline, tyrosine and methionine were significantly lower in the EBM group compared to the 3 formulae groups (P < 0.05).

Values calculated from plasma amino acids is shown in Table V. Total amino acids, aromatic amino acids and branch chain amino acids were lowest in Group D compared to the 3 infant formulae groups (P < 0.05) but there was no significant difference in amino acid molar ratio.

There was no difference in the incidence of feeding problems between the groups but 6 cases of necrotising enterocolitis occurred during the study, 2 in Group A, 3 in Group B and 1 in Group C. None occurred in Group D.

TAB

LE

III

Milk

intake, grow

th and biochem

istry by

study group

(A)

(B)

SMA

-LBW

(n = 25)

Prematalac

(n = 25) (C

) Preaptam

il (n = 25)

(D)

EB

M(n

=lO)

Significance (P)

AvB

vC

(A, B

, C)yD

Volum

e

(ml/kg

per day) E

nergy (kcal/kg

per day) Protein

(g/kg per day)

Sodium

(mg/kg

per day) W

eight gain

(g/day) (g/kg

per day) Length

gain cm

/wk

OFC

gain

(cm/w

k) Sodium

(mm

oI/I) U

rea (m

moI/l)

Total protein

(g/I) O

smolality

(mosm

oI/kg) C

alcium

(mm

oI/I)

172 520

138 +16

3.4 +

0.4

55 +6

32.5 *

8.4 35.4

k 6.9

18.0 +

4.1 19.4

* 3.7

1.40~ 0.60

1.38* 0.65

1.15+ 0.31

137.5 +

2.7

1.28* 0.53

42.5 *

4.7

281 +

8

2.32* 0.07

162 k18

128 * 14

3.9 *

0.4

97 *11

1.13+ 0.28

139.1 f

2.1

1.91+ 0.65

42.2 f

4.3

285 f

8

2.3 f

0.13

174 *21

128 k15

3.6 f

0.5

60 *7

28.8 f

7.4 15.9

f 4.1

1.46* 0.51

1.07+ 0.26

136.3 f

2.5

1.88+ 0.59

43.4 f

4.8

281 f

6

2.27+ 0.17

179 k12

127 +21

2.6 f

0.3

51 *5

28.1 *10.3

16.2 f

5.4

1.13+ 0.35

1.09 + 0.23

136.5 *

1.8

1.33* 0.68

42.2 +

3.2

274 *18

2.31_+ 0.06

N.S.

< 0.05

< 0.01

=z 0.001

-= 0.01 -z 0.01

N.S.

N.S.

< 0.01

< 0.001

N.S.

N.S.

N.S.

N.S

N.S.

N.S.

N.S.

N.S.

N.S.

N.S

N.S

N.S.

N.S.

N.S

N.S.

N.S.

Values

are mean + S.D

. N

.S. = not

significant.

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TABLE IV

Plasma amino acids by study group

Ammo acid

(rmol/B (A) (B) (C) (D) Significance (P) SMA-LBW Prematalac Preaptamil EBM AvBvC (n = 25) (n = 25) (n = 25) (n =lO)

(A, B, C)yD

GUY 197 + 53 198 f 32 213 f 51 179 +41 N.S. Pro 218 + 42 271 f 88 252 f 71 197 +26 N.S. Glu 112 + 65 104 f 45 125 + 73 105 557 N.S. Ser/glutamine 580 +147 624 +134 560 +130 496 +73 N.S. Phe 45 f 9 56 + 15 53 * 22 39 * 9 < 0.05

Tyr 104 + 30 165 f 98 131 * 58 79 i20 N.S. Leu 92 f 31 99 + 27 97 f 31 84 k10 N.S. Be 46 * 17 52 f 15 55 f 18 42 + 8 N.S. Met 32 k 9 36 f 10 38 + 9 28 5 4 N.S.

Cys 21 * 7 29 + 8 39 f 11 30 + 7 i 0.05

Arg 56 _t 25 70 + 36 67 + 40 54 *34 N.S. His 74 * 14 91 k 32 78 + 20 72 *16 N.S.

