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Blood biochemical profile of very preterm infants before and after trophic feeding with exclusive human milk or with formula milk

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  • Balearic Health Sciences Research Institute (IDISBA)

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To determine whether feeding type of trophic feeds affect haematological and biochemical markers in the very preterm infant. Fifty-six very preterm infants were enrolled in this retrospective study (30 infants were included in the only human milk-fed group and 26 in the formula-fed group). Routine haematological and biochemical variables were collected in both groups on days 1 and 4 of life and fourteen serum markers were measured. There were no significant differences between the two groups before starting trophic feeds. After starting trophic feeds, sodium and lactate levels were significantly higher in the human milk-fed group compared with those measured in the formula-fed group. The study demonstrates that supplementation of minimal enteral feeding with human milk does affect biochemical profiles in very preterm infants. Small amounts of enteral feedings of formula and/or human milk may result in different metabolic responses; these differences are reflected by different serum biochemistries.
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Blood biochemical prole of very preterm infants before and after trophic
feeding with exclusive human milk or with formula milk
Sergio Verd
a,
,MaríaJoséGarcía
b
, Antonio Gutiérrez
c
, Eli Moliner
b
,EstherLópez
b
, Gemma Ginovart
b
a
Department of Paediatrics, Hospital de la Santa Cruz y San Pablo, 90 Mas Casanovas St., 08041 Barcelona, Spain
b
Neonatal Unit, Department of Paediatrics, Hospital de la Santa Cruz y San Pablo, 90 Mas Casanovas St., 08041 Barcelona, Spain
c
Division of Hematology, Molecular Biology Unit, Hospital Son Espases, Valldemossa Road 79, 07010 Palma de Mallorca, Spain
abstractarticle info
Article history:
Received 22 December 2013
Received in revised form 10 February 2014
Accepted 14 February 2014
Available online 24 February 2014
Keywords:
Breast milk
Minimal enteral nutrition
Preterm infant
Acidosis
Ions
Objectives: To determine whether feeding type of trophic feeds affect haematological and biochemical
markers in the very preterm infant.
Design and methods: Fifty-six very preterm infants were enrolled in this retrospective study (30 infants
were included in the only human milk-fed group and 26 in the formula-fed group). Routine haematological
and biochemical variables were collected in both groups on days 1 and 4 of life and fourteen serum markers
were measured.
Results: There were no signicant differences between the two groups before starting trophic feeds. After
startingtrophic feeds, sodium and lactatelevels were signicantly higherin the human milk-fed groupcompared
with those measured in the formula-fed group.
Conclusion: The study demonstrates that supplementation of minimal enteral feeding with human milk
does affect biochemical proles in very preterm infants. Small amounts of enteral feedings of formula and/or
human milk may result in different metabolic responses; these differences are reected by different serum
biochemistries.
© 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Introduction
In the rst postnatal days disturbances in the uid and electrolyte
balance occur frequently in very preterm infants. This imbalance can
lead to neurological impairment, amongst others [1,2].Previousstudies
have been designed to compare the biochemical status of newborn in-
fants fed human milk (HM) with that of similar infants fed formula.
No differences have been found in mean serum concentrations of
potassium, chloride, calcium, urea nitrogen, blood glucose, lactate or
pyruvate concentrations between feeding groups [3,4]. However, the
values for serum total proteins, albumin, gamma-globulins, serum cho-
lesterol, triglyceride, alanine aminotransferase, aspartate aminotrans-
ferase, gamma-glutamyltransferase, total bilirubin, direct bilirubin,
methionine, threonine, ketonebody and sodium levels were signicant-
ly higher in the breast-fed group compared with those measured in the
formula-fed group [48].
The milk amount required for this metabolic effect is not known.
These studies were carried out on full term neonates at or beyond day
5 of life, involving infants on nutritive milk feeds [9]. To date, no study
has been carried out to determine specically the effect on very preterm
neonates of nutritionally insignicant volumes designed to stimulate
the developing gastrointestinalsystem (gut priming or trophic feeding).
We hypothesise that a very small amount of human milk in the rst
days of life is enough to change the metabolic response of very preterm
infants.
In our neonatal intensive care unit (NICU), we recently implemented
the strategy to use pasteurized human donor breast milk (DM) on
preterm infants whose mothers suffered from breastmilk shortage.
Motivated by the scarce data available in the literature, we decided to
analyse our data in order to verify that our shift to exclusive human
milk trophic feeding during the rst four days of life was associated
with changes of biochemical and haematological markers in the prema-
ture baby.
