Scott Morris

Effect of increasing protein content of human milk fortifier on growth in preterm infants born at <31 wk gestation: a randomized controlled trial

BACKGROUND Preterm human milk-fed infants often experience suboptimal growth despite the use of human milk fortifier (HMF). The extra protein supplied in fortifiers may be inadequate to meet dietary protein requirements for preterm infants. OBJECTIVE We assessed the effect of human milk fortified with a higher-protein HMF on growth in preterm infants. DESIGN This is a randomized controlled trial in 92 preterm infants born at <31 wk gestation who received maternal breast milk that was fortified with HMF containing 1.4 g protein/100 mL (higher-protein group) or 1.0 g protein/100 mL (current practice) until discharge or estimated due date, whichever came first. The HMFs used were isocaloric and differed only in the amount of protein or carbohydrate. Length, weight, and head-circumference gains were assessed over the study duration. RESULTS Length gains did not differ between the higher- and standard-protein groups (mean difference: 0.06 cm/wk; 95% CI: -0.01, 0.12 cm/wk; P = 0.08). Infants in the higher-protein group achieved a greater weight at study end (mean difference: 220 g; 95% CI: 23, 419 g; P = 0.03). Secondary analyses showed a significant reduction in the proportion of infants who were less than the 10th percentile for length at the study end in the higher-protein group (risk difference: 0.186; 95% CI: 0.370, 0.003; P = 0.047). CONCLUSIONS A higher protein intake results in less growth faltering in human milk-fed preterm infants. It is possible that a higher-protein fortifier than used in this study is needed. This trial was registered with the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) as ACTRN12606000525583.

Delayed versus Immediate Cord Clamping in Preterm Infants

Background The preferred timing of umbilical‐cord clamping in preterm infants is unclear. Methods We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late‐onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention‐to‐treat basis, accounting for multiple births. Results Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed‐clamping group and 9.0% in the immediate‐clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities. Conclusions Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088.)

Neurodevelopmental outcomes at 7 years’ corrected age in preterm infants who were fed high-dose docosahexaenoic acid to term equivalent: a follow-up of a randomised controlled trial

Objective To determine if improvements in cognitive outcome detected at 18 months’ corrected age (CA) in infants born <33 weeks’ gestation receiving a high-docosahexaenoic acid (DHA) compared with standard-DHA diet were sustained in early childhood. Design Follow-up of a multicentre randomised controlled trial. Randomisation was stratified for sex, birth weight (<1250 vs ≥1250 g) and hospital. Setting Five Australian tertiary hospitals from 2008 to 2013. Participants 626 of the 657 participants randomised between 2001 and 2005 were eligible to participate. Interventions High-DHA (≈1% total fatty acids) enteral feeds compared with standard-DHA (≈0.3% total fatty acids) from age 2–4 days until term CA. Primary outcome Full Scale IQ of the Wechsler Abbreviated Scale of Intelligence (WASI) at 7 years CA. Prespecified subgroup analyses based on the randomisation strata (sex, birth weight) were conducted. Results 604 (92% of the 657 originally randomised) consented to participate (291 high-DHA, 313 standard-DHA). To address missing data in the 604 consenting participants (22 for primary outcome), multiple imputation was performed. The Full Scale IQ was not significantly different between groups (high-DHA 98.3, SD 14.0, standard-DHA 98.5, SD 14.9; mean difference adjusted for sex, birthweight strata and hospital −0.3, 95% CI −2.9 to 2.2; p=0.79). There were no significant differences in any secondary outcomes. In prespecified subgroup analyses, there was a significant sex by treatment interaction on measures of parent-reported executive function and behaviour. Scores were within the normal range but girls receiving the high-DHA diet scored significantly higher (poorer outcome) compared with girls receiving the standard-DHA diet. Conclusions Supplementing the diets of preterm infants with a DHA dose of approximately 1% total fatty acids from days 2–4 until term CA showed no evidence of benefit at 7 years’ CA. Trial registration number Australian New Zealand Clinical Trials Registry: ACTRN12606000327583.

Neurodevelopmental Outcomes of Preterm Infants Fed High-Dose Docosahexaenoic Acid : A Randomized Controlled Trial

