Multicentre trial on feeding low birthweight infants: effects of diet on early growth.

A large multicentre study on the short and long term clinical and developmental outcome of infants randomised to different diets is being undertaken. This report represents an interim analysis of the early postnatal growth performance of an unselected population of 194 preterm infants (gestation, mean (SD) 31 . 0 (2 . 9) weeks; birthweight, mean (SD) 1364 (294) g), both ill and well, examined in two (of four) parallel trials. One trial compared banked breast milk with a new preterm formula (primary trial); the other compared these diets as supplements to maternal milk (supplement trial). A major dietary effect on the number of days taken to regain birthweight and subsequent gains in weight, length, and head circumference was observed in the primary trial. Infants fed banked breast milk and weighing less than 1200 g at birth took a calculated additional three weeks to reach 2000 g compared with those fed on the preterm formula. A significant influence of diet on body proportions was seen in the relation between body weight, head circumference, and length. Similar though smaller differences in growth patterns were seen in the supplement trial. By the time they reach 2000 g, infants of birthweights 1200 to 1849 g fed on banked breast milk and infants below 1200 g fed on either banked breast milk or maternal milk supplemented (as necessary) with banked breast milk, fulfilled stringent criteria for failure to thrive (weight less than 2 SD below the mean for age). Only infants fed the preterm formula as their sole diet had maintained their birth centile by discharge from hospital. The misleading nature of comparisons between extrauterine and intrauterine steady state weight gains is emphasised.     

Stool water in preterm neonates.

Data are presented on faecal water losses in 93 preterm infants being fed breast milk (72 infant days) or formula (280 days). Losses per kg increased to 4 weeks, when they amounted to 11% of water requirement in infants fed breast milk and 8% in infants fed formula.     

Zinc deficiency in rapidly growing preterm infants

Symptomatic zinc deficiency was observed in a 24-week gestation, 640g birthweight infant fed exclusively with maternal breast milk. Our hypothesis was that subclinical Zn deficiency is not uncommon in very low birthweight infants because fortified human milk and preterm formula may contain little Zn. Zinc serum concentrations determined in 26 consecutive very low birthweight infants (gestational age 23-32, median 27 weeks), prior to discharge, at a chronological age of 37-121 (median 72) d, were found between 1.0 and 14.0 (median 6.4) μmol/l, in 14 infants they were below the normal range of 7.6-15.0μmol/l. Serum alkaline phosphatase and iron intake did not correlate with Zn concentrations. Nutritional supply of Zn and other trace elements by breast milk fortifiers and infant formulas currently used in Germany does not appear to meet the demands of rapidly growing extremely low birthweight infants during the first months of life.     

Energy expenditure in human milk- versus formula-fed preterm infants

OBJECTIVE: We compared energy expenditure (EE) of preterm infants fed their mother's milk versus preterm infant formula.Study design A prospective, randomized crossover study of 13 healthy, appropriate weight for gestational age, gavage-fed, preterm infants. Before the study and according to our feeding protocol, infants uniformly received alternate feeds of human milk and formula. Each infant was randomly assigned to 24 hours of formula feeding followed by 24 hours of breast milk or the reverse. Infants were studied asleep, at the end of each 24-hour period. EE was measured by indirect calorimetry 1 hour before feeding, 20 minutes during feeding, and 1 hour after feeding in a servo-controlled convective incubator. Energy content of human milk was analyzed by bomb calorimetry. RESULTS: EE was significantly lower in breast milk-fed infants during prefeeding (52+/-6 vs 57+/-10 kcal/kg per 24 hours) (P<.05), per feeding (55+/-6 vs 60+/-10 kcal/kg per 24 hours) (P<.05), and at the postfeeding measurement (60+/-7 vs 65+/-7 kcal/kg per 24 hours) (P=.059). After correction of the results for the actual measured energy intake, all statistical differences reached the <.05 level. CONCLUSIONS: Preterm infants have lower EE when they are fed breast milk than when they are fed preterm infant formula.     

