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Abstract
Objective To determine whether purposely designed nutritional guidelines for extremely low birthweight (ELBW; birth weight <1000 g) babies result in protein intakes that meet international consensus recommendations, and whether this results in improved growth from birth to discharge.
Design A prospective cohort study of nutritional intakes and growth in ELBW babies.
Setting A tertiary neonatal intensive care unit in New Zealand.
Patients 100 ELBW babies who survived for the first month of life, 50 before the introduction of the guideline (Lo Pro) and 50 after (Hi Pro).
Intervention Introduction of a nutritional guideline aimed at increasing protein intakes to meet international consensus recommendations.
Main outcome measures Weekly protein intakes over the first month of life and growth until discharge.
Results Hi Pro babies had significantly higher protein intakes in the first month of life than Lo Pro babies (mean (SD), 3.8 (0.3) vs 3.3 (0.4) g/kg.day, p<0.0001) and a significantly greater growth velocity (GV) over the first 30 days after regaining birth weight (19.5 (5.0) vs 16.2 (5.4) g/kg.day, p<0.002). Hi Pro babies had a significantly lesser Z-score change between birth and discharge than Lo Pro babies for weight (0.0 (1.2) vs −0.9 (1.1), p=0.001), length (−0.8 (0.8) vs −1.2 (1.1), p=0.02) and head circumference (−0.2 (1.1) vs −1.1 (1.6), p<0.001).
Conclusions Simple, standardised nutritional guidelines can result in recommended protein intakes for ELBW babies being achieved and result in increased GV. Downward crossing of centiles between birth and discharge, common in ELBW babies, is significantly reduced for weight, length and head circumference.
- Growth
- Nutrition
- Neonatology
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What is already known on this topic
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Consensus guidelines for ELBW babies to achieve intrauterine rates of growth recommend 4.0–4.5 g/kg.day protein after the first week of life.
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In clinical practice, recommended protein intakes frequently are not achieved and postnatal faltering growth is common.
What this study adds
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Recommended protein intakes can be achieved using standard intravenous nutrition solutions and commercial breast milk fortifiers.
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Increasing protein intake is associated with significantly reduced downward crossing of centiles for weight, length and head circumference between birth and discharge.
Introduction
Nutrition in the first month of life has the potential to influence clinical outcomes, growth, body composition and neurodevelopmental outcomes for extremely low birthweight (ELBW) babies.1–4 Recommended protein intakes for ELBW babies have steadily increased,5–7 but it is not known whether current consensus recommended protein intakes (4.0–4.5 g/kg.day)5 ,7 reduce postnatal faltering growth or improve clinical outcomes. Furthermore, it is not clear whether recommended protein intakes can be achieved reliably using standard intravenous nutrition solutions.
We previously have reported that in our neonatal intensive care unit (NICU) babies <1500 g failed to meet consensus-recommended protein intakes and had faltering postnatal growth.8 A suite of changes to the intravenous nutrition solution composition, and enteral feeding policy, were implemented to address these deficits. It was not deemed ethical to investigate these changes through a randomised controlled trial because this would have meant the control group continuing to receive protein intakes below international recommendations. To determine whether the changes were successful in increasing protein intakes and reducing faltering postnatal growth, we undertook a prospective study of a cohort of 50 ELBW (Lo Pro) babies before, and a further 50 ELBW babies (Hi Pro) after, the implementation of the new nutritional policy. A sample size of 50 babies per group was determined to be sufficient to detect a difference of 0.4 Z-score in crown-heel length (SD=0.9, α=0.05, β=0.2).
We hypothesised that (1) adherence to a nutritional guideline utilising standard (not individualised) intravenous solutions and close attention to enteral feeds and their fortification would achieve recommended intakes for energy, protein and most other nutrients and (2) achieving recommended intakes would improve growth.
Methods
The Lo Pro cohort was born between April 2006 and July 2007. Forty-five of these babies were included in a prior publication reporting nutrition in our NICU.9 The Hi Pro cohort was born between August 2009 and November 2010. The time period between the cohorts was required to develop and fully implement the nutrition policy. For both cohorts, consecutive babies who weighed <1000 g at birth, received intravenous nutrition, were admitted within 24 h of birth and remained in our NICU for at least 30 days were included. Exclusion criteria were multiple birth >2, due to the likely impact on nutrition, size at birth and growth velocity (GV), and babies with an inborn error of metabolism likely to affect nutrient tolerance or growth. We used two standardised intravenous nutrition solutions (TrophAmine, B Braun Medical, Irvine, USA), a ‘starter’ solution for the first 2 days, and ‘P100’ thereafter (table 1). Intralipid 20% (Fresenius Kabi AB, Uppsala, Sweden) commenced on day 1 at 1 g/kg.day, increasing to 3 g/kg.day by 3 days. Enteral feeds were increased by 10–20 ml/kg.day as tolerated to a total of 180 ml/kg.day. Differences between total fluid intake prescribed and the sum of the intravenous nutrition solution, lipid, enteral feeds and medication infusions was made up with 10% dextrose.