Method
DM has been available in our NICU since April 2009. Thereafter, tro-
phic feeds consisted of non-fortied DM when there was an insufcient
mother's breastmilk supply. Until April 1, 2009, the nutrition regimen
consisted of preterm formula when there was an insufcient mother's
breastmilk supply.
This is a preliminary report that compares laboratory results of in-
fants who received only-HM with a historical cohort that received any
Clinical Biochemistry 47 (2014) 584587
Abbreviations: DM, pasteurized human donor breast milk; HM, human milk; NICU,
neonatal intensive care unit.
Corresponding author.
E-mail address: drsverd@gmail.com (S. Verd).
http://dx.doi.org/10.1016/j.clinbiochem.2014.02.017
0009-9120/© 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Contents lists available at ScienceDirect
Clinical Biochemistry
journal homepage: www.elsevier.com/locate/clinbiochem
amount of formula. We performed a retrospective search for laboratory
results for the rst four days of postnatal life from eligible infants
(b30 weeks of gestational age admitted to our NICU between 1st
January 2007 and 31st December 2012). Day 1 sample was taken before
starting feeds from every infant's rst available blood test result on day
1 of life. Day 4 sample was taken after starting feedsfrom every infant's
last available blood test result on day 4 of life. The following exclusion
criteria were the same for both groups: death on day 1 of life, admission
to the NICU after day 1 of life and fasting until day 5 of life. There was
one additional exclusion criterion for the historical cohort: exclusively
breastfed infants. Finally, 30 infants made up the experimental group
and 26 infants, the historical group.
Clinical features and laboratory parameters were collected from the
hospital charts. Infant growth wasclassied as small for gestational age
using the Fenton chart. Table 1 presents the variables considered to as-
sess the comparability of the two groups. The study was approved by
the Institutional Review Boards of our Hospital and informed consent
was obtained from parents of all infants.
Standard care
Enteral feeding was usually initiated on the second day of life. Every
infant received 1 mL every 3 h, with daily increments b10 mL/kg/day
according to clinical condition. Whenever possible, parenteral nutrition
was initiated on the second day of life. All infants received standard
management in the NICU. None of these practices changed over the
course of the study periods.
Evaluation of biochemical and haematological parameters
Electrolyte levels were measured by indirect Ion Selective Electrode
on the Abbott Architect CI16000 laboratory analyser. Conventional lab-
oratory analyses of pH and blood gases were performed with bench-top
analysers (GEM 3500 Premier).
Biochemical parameters were also measured by the Abbott Architect
CI16000 laboratory analyser. Complete blood count and the differential
leukocyte count were carried out on blood samples by a cell counter
(Sysmex XE-500, USA).
Statistical analysis
The data were analysed using the SPSS statistical package. Categori-
cal variables were compared by means of the χ
2
test or, when appropri-
ate, Fisher's exact test. Continuous variables were compared by means
of the t-test. Multivariate analysis was not performed because it is not
recommended for small samples.
Results
As shown in Table 1, only-HM and formula groups were comparable
in terms of maternal and infant characteristics, except in the case of age
at the onset of enteral feeds. Table 2 shows that there were no statisti-
cally signicant differences in laboratory results between the two
groups before starting the feeds.
After starting trophic feeds
Serum sodium levels (mean 141 versus 142 mmol/L; p = 0.026)
and serum lactate levels (mean 1.4 versus 1.6 mmol/L; p = 0.049)
were signicantly decreased in the formula group compared to the
only-HM group.
Glycaemia levels were close to signicantly decreased in the
formula group compared to the only-HM group (mean 5.8 versus
7.6 mmol/L; p = 0.065).
There were no statistical differences in any other biochemical or
haematological markers between groups.
Multiple births: surfactant therapy
There were considerable numbers of multiple births and of infants
requiring an exogenous surfactant. Hence, we have analysed if there
are any signicant differences in baseline biochemical parameters be-
tween these groups and if they respond similarly to trophic feeds.
Single births compared to multiple births. Baseline levels of sodium (136
versus 134; p = 0.019), haemoglobin (14.6 versus 15.5; p = 0.03)
and leukocyte count (13,320 versus 8260; p = 0.008) were signicantly
different. On day 4, levels of sodium (142 versus 137; p = 0.035),
haemoglobin (13 versus 13.8; p = 0.005) and potassium (4.3 versus
5.5; p = 0.033) were signicantly different.