Plasma amino acids in small preterm infants fed on human milk or formula.

Plasma amino acids were measured in 35 preterm infants, of whom 11 weighed less than 1000 g and 24 weighed between 1000 g and 1500 g at the time of sampling. Repeat samples were obtained in 18 at least seven days later. Seventeen infants were fed with preterm formula milk and 18 with expressed maternal breast milk at one to two hourly intervals during the study period. Formula fed infants gained weight faster than those fed on breast milk but there was little difference in amino acid patterns. Infants fed on breast milk were more likely to have concentrations of essential amino acids below the mid trimester fetal range than formula fed infants, but few infants in either feeding group had values above the fetal range. Those that did were equally distributed between both groups. Only two samples approached toxic concentrations, both in the group fed breast milk. The ratio of branched chain to aromatic amino acids was higher in the group fed on formula after correction for post conceptional age, implying that liver maturation may be accelerated by formula feeding. No correlations were found between plasma amino acid concentrations and nitrogen retention or metabolisable energy intake.     

Early follow-up of very low birth weight infants after hospital discharge with respect to growth and mineral homeostasis

Very low birth weight infants from two previous in-hospital feeding studies were investigated at follow-up after hospital discharge at a mean postnatal age of 12 weeks. Of infants who had received human milk in hospital (own mother's or pooled), 26 were seen at follow-up, of whom only 8 remained exclusively breast fed. Of those fed a formula in hospital, 31 were seen at follow-up. Those infants who had been fed human milk while in hospital demonstrated slower linear growth over the 6-week period of this study. Only those fed exclusively human milk from birth to the time of follow-up showed elevated serum alkaline phosphatase and low serum phosphate values, while those fed human milk in hospital, but completely or partially formula fed thereafter, had values similar to those fed formula throughout. Alkaline phosphatase values greater than 675 IU/L were associated with either exclusive breast feeding or vitamin D depletion. Of the two cases of rickets diagnosed on wrist x-rays, one infant had been exclusively breast fed and the other was vitamin D depleted.     

Protein hydrolysate formula maintains homeostasis of plasma amino acids in preterm infants.

BACKGROUND: Plasma amino acid concentrations were measured in preterm infants who were fed either a new hydrolyzed cow's milk protein formula or a standard preterm infant formula. It was hypothesized that feeding with the hydrolysate results in preprandial amino acid concentrations that are significantly different from the concentrations found when feeding with the standard formula. METHODS: Fifteen preterm infants, median gestational age, 29 weeks (range, 24-32 weeks); birth weight, 1241 g (range, 660-1900 g); and postnatal age, 18 days (range, 7-54 days) receiving full enteral feedings (>150 ml/kg x day), were enrolled. The intervention was randomized allocation to the formula with hydrolyzed or natural cow's milk protein (the whey/casein ratio was 60:40 in both formulas). In a crossover design, each formula was fed for 5 days, and plasma amino acids were analyzed on day 4 or 5 of each 5-day period. RESULTS: In spite of the 12% higher amino acid intake with hydrolysate formula, the median individual plasma amino acid concentrations were virtually identical with both formulas, and they were within the 10th and the 90th percentile of the reference of levels in the umbilical cord artery after elective cesarean delivery or of breast-fed newborn infants. The median concentrations of lysine and aspartic acid were higher with hydrolyzed formula feeding (p<0.05; two-tailed Mann-Whitney test). With both formulas, single amino acid concentrations were out of the reference values. CONCLUSION: Virtually identical plasma amino acid concentration patterns were measured with the new hydrolyzed preterm infant formula and the standard preterm infant formula, but longitudinal studies are required before the studied protein hydrolysate can be recommended for preterm feeding in general.     

Effect of diet on infant subcutaneous tissue triglyceride fatty acids.