Composition of the intravenous nutrition solutions per litre, and nutrient intake for babies on full intravenous nutrition
Nutrition policy changes in the Hi Pro group unless medically contraindicated
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Commence intravenous nutrition, lipid and enteral feeding on day 1.
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The protein concentration of P100 was increased to 42 g/l (table 1).
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Maximum intravenous protein intake increased to 4 g/kg.day (table 1).
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Human breast milk fortifier (HMF) brand changed so that HMF added 1.0 g protein/100 ml breast milk.
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HMF added to breast milk before full feeds reached, initially when enteral feeds reached 100 ml/kg.day then when 2-hourly feeds of 5 ml were tolerated.
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Preterm formula brand changed resulting in increased protein intake to 2.5 g/100 ml formula.
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Formula-fed babies had feeds initiated with preterm rather than term formula.
For the Lo Pro cohort, the day of commencing intravenous nutrition, lipid and enteral feeding was not specified in the nutrition policy and, therefore, varied. The protein concentration of P100 was lower and provided a maximum of 3.8 g/kg.day. The breast milk fortifier in use added 0.8 g protein/100 ml breast milk, and was not commenced until full enteral feeds were tolerated, usually for at least 24 h. When formula was required, feeds were initiated with term, rather than preterm, formula and continued until full enteral feeds were reached. The preterm formula for the Lo Pro cohort provided 2 g/100 ml protein. The energy concentration of both the preterm formula and breast milk fortifier was similar for both cohorts. The aim of the nutrition policy changes was primarily to increase protein but not energy intake and, therefore, to increase the protein to energy ratio.
Total enteral and intravenous intakes for the first 4 weeks of life were recorded daily; mean daily protein and energy intakes were calculated based on actual intakes. Day 1 was defined as the first full 24 h period after birth. Full enteral feeds were defined as the day when no further intravenous nutrition was given. Energy and protein intakes were calculated using preterm transitional breast milk composition for the first 2 weeks (65 kcal and 1.5 g protein/100 ml) and mature breast milk composition thereafter (72 kcal and 1.4 g protein/100 ml).10 Daily (sample closest to 08:00) serum sodium and potassium concentrations and base deficit for the first 30 days of life were extracted from the patient records. All blood glucose concentrations for the first 30 days were recorded.
Infants were weighed on alternate days, or twice per week, as per protocol. For weight data, weeks 1–4 were determined individually for each baby by dividing the 30 days of the study into four reasonably equal time periods where a weight was available on the last day. Data are expressed as g/kg.day accounting for minor variation in weight intervals. Babies were weighed nude using electronic scales accurate to ±10 g. Crown-heel length was measured with a Harpenden neonatometer (Holtain, Dyfed, Wales) when clinically feasible or a paper tape measure.11 Head circumference was measured using a paper tape measure.12
GV was calculated using: GV=(1000×ln(Wn/W1))/(Dn−D1) where W=weight (g) and D=day of life on days n (end of time interval) and 1 (beginning of time interval).13 Growth data SD Z-scores were calculated individually for each baby using Australian normative data.14
Comorbidities were defined as follows: chronic lung disease (CLD), oxygen requirement at 36 weeks’ postconceptional age; NEC, Bell's stage 2 or higher15; severe intraventricular haemorrhage, grade 3 or 416; late-onset sepsis, positive bacterial culture after 7 days of life in cerebrospinal fluid, urine or blood with clinical signs of infection requiring ≥48 h antibiotics; hyperglycaemia, blood glucose concentration >10 mmol/l17; hypoglycaemia, blood glucose concentration <2.6 mmol/l.18
Data analysis
Data were analysed using JMP5 (SAS Institute INC, Cary, North Carolina, USA). Continuous data were transformed to approximate normality where appropriate and analysed with an unpaired t test or repeated measures analysis of variance (ANOVA). Data that could not be satisfactorily transformed were analysed by non-parametric Wilcoxon test. Nominal variables were assessed by Fisher's exact test. Associations between nutrient intakes and growth were investigated using linear regression analyses. All data are presented as numbers (%) or as mean (SD). Statistical significance was assumed at p<0.05.