Effect of exogenous surfactant. Baseline aspartate aminotransferase
levels were signicantly decreased in the without exogenous surfac-
tantgroup (25.5 vs 35.5; p = 0.017). On day 4, platelet count was
signicantly increased in the without exogenous surfactantgroup
(272,500 vs 161,000; p = 0.016).
There were no statistical differences in any other biochemical or
haematological markers between these groups.
Discussion
Comparison with other studies.
A recent international survey observed that most of the units with
access to DM start enteral feeding on the rst day of life and advance
more rapidly than units without access to DM [10]. These data are in
line with our ndings, where DM recipients exhibit an earlier onset of
enteral feeds.
Slight differences in sodium intake do not change sodium levels in
adults and supplemented diets (45 mmol sodium/day versus 11.5
Table 1
Premature newborn characteristics an d postnatal outcom e in the rst six days of life
according to type of feeding.
Baseline characteristics Formula
a
N=26
Human milk
a
N=30
P
Demographics
Gender (M/F), n 11/15 13/17 1.000
Primiparous, n (%) 10 (42%) 19 (63%) 0.11
Gestational age (wk), mean ± SD 27.36 ± 1.52 26.88 ± 1.54 0.67
Multiple births, n (%) 8 (32%) 8 (27%) 0.66
NI from another hospital, n (%) 4 (16%) 2 (7%) 0.27
Birth weight (g), mean ± SD 1000 ± 221 899 ± 237 0.55
Small for gestational age,n (%) 3 (12%) 5 (17%) 0.62
Perinatal care
Prenatal steroids, n (%) 20 (83%) 29 (97%) 0.093
Mode of delivery (V/CS), n 11/13 18/12 0.30
Apgar 5th minute, mean ± SD 8.13 ± 1.55 8.48 ± 1.05 0.10
Respiratory interventions
Exogenous surfactant, n (%) 18 (72%) 20 (67%) 0.67
Other interventions
Age at onset of enteral feeds (days),
mean ± SD
2.24 ± 0.83 1.97 ± 0.32 0.002
Postnatal outcomes
Early onset sepsis, n (%) 6 (24%) 3 (10%) 0.16
IVH grades 34, n (%) 2 (8%) 2 (7%) 0.42
Abbreviations: CPAP continuous positive airway pressure; CS Caesarean section;
Ffemale; g grams; IPPV intermittent positive pressure ventilation; IVH
intraventricular haemorrhage; M male; n number; NI newborn infant; SD
standard deviation; V vaginal delivery; wk weeks.
a
Given as a supplement to mother's own breast milk.
Signicant at the 0.05 level.
585S. Verd et al. / Clinical Biochemistry 47 (2014) 584587
mmol sodium/day) have been seen not to change sodium levels in very
pretermneonates from the 5th to the 11th postnatal day [11]. Therefore,
elevated breast milk sodium concentration is not regarded as responsi-
ble for elevated plasma sodium levels. Conversely, recent evidence sug-
gests that articialfeedings appear to exerta separate detrimental effect
when they replace breast milk as initial postnatal nutrition [12].
Our data are in agreement with those of Anctil et al. [13]. They have
unequivocally shown that mean blood sodium concentration was sig-
nicantly higher in exclusively breastfed infants, when compared to
formula-fed infants. It is worthy to note that as the volume of breast
milk supplied increases, the sodium blood level gap between exclusive-
ly breastfed infants and non-exclusively breastfed infants widens (from
1 mmol/L in our study to 6 mmol/L in Anctil's study).
Mean lactate levels in our sample are close to hyperlactataemia
(2 mmol/L) on day 1, whereas on day 4 they are well below this g-
ure. This is at odds with previous analyses which have noted that lactic
acid levels decline rapidly in the rst postnatal week [14].Thisdecline
can be explained in part by the metabolic effects of feeding practices
in the preterm infant. Lucas et al. [15] measured blood levels of several
metabolites and hormones before and after the rst feed of breastmilk
in a group of neonates. They found that the mean fasting lactate blood
level was 2.0 mmol/L and the mean lactate blood level after an infusion
of 2.5 mL of breastmilk/kg/h was 1.67 mmol/L.
Our study has several limitations owing to its retrospective design,
including the risk of conrmation bias. Hence, the comparison of groups
according to feeding type could not be controlled. To minimise these
limitations, we have adjusted for prenatal and postnatal characteristics
to reduce confounding, but there is a potential confounding impact of
age at start of enteral feeds. It is unlikely that by day 4 the babies re-
ceived different cumulative volumes of milk because of cautious ad-
vances of b10 ml/kg/day. Our data are particularly robust thanks to
the lack of variability of objective standardised laboratory results. The
descriptive design of this study yields enlightening conclusions,
avoiding unethical experimental trials.