Having demonstrated a deficiency in infant cerebral cortex docosahexaenoic acid of formula fed compared with breast milk fed infants, we sought to identify why the extensive subcutaneous tissue triglyceride fatty acid reserves in term new-born infants appeared to be ineffectual in its prevention. In addition to 24 term and six preterm infants who died from 'cot death', tissue was analysed from four perinatal surgical patients and in the former the results were correlated with dietary milk intake. The higher amounts (about 15% by weight) of unsaturated linoleic acid supplied in the formula milks were quantitatively incorporated into the subcutaneous tissue largely at the expense of the saturated palmitic acid possibly compromising adipocyte fluidity. The six preterm infants were in two formula fed groups and there was only one significant difference, namely a higher subcutaneous tissue concentration of alpha-linolenic acid in one of the preterm groups, distinguishing them from their term counterparts. This may imply that the enzymes involved in absorption and digestion of fatty acids are mature in the preterm infant. From birth the mean weight percentage of docosahexaenoic acid (0.4%) fell rapidly to undetectable levels (< 0.05%) in the formula fed group after about two months. It is therefore concluded that if breast feeding is not possible then a minimum daily requirement of 30 mg docosahexaenoic acid (approximately 0.2 g/100 g fatty acids) should be supplied in formulas designed for term infants to prevent the cerebral cortical deficiency of docosahexaenoic acid.     

Individualized protein fortification of human milk for preterm infants: comparison of ultrafiltrated human milk protein and a bovine whey fortifier.

BACKGROUND: To improve the nutritional management of pre-term infants, a new individualized human milk fortification system based on presupplementation milk protein analyses was evaluated. METHODS: In an open, prospective, randomized multicenter study, 32 healthy preterm infants (birth weights, 920-1750 g) were enrolled at a mean of 21 days of age (range, 9-36 days) when tolerating exclusive enteral feedings of 150 ml/kg per day. All infants were fed human milk and were randomly allocated to fortification with a bovine whey protein fortifier (n = 16) or ultrafiltrated human milk protein (n = 16). All human milk was analyzed for protein content before fortification with the goal of a daily protein intake of 3.5 g/kg. During the study period (mean, 24 days) daily aliquots of the fortified milk were obtained for subsequent analyses of the protein content. RESULTS: Both fortifiers were well tolerated, and growth gain in weight, length, and head circumference, as well as final preprandial concentrations of serum urea, transthyretin, transferrin, and albumin were similar in both groups. The ultimate estimated protein intake was equivalent in both groups (mean 3.1+/-0.1 g/kg per day). Serum amino acid profiles were similar in both feeding groups, except for threonine (significantly higher in the bovine fortifier group) and proline and ornithine (significantly higher in the human milk protein group). CONCLUSIONS: Protein analyses of the milk before individual fortification provides a new tool for an individualized feeding system of the preterm infant. The bovine whey protein fortifier attained biochemical and growth results similar to those found in infants fed human milk protein exclusively with the corresponding protein intakes.     

Quantifying breast milk intake by term and preterm infants for input into paediatric physiologically based pharmacokinetic models

Despite the many benefits of breast milk, mothers taking medication are often uncertain about the risks of drug exposure to their infants and decide not to breastfeed. Physiologically based pharmacokinetic models can contribute to drug‐in‐milk safety assessments by predicting the infant exposure and subsequently, risk for toxic effects that would result from continuous breastfeeding. This review aimed to quantify breast milk intake feeding parameters in term and preterm infants using literature data for input into paediatric physiologically based pharmacokinetic models designed for drug‐in‐milk risk assessment. Ovid MEDLINE and Embase were searched up to July 2, 2019. Key study reference lists and grey literature were reviewed. Title, abstract and full text were screened in nonduplicate. Daily weight‐normalized human milk intake (WHMI) and feeding frequency by age were extracted. The review process retrieved 52 studies. A nonlinear regression equation was constructed to describe the WHMI of exclusively breastfed term infants from birth to 1 year of age. In all cases, preterm infants fed with similar feeding parameters to term infants on a weight‐normalized basis. Maximum WHMI was 152.6 ml/kg/day at 19.7 days, and weighted mean feeding frequency was 7.7 feeds/day. Existing methods for approximating breast milk intake were refined by using a comprehensive set of literature data to describe WHMI and feeding frequency. Milk feeding parameters were quantified for preterm infants, a vulnerable population at risk for high drug exposure and toxic effects. A high‐risk period of exposure at 2–4 weeks of age was identified and can inform future drug‐in‐milk risk assessments.     