Ethical approval was not required for this study.
Results
Patient characteristics were similar in both cohorts (table 2). Total energy intake was similar in all weeks except week 1 (table 3), due to more Hi Pro babies commencing intravenous lipid on day 1 (92% vs 66%, p=0.003). Mean daily protein intake in the Lo Pro cohort did not reach the recommended range at any time, and was significantly less than in the Hi Pro cohort (p=0.0007), in which mean daily protein intakes met recommended levels throughout (table 3). The mean total protein intake in the Hi Pro cohort reached 3.5 g/kg.day on day 5 and increased to 4 g/kg.day by day 7. The greatest difference between the two cohorts was on day 7 (Lo Pro 2.8 (0.7) vs Hi Pro 4.1 (0.7) g/kg.day; p=0.0001.
Baseline characteristics of babies in the Lo Pro and Hi Pro cohorts
Total fluid, energy and protein intakes weeks 1–4
The first feed was expressed mother's own breast milk for all babies, and the majority of babies in both cohorts had feeds of only expressed breast milk for the first 30 days of life, by which time only two babies in each cohort were completely formula fed. Breast milk fortifier was added 4 days earlier in the Hi Pro cohort than in the Lo Pro cohort (p=0.003; table 4).
Enteral feeding data during the first 30 days of life
There was no difference between the cohorts for electrolyte concentrations, blood glucose concentrations or the incidence of hypoglycaemia or hyperglycaemia (data not shown). The Hi Pro cohort had a significantly lesser base deficit than the Lo Pro cohort throughout (week 1: −3.7±2.3 vs −5.0±1.8 mmol/L, p=0.002; week 2: −0.8±2.8 vs −2.8±3.1 mmol/L, p=0.001; week 3: −0.8±2.8 vs −3.3±3.3 mmol/L, p=0.0001; week 4: 0.2±3.0 vs −1.7±2.9 mmol/L, p=0.002). There were no differences between the two cohorts for most comorbidities or for death, and length of stay was similar (table 5). More babies in the Hi Pro cohort developed CLD (table 5). There were no significant differences between babies who developed CLD and those who did not in either mean lipid intake in the first week (2.3 (0.5) vs 2.3 (0.4) g/kg.day; p=0.6) or protein intake in the first 30 days (3.5 (0.4) vs 3.6 (0.4) g/kg.day; p=0.51).
Mortality and morbidity from birth to discharge
GV over the first 30 days in the Hi Pro cohort was 20% greater than the Lo Pro cohort (p=0.002; table 6). In both cohorts, there was a significant fall in Z-scores for weight, crown-heel length and head circumference over the first month of life (figure 1). However, babies in the Hi Pro cohort grew better than those in the Lo Pro cohort, and were significantly heavier (p=0.03) and longer (p=0.03) at 4 weeks of age. Between birth and discharge, the Hi Pro cohort had significantly lesser decreases in Z-score for weight, length and head circumference than the Lo Pro cohort (figure 1). For weight, the Hi Pro cohort had no overall change in weight Z-score between birth and discharge.
Time to regain birth weight and growth velocity in the first month of life
Z-scores for weight (top panel), length (middle panel) and head circumference (bottom panel) from birth to discharge. ●=Lo Pro babies; ◻=Hi Pro babies. Data are mean±SD. p Values represent the time×group interaction on repeated measures ANOVA analysis. ANOVA, analysis of variance.
Discussion
We have demonstrated that recommended protein intakes can be achieved in ELBW babies without individualised nutritional prescriptions. The protein intakes reported in this study are above those reported in many studies,3 ,19–22 resulting in growth velocities at the upper level of the currently recommended range, and achieved the goal of matching intrauterine weight gain at discharge.23 ,24 Achieving these protein intakes and growth velocities abrogated postnatal growth faltering for weight, and mitigated that for length and head circumference, supporting the concept that early higher protein intakes are necessary to more closely approximate growth in utero and prevent the downward crossing of centiles that is so common in ELBW babies. However, our data also suggest that the currently recommended level of protein and, perhaps, energy may not be high enough to achieve intrauterine GV (reported to be approximately 21 g/kg.day between 23 and 27 weeks’ gestation)25 in the first month, and may need to be increased. An alternative explanation is that the protein content of breast milk has been overestimated and, thus, babies in the Hi Pro cohort actually received less than 4 g/kg.day that we have calculated.