Infants born before 33 weeks’ gestation are at high risk of developmental disorders and learning disabilities. An inadequate endogenous supply of docosahexaenoic acid (DHA), a major brain lipid, may contribute to this poor developmental outcome. Trials evaluating the possible benefit of dietary DHA on the neurodevelopment of preterm infants have been inconclusive. This randomized, double-blind, controlled trial was designed to evaluate the long-term efficacy of a high-dose DHA enteral feed on the neurodevelopment of preterm infants born at less than 33 weeks’ gestation. A total of 657 infants were randomized to receive an enteral feed containing 1% total fatty acids (high-DHA group, n = 322) or a standard feed containing 0.3% total fatty acids (standard-DHA group, n = 335) from day 2 to 4 of life until term corrected age. The data were stratified by birth weight ( 1250 g) and infant gender. At 18 months follow-up, neurodevelopment was assessed using the Bayley Mental Development Index (MDI). In the whole study group, no difference was found in the unadjusted MDI scores of the children receiving high versus standard DHA feeds (mean difference: 1.9, 95% CI:-1.0–4.7), or among boys in the high versus standard feed groups. Adjustment for confounding variables did not change these results. However, girls receiving high-DHA feeds had significantly higher MDI scores than those receiving standard-DHA feeds (unadjusted mean difference: 4.7; 95% CI: 0.5–8.8, P = 0.03; adjusted mean difference: 4.5; 95% CI: 0.5–8.5, P = 0.03). Although ingestion of a high-DHA dose does not increase the MDI scores of all preterm infants born before 33 weeks, it was associated with an increase of MDI scores among girls. These data suggest that future trials with higher doses should be considered.

Pre- and post-term growth in pre-term infants supplemented with higher-dose DHA: A randomised controlled trial

The effect of the dietary n-3 long-chain PUFA, DHA (22 : 6n-3), on the growth of pre-term infants is controversial. We tested the effect of higher-dose DHA (approximately 1 % dietary fatty acids) on the growth of pre-term infants to 18 months corrected age compared with standard feeding practice (0·2-0·3 % DHA) in a randomised controlled trial. Infants born < 33 weeks gestation (n 657) were randomly allocated to receive breast milk and/or formula with higher DHA or standard DHA according to a concealed schedule stratified for sex and birth-weight ( < 1250 and ≥ 1250 g). The dietary arachidonic acid content of both diets was constant at approximately 0·4 % total fatty acids. The intervention was from day 2 to 5 of life until the infants expected date of delivery (EDD). Growth was assessed at EDD, and at 4, 12 and 18 months corrected age. There was no effect of higher DHA on weight or head circumference at any age, but infants fed higher DHA were 0·7 cm (95 % CI 0·1, 1·4 cm; P = 0·02) longer at 18 months corrected age. There was an interaction effect between treatment and birth weight strata for weight (P = 0·01) and length (P = 0·04). Higher DHA resulted in increased length in infants born weighing ≥ 1250 g at 4 months corrected age and in both weight and length at 12 and 18 months corrected age. Our data show that DHA up to 1 % total dietary fatty acids does not adversely affect growth.

Characterization of Fatty Acid Clearance in Premature Neonates during Intralipid Infusion

This study reports the clearance of plasma triglyceride and phospholipid fatty acids during Intralipid 20% infusion (Pharmacia, Sweden) in nine ventilated preterm infants receiving parenteral nutrition. Blood samples were taken during lipid infusion and over a subsequent period of 36 h of fat-free parenteral nutrition. Plasma triglyceride fatty acids showed a uniform and rapid decline after lipid was stopped from the peak values recorded during infusion. In contrast, plasma phospholipid fatty acids showed a variable decline during fat-free nutrition. This variability appeared to be the result of a differing contribution of infused egg yolk phospholipid fatty acids to the measured plasma values, and to changing fatty acid composition of endogenous phospholipid in response to fat free nutrition. Red cell phospholipid fatty acid composition was stable over the 36-h clearance study period. These results indicate the complexity of interpretation of plasma fatty acids during lipid infusion. We conclude that red cell phospholipid fatty acids provide the only stable measure of tissue fatty acid composition in parenterally fed preterm infants.

Docosahexaenoic Acid and Bronchopulmonary Dysplasia in Preterm Infants

BACKGROUND Studies in animals and in humans have suggested that docosahexaenoic acid (DHA), an n‐3 long‐chain polyunsaturated fatty acid, might reduce the risk of bronchopulmonary dysplasia, but appropriately designed trials are lacking. METHODS We randomly assigned 1273 infants born before 29 weeks of gestation (stratified according to sex, gestational age [<27 weeks or 27 to <29 weeks], and center) within 3 days after their first enteral feeding to receive either an enteral emulsion providing DHA at a dose of 60 mg per kilogram of body weight per day or a control (soy) emulsion without DHA until 36 weeks of postmenstrual age. The primary outcome was bronchopulmonary dysplasia, defined on a physiological basis (with the use of oxygen‐saturation monitoring in selected infants), at 36 weeks of postmenstrual age or discharge home, whichever occurred first. RESULTS A total of 1205 infants survived to the primary outcome assessment. Of the 592 infants assigned to the DHA group, 291 (49.1% by multiple imputation) were classified as having physiological bronchopulmonary dysplasia, as compared with 269 (43.9%) of the 613 infants assigned to the control group (relative risk adjusted for randomization strata, 1.13; 95% confidence interval [CI], 1.02 to 1.25; P=0.02). The composite outcome of physiological bronchopulmonary dysplasia or death before 36 weeks of postmenstrual age occurred in 52.3% of the infants in the DHA group and in 46.4% of the infants in the control group (adjusted relative risk, 1.11; 95% CI, 1.00 to 1.23; P=0.045). There were no significant differences between the two groups in the rates of death or any other neonatal illnesses. Bronchopulmonary dysplasia based on a clinical definition occurred in 53.2% of the infants in the DHA group and in 49.7% of the infants in the control group (P=0.06). CONCLUSIONS Enteral DHA supplementation at a dose of 60 mg per kilogram per day did not result in a lower risk of physiological bronchopulmonary dysplasia than a control emulsion among preterm infants born before 29 weeks of gestation and may have resulted in a greater risk. (Funded by the Australian National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820.)