Early diet in preterm babies and developmental status in infancy.

Few data from randomised prospective studies address whether early diet influences later neurodevelopment in man. As part of a larger multicentre trial, 502 low birthweight infants were assigned randomly, for a median of 30 days, to receive a preterm formula or unfortified donor breast milk as sole diets or as supplements to their mothers'' expressed milk. Surviving infants were assessed at nine months after their expected date of delivery without knowledge of their feeding regimen. The mean developmental quotient was 0.25 standard deviations lower in those fed donor breast milk rather than preterm formula. In infants fed their mother''s expressed milk, however, the disadvantage of receiving banked milk compared with preterm formula as a supplement, was greater when the supplement was over half the total intake, and approached five points, representing 0.5 standard deviations for developmental quotient. Infants fed donor breast milk were at particular disadvantage following fetal growth retardation, with developmental quotients 5.3 points lower. We suggest that the diet used for low birthweight babies over a brief, but perhaps critical, postnatal period has developmental consequences that persist into infancy; infants who are small for gestational age are especially vulnerable to suboptimal postnatal nutrition.     

Measurement of bone mineral density by dual energy X-ray absorptiometry in preterm infants fed human milk or formula

Bone mineralization of healthy preterm infants fed human milk were compared with that of similar fed preterm formula. Bone mineralization was studied by dual energy X-ray absorptiometry in 43 preterm infants divided into two groups; 21 preterm infants were fed with maternal breast milk and 22 preterm infants with a preterm formula containing 70 mg calcium and 35 mg phosphorus per decilitre. Conclusion Preterm infants fed breast milk had lower bone mineral density than the preterm formula-fed group. Fortifying preterm human milk with calcium and phosphorus will improve bone mineralization in preterm infants. Received: 26 November 1996 and in revised form: 26 August 1997 / Accepted: 9 September 1997     

Breast milk jaundice in premature infants.

In randomised study of 186 preterm infants those fed on maternal or banked breast milk had a significantly higher peak bilirubin concentration and a more prolonged jaundice than infants fed an artificial preterm formula and were over four times more likely to achieve plasma bilirubin values above 200 mumol/l (11.7 mg/100 ml). This dietary effect was seen even in a high risk subgroup of sick ventilated infants below 1500 g who were receiving restricted enteral intakes. We suggest that breast milk jaundice in preterm infants may increase clinical intervention. Our findings are discussed in the light of epidemiological data suggesting an association between moderate hyperbilirubinaemia (greater than 170 mumol/l) and neurodevelopmental outcome.     

Does gastric acid protect the preterm infant from bacteria in unheated human milk?

Although preterm mother's milk has greater nutritional and anti-infective properties than donor milk, it may be highly contaminated with bacteria. We therefore asked three questions: what is the fate of these bacteria in the preterm infant's stomach, is gastric pH important, and what factors affect gastric pH? pH, colony count and bacterial identification were performed on the milk and on serial gastric aspirates in 20 preterm infants on 25 occasions. Seventeen milk samples grew bacteria, five potentially pathogenic and 12 non-pathogenic. Twelve of 25 prefeeding gastric samples were sterile, but following the feeding all the samples grew non-pathogenic bacteria and 70% grew potential pathogens. With time pH decreased and by 2-h samples with pH less than 3.5 had no bacterial growth; Candida albicans still flourished in a low pH (mean 2.8). We concluded that a low gastric pH may be more important than the bacterial count of the milk. In a second study, 91 serial gastric pH measurements were made on 12 preterm infants. pH tended to decrease with increasing age and was significantly lower in infants fed exclusively human milk (2.7 vs. 3.6; human milk versus formula P less than 0.02) We speculate that human milk may influence gastric acid production and thus protect the preterm infant from bacteria in the milk.     