LYS 148 f 40 152 + 71 198 f 74 127 k27 i 0.05 Orn 89 + 30 141 f 81 97 + 35 78 *28 N.S. Val 146 f 75 186 f 52 164 f 48 124 +21 N.S. Ala 286 + 75 311 +101 350 *144 288 *96 N.S. Thr 316 f 76 293 +llO 259 f 79 189 +69 N.S.

Asp 11.4+ 3.0 ll.O+ 2.6 14.8* 9.8 11.7+ 5.7 N.S.

N.S. i 0.05 N.S. N.S. N.S. i 0.05 N.S. N.S. < 0.05 N.S. N.S. N.S. N.S. N.S. N.S. N.S. < 0.05 N.S.

N.S. = not significant. Values are means f S.D.

The length of time babies spent in the nurseries was not significantly different among groups.

Discussion

Until recently, expressed breast milk was favoured as the method of nutrition for the premature infant. Its immunological properties may help to prevent infection [12] and reduce the incidence of necrotising enterocolitis [l].

Adequate growth of the low birth weight infant is important for normal neuro- logical development since brain growth occurs mainly from the second half of the third trimester of pregnancy until the second year of life [5].

In order to attain intrauterine rates of growth the preterm infant has increased nutritional requirements. Breast milk from a mother with a preterm infant has a higher protein, energy and sodium content than a mother at term [lo] approximating more closely to the nutritional requirements of the preterm infant. In spite of this, studies have shown that growth of infants fed on expressed breast milk is less than infants fed on modified cow’s milk formulae [3].

Optimum growth of the premature infant has not been clearly defined. Some feel that the goal should be the intrauterine growth rate of the third trimester of pregnancy; thus a 32-36 week gestational age fetus should grow at a rate of 30.7

103

104

g/day. In our study babies fed SMA-Low Birth Weight formula and Prematalac approximated to this but those fed on EBM or Preaptamil did not.

When we compared weight gain on the three artificial formulae, those infants fed with Preaptamil had a significantly lower weight gain compared to the others. Because of this difference, we could not compare weight gain of the 3 formulae as a group with EBM.

Weight gain was greatest with Prematalac at 19.4 g/kg per day. This was not due to either a higher volume of feeds nor a higher energy intake but probably to water retention from the significantly higher sodium intakein that group. Support for the idea is that the increased weight gain was not accompanied by increased gain in length or occipito-frontal circumference. Although no cases of hypernatraemia were recorded the mean serum sodium concentration of these infants was significantly higher than the other groups. It would be of value in further studies to measure urine electrolyte excretion.

Optimum protein requirements of the premature infant are not clearly known. Protein content of expressed breast milk has been shown to be insufficient for small preterm infants [7]. Conversely studies have shown neurological problems at follow- up in infants fed high protein formulae [9]. High protein feeds have also been shown to produce metabolic effects in the form of acidosis and azotaemia [l&4] with no increase in linear growth above a level of 4.5 g/day [19].

We found significantly higher protein intakes in infants fed Prematalac. The questionable advantage of this may be offset by possible disadvantages. The same babies had the highest sodium, urea and serum osmolality values.

High plasma amino acids probably resulted from the increased protein load which could lead to high free amino acid levels [19] and cause unfavourable amino acid imbalances [20]. Aromatic amino acids might have most significance clinically as problems associated with high levels of tyrosine and phenylalanine have been reported [15,16].

Low birth weight formulae have been shown to be suitable for feeding the preterm infant but manufacturers should guard against producing milks with too high a protein or salt content. Some clinicians will continue to use EBM from mothers who have premature infants particularly for initial feeding of the sick preterm infant. As it has been suggested that EBM in increased quantities is the milk of choice for the preterm infant [13] it would be useful in further studies to compare low birth weight formulae with high volume EBM in feeding preterm infants.

Acknowledgements

We thank the Nursing and Medical Staff of Royal Maternity and Jubilee Maternity Nurseries, Belfast, for their assistance, Mr. Kelvin McCracken for analys- ing the breast milk, Mr. Raymond Moore for analysirig the amino acids, Mr. Chris Patterson for statistical advice and Mrs. Carol Montgomery and Mrs. Lynda Thompson for typing the manuscript.

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