Prediction of body water compartments in preterm infants by bioelectrical impedance spectroscopy

Background/Objectives:To evaluate nutritional interventions in preterm infants, a simple, accurate assessment of the type of growth, that is, change in body composition through the relative contributions of lean body tissue and fat mass to weight gain, is needed. Bioelectrical impedance may provide such a method. The aim of this study was to develop resistivity coefficients appropriate for use in bioelectrical impedance spectroscopy (BIS) analysis of body water volumes in preterm infants.Subjects/Methods:A total of 99 preterm infants were enrolled (mean gestational age 32 completed weeks). Total body water (TBW) and extracellular water (ECW) were determined using the reference methods of deuterium and bromide dilution. BIS measurements taken at the same time allowed calculation of resistivity coefficients. Predictions of TBW and ECW obtained using these coefficients were then validated against volumes determined using the reference methods in a separate cohort of infants.Results:Data were available for 91 preterm infants. BIS-predicted TBW and ECW correlated well with the measured volumes (Pearson’s rp=0.825 and 0.75, respectively). There was a small bias (TBW 10 ml and ECW 40 ml) but large limits of agreement (TBW±650 ml and ECW ±360 ml).Conclusions:BIS appears to have limited clinical utility; however, the relatively small bias means that it may be useful for measurements within a population or for comparisons between groups in which population means rather than individual values are compared.

A novel approach to standardised recording of bleeding in a high risk neonatal population

Background Bleeding assessment tools have been developed in other specialties to standardise the recording of bleeding for clinical haemostatic outcomes in transfusion trials, but such tools have not been developed for routine use in neonatology. Aim The objective of this study was to develop, refine and evaluate a neonatal bleeding assessment tool (NeoBAT) to standardise the clinical recording of bleeding in premature and term neonates in an intensive care setting. Methods This prospective neonatal international multicentre study included all episodes of bleeding in infants admitted to the intensive/high dependency care nursery over a 2–4-week period. The NeoBAT was developed to record neonatal bleeding episodes. We tested its reliability and reproducibility with duplicate assessments. Results Duplicate assessments revealed 98% concordance. Bleeding occurred in 25% (37/146) of infants overall and was most common in preterm infants. 11% (16/146) infants had major/severe bleeds, 1% (2/146) moderate and 13% (19/146) minor bleeds. Conclusions Bleeding is common in premature and term neonates admitted to intensive/high dependency care nurseries. This novel bleeding assessment tool facilitates prospective recording of bleeding events in neonatal intensive care settings and may allow standardised bleeding assessments in this high risk population.

Developmental sensitivity of the piglet brain to docosahexanoic acid.

Human formula-fed infants have a lower concentration of docosahexanoic acid (DHA) in cerebral cortex compared with breast-fed infants. It is uncertain whether this biochemical deficit is reversible in later infancy. We used a piglet model to determine whether a critical window exists for the deposition of DHA in cerebral cortex during early postnatal development. Milk formula supplemented with DHA was fed to piglets for one of two 14-day periods commencing at either 2 or 16 d of life (early or late supplementation). Comparison of cortical DHA levels in response to supplemented formula was made with age-matched piglets receiving a control formula devoid of DHA. The level of DHA incorporated into whole brain during supplemented formula-feeding seemed to be less with increasing postnatal age. However, when cerebral cortex was examined, dietary DHA was efficiently incorporated during both early and late supplementation periods. Thus, analysis of whole brain was misleading, emphasizing the need to consider the effect of myelination when interpreting developmental changes in brain fatty acids. We conclude that the piglet cerebral cortex is responsive to dietary DHA during the postnatal phase of the brain growth spurt. The lower cortical DHA levels of human formula-fed infants may, therefore, be reversible in later infancy. Plasma phospholipid DHA levels were approximately doubled and liver phospholipid DHA levels increased 50% relative to starting values during control formula-feeding. This suggests a higher rate of DHA synthesis in the piglet in comparison with the human infant, which may be an important limitation of the piglet model.