Postprandial plasma amino acids in preterm infants: influence of the protein source

Preprandial plasma amino acid concentrations have been used extensively as a marker of the nutritional value of dietary proteins in preterm infants. This study investigated the postprandial plasma amino acid profiles of preterm infants fed with different dietary proteins at similar protein intakes during the first weeks of life. In 12 preterm infants, pre- and postprandial plasma amino acid concentrations were measured before the removal of an indwelling central venous catheter placed for parenteral nutrition. All infants received breast milk until the time of study. At the start day of the study, infants were randomized to receive a test meal of 10 ml/kg, either of breast milk fortified with breast milk protein to reach a protein content of 2.0 g/dl or of a bovine milk preterm formula with a protein content of 2.0 g/dl (whey/casein ratio 60/40). Five samples of 100 microl blood were obtained immediately before and 15, 30, 45 and 60 min after the test meal. The plasma amino acid analysis was performed by a reversed-phase high-performance liquid chromatography based on o-phthaldialdehyde/2-mercaptoethanol pre-column derivatization. In both groups, the plasma amino acid concentrations increased within the first 30 min and the levels did not return to the preprandial baseline during the observation period. Fifteen minutes after the test meal, the plasma levels of all essential amino acids with the exception of histidine were higher in the bovine milk formula fed infants than in the fortified breast milk fed infants. The sum of plasma essential amino acid levels found in the formula fed infants were significantly (p < 0.05) higher than the levels found in the fortified breast milk fed infants at 15, 30 and 45 min. The kinetics of individual amino acids were influenced by the different quality of the protein even when the intakes in the groups were similar, as demonstrated for histidine and phenylalanine. The data indicate that postprandial plasma amino acid concentrations depend significantly on the dietary amino acid source and cannot simply be calculated from the amino acid composition of dietary proteins. Therefore, postprandial plasma amino acid concentrations should be included in the nutritional evaluation of dietary proteins in preterm infants.     

Nitrogen and mineral balance in preterm infants fed human milks or formula

Growth as well as nitrogen, calcium, sodium, and potassium balances were evaluated in 16 preterm infants weighing less than 1,600 g at birth, who were fed either their mother's milk, donated mature human milk, or standard commercial formula. Birthweight, gestational age, age of balance, and energy and fluid intakes were similar between groups. There were no differences between groups in the rate of growth. The infants fed their mother's milk (obtained 11-30 days into lactation) demonstrated nutrient balance similar to infants fed mature human milk. Infants fed standard commercial formula demonstrated significantly greater intake and retention of calcium compared to either human milk group. Infants fed either their mother's milk or mature human milk demonstrated net nitrogen and calcium retention below estimates of fetal nitrogen and calcium accretion. Infants fed standard formula demonstrated retentions that more closely approach the fetal estimates. This study did not demonstrate an advantage to feeding premature infants their mother's milk when compared to the feeding of mature donor milk.     

Effects of exclusive formula or breast milk feeding on oxidative stress in healthy preterm infants.

BACKGROUND: Compared to formula, breast milk is considered to have superior antioxidant properties and consequently may reduce the occurrence of a number of diseases of prematurity associated with oxidative stress. AIMS: To test whether the antioxidant properties of breast milk in healthy premature infants are different to those of formula milk by comparing vitamin E levels in milk and determining the excretion of malondialdehyde (MDA) in urine. METHODS: Vitamin E was measured in the breast milk of 20 mothers who had given birth prematurely. Urinary MDA was measured in 10 exclusively breast milk fed and 10 exclusively formula fed healthy preterm infants receiving no vitamin supplements. MDA was measured after derivatisation with 2,4-dinitrophenylhydrazine and consecutive HPLC with UV detection. RESULTS: Urinary MDA concentrations were consistently very low (0.074+/-0.033 microM/mM Cr and 0.078+/-0.026 microM/mM Cr in breast and formula fed infants respectively) and not significantly different between healthy breast milk and formula fed infants. Both breast and formula milk contained satisfactory levels (0.3-3.0 mg/100 ml) of vitamin E. CONCLUSION: Antioxidant properties of both breast milk and formulae are sufficient to prevent significant lipid peroxidation in healthy premature infants.     