The Hi Pro cohort had a significantly better base deficit in the first month than the Lo Pro cohort. This may be due to higher oxidation of protein for energy in the Hi Pro cohort. Blood urea concentrations are not reported in this study because they were not routinely measured in our NICU. Other studies have found no difference in blood urea and ammonia concentrations, or in acid base balance between cohorts receiving high and low protein intakes even when early intravenous protein intakes reached 4 g/kg.day.26–31
The standard intravenous nutrition solutions used in our study supplied almost all recommended nutrients, except full energy, in only 30 ml/kg.day for the first 48 h and thereafter in 111 ml/kg.day of fluid. The rationale for providing full nutrition in small volumes is twofold. First, evidence suggests that restriction of water in the first week of life in preterm babies reduces the risk of patent ductus arteriosus and NEC, and may reduce the risk of CLD and death,32 and our unit, therefore, prescribes 60 ml/kg.day as the initial fluid volume. Second, our previous study demonstrated that when full nutrition is provided only within the total prescribed fluid volume, additional infusions (such as inotropic support, sedation/analgesia and antibiotics) inevitably mean that nutritional fluid is replaced with the medications’ diluent which, at best, from a nutritional perspective, is 10% dextrose.8 By concentrating full protein requirements in a smaller volume, fluid volume required for intravenous medications displaces the equivalent volume of 10% dextrose rather than of intravenous nutrition solution, because the total fluid intake is made up with 10% dextrose ‘piggy-backed’ with the intravenous nutrition.9 As many medications can be made up in 10% dextrose, this usually results in no loss of nutrition; if alternative diluents are necessary, then energy, but not protein, intake may decrease.33
There are some important differences between the nutritional management of babies in this study and much of the published data for ELBW babies, which are predominantly based on babies who received intravenous nutrition for longer and who were then formula fed.23 ,34–36 By contrast, 80% of the babies in the Hi Pro cohort received 4 g/kg.day protein in the first week of life, and almost half received 4 g/kg.day by day 5. Most received 3 g/kg.day lipid by day 3. All the babies in both cohorts had enteral feeds initiated with mother's own breast milk, and reached full enteral feeds by the end of the second week, and the majority had only mother's own breast milk for the first 30 days of life. This nutritional management meets current international consensus nutritional recommendations,5 and yet, still did not achieve intrauterine GV for length in the first month of life.
Short-term clinical outcomes were similar in the two groups, apart from the higher incidence of CLD in the Hi Pro cohort. However, there was no significant difference between the Hi Pro and Lo Pro cohorts in the number of babies who died of CLD or who went home on oxygen. The finding that babies in both cohorts who developed CLD had similar fluid, lipid and protein intakes suggests that this finding is probably due to chance. Nevertheless, future randomised controlled trials of nutrition in ELBW babies should monitor respiratory outcomes.
Limitations of this study are the potential bias inherent in non-randomised studies, and the possibility that there were changes in management practices over the duration of the study which may have affected the cohorts differently as they were not contemporaneous. The sample size was too small to reliably detect differences in clinical outcomes. The predominant use of expressed breast milk in the first month of life is a strength, but also means that once enteral feeds were established, energy and nutrient intakes are estimates.
We conclude that it is possible to achieve recommended nutritional intakes with commercially available concentrated intravenous nutrition solutions, feeds and fortifiers. The nutrition policies developed in this study are easily translatable to other newborn services both nationally and internationally. Higher protein intakes were associated with significantly better GV and less faltering growth for weight, crown-heel length and head circumference from birth to discharge. Future studies, ideally involving randomised controlled trials, should investigate whether current recommended protein intakes are appropriate for optimum clinical, neurodevelopmental and long-term metabolic health outcomes for ELBW babies.
Acknowledgments
We thank Jane Harding and Carl Kuschel who helped design the concentrated IVN solutions, Carl for all IT support and Helen Lamb for her assistance with data collection. We acknowledge the assistance of National Women's Health Newborn Services medical and nursing staff and thank them for their support to implement the new policy.
References
Footnotes
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Contributors BEC wrote the study proposal, applied for ethics approval, collected and analysed the data, and wrote the first draft of the manuscript. FB advised on the study proposal, ethics approval, and supervised the data analysis. Both authors contributed to and approved the final manuscript.
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Competing interests None.
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Ethics approval The Northern Regional Ethics Committee (Auckland, New Zealand).
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Provenance and peer review Not commissioned; externally peer reviewed.
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