Plasma fibronectin concentrations in breast fed and formula fed neonates.

Plasma fibronectin concentration was measured in neonates of 2 to 5 days of age. Although breast fed and formula fed infants were similar in demographic characteristics, the mean (SD) plasma concentration of fibronectin in 26 breast fed infants, 237 (117) mg/l, was significantly higher than in 27 formula fed infants (171 (91) mg/l). Fibronectin was detected in five colostrum specimens (mean concentration 13.4 mg/l). Similar bands were detected after gel electrophoresis of purified adult plasma fibronectin and whole plasma from breast fed and formula fed neonates after staining or immunoblotting. Fibronectin isolated from breast milk also appeared similar to purified plasma fibronectin. It is possible, although unlikely, that fibronectin is absorbed intact from ingested colostrum. Alternatively, a factor(s) might be present in colostrum that contributes to the regulation of plasma fibronectin concentration.     

Breastfeeding and long-chain polyunsaturated fatty acid intake in the first 4 post-natal months and infant cognitive development: an observational study

The aim of this study was to examine infant feeding and the long-chain polyunsaturated fatty acid (LCPUFA) concentration of breast milk and formulas in relation to infant development. The prospective Pregnancy, Infection and Nutrition Study (n=358) collected data on breastfeeding, breast milk samples and the formulas fed through 4months post-partum. At 12months of age, infants' development was assessed (Mullen Scales of Early Learning). Linear regression was used to examine development in relation to breastfeeding, breast milk docosahexaenoic acid (DHA) and arachidonic acid (AA) concentration, and DHA and AA concentration from the combination of breast milk and formula. The median breast milk DHA concentration was 0.20% of total fatty acids [interquartile range (IQR)=0.14, 0.34]; median AA concentration was 0.52% (IQR=0.44, 0.63). Upon adjustment for preterm birth, sex, smoking, race and ethnicity and education, breastfeeding exclusivity was unrelated to development. Among infants exclusively breastfed, breast milk LCPUFA concentration was not associated with development (Mullen composite, DHA: adjusted β=-1.3, 95% confidence interval: -10.3, 7.7). Variables combining DHA and AA concentrations from breast milk and formula, weighted by their contribution to diet, were unassociated with development. We found no evidence of enhanced infant development related to the LCPUFA content of breast milk or formula consumed during the first four post-natal months.     

Faecal excretion in infants

Data on normal defaecation patterns in relation to diet during the first months of infancy are very limited. We therefore investigated in a prospective study faecal weight and gastro-intestinal passage time of breast fed (n=12) and formula fed (n=14) male infants. These were studied in 72 h collecting periods at the age of 17, 35, 57, 87 and 113 (±4) days. Breast fed infants had a significantly lower daily dry faecal weight than formula fed infants in all periods investigated (median at the age of 113 days: 0.28 (0.17–0.75) g/kg and 0.81 (0.22–1.2) g/kg, respectively). Breast fed infants showed a large variation of gastro-intestinal passage time (6.79 h [range: 1.79–13.38 h] at the age of 17 days, 21.84 h [range: 5.41–75 h] at the age of 113 days). Comparable values of formula red infants were 13.75 h (range: 7.13–35.25 h) and 17.42 h (range: 5.38–36.5 h). Despite the efforts of approximation of infant formula to breast milk, differences of defaecation patterns in relation to diet are still relevant at this age and have to be considered in clinical practice.These data have been presented in part at the 26th Scientific Meeting of the German Society of Nutrition, Bonn, 6–7 April 1989.