Conclusion
This study demonstrates that trophic feeding with human milk is
reected by different serum biochemistries. It appears that a very
small amount of human milk in the rst days of life affect metabolic re-
sponse of very preterm infants.
Acknowledgments
We thank the families of patients who agreed to participate in the
study. The authors would like to acknowledge nurses and paediatricians
working at the nursery section and, Cecília Martínez-Brú, M.D. and the
technical staff who have performed the analyses. We thank Berta
Verd, M.Sc., for editing the manuscript and Prof. Micah Leshem for
proof reading and thoughtful contributions.
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Table 2
Comparison of serum biochemical values and hematologic characteristics in preterm infants fed with supplements of donor milk or formula.
Variable
Median (interquartile range)
Formula
a
Number of patients = 26
Human donor milk
a
Number of patients = 30
P
DOL 1, before initiation of enteral feeds
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Bicarbonate, mEq/L 20 (18.620.7) 20 (1920.8) 0.50
Lactic acid, mmol/L 1.4 (1.11.8) 1.6 (1.42.7) 0.049
Abbreviations: AST aspartate aminotransferase; DOL day of life; IU international units; mEq milliequivalents; mmol millimols; L litre; WBCs white blood cells.
a
Given as a supplement to mother's own breast milk.
Signicant at the 0.05 level.
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The goal was to analyze the relationship between changes in serum sodium levels during the first month of life and impaired functional outcomes at 2 years of age for very preterm infants. All very preterm infants who were born at <33 weeks of gestation between January 1, 2003, and July 31, 2004, were hospitalized in the NICU, and survived to discharge were included in this study. Changes in serum sodium levels were measured, and infants were evaluated at corrected age of 2 years. The analysis involved 237 patients, for whom 3927 serum sodium determinations were performed during the first month of life. We defined 3 tertiles of changes in serum sodium levels. A total of 84 infants demonstrated small changes in serum sodium levels (<8 mEq/ L), 86 demonstrated large changes (8 -13 mEq/L), and 67 demonstrated very large changes (13 mEq/L). The reference group was represented by the first tertile. At 2 years of age, large and very large changes in serum sodium levels were significantly associated with risk of impaired functional outcomes, after adjustment for gestational age and perinatal and neonatal hospitalization characteristics (large changes: odds ratio: 3.5 [95% confidence interval: 1.1-11.8]; P = .04; very large changes: odds ratio: 5.1 [95% confidence interval: 1.3-13.6]; P = .02). Although large and very large changes in serum sodium levels may simply reflect the severity of illness and/or the quality of care, a causal relationship with outcomes cannot be excluded. Cautious fluid and electrolyte management is recommended for very premature infants.
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Background: The nutritional requirements of prematurely born infants are different from those of babies born at term. Inadequate or inappropriate dietary intake in the neonatal period may have long term adverse consequences on neurodevelopmental function. The late effect of neonatal sodium deficiency or repletion in the premature human infant on neurological development and function has not been examined, despite evidence in animals of a serious adverse effect of salt deprivation on growth of the central nervous system. Methods: Thirty seven of 46 children who had been born prematurely (gestational age of 33 weeks or less) and allocated to diets containing 1-1.5 mmol sodium/day (unsupplemented) or 4-5 mmol sodium/day (supplemented) from the 4th to the 14th postnatal day were recalled at the age of 10-13 years. Detailed studies of neurodevelopmental performance were made, including motor function and assessment of intelligence (IQ), memory and learning, language and executive skills, and behaviour. Sixteen of the children were found to have been in the supplemented group and 21 in the unsupplemented group. Results: Children who had been in the supplemented group performed better in all modalities tested than those from the unsupplemented group. The differences were statistically significant (analysis of variance) for motor function, performance IQ, the general memory index, and behaviour as assessed by the children's parents. The supplemented children outperformed the unsupplemented controls by 10% in all three components of the memory and learning tests (difference not significant but p < 0.1 for each) and in language function (p < 0.05 for object naming) and educational attainment (p < 0.05 for arithmetic age). Conclusion: Infants born at or before 33 weeks gestation require a higher sodium intake in the first two weeks of postnatal life than those born at or near term, and failure to provide such an intake (4-5 mmol/day) may predispose to poor neurodevelopmental outcome in the second decade of life.
Article
The feeding of human milk (milk from the infant's own mother; excluding donor milk) during the newborn intensive care unit (NICU) stay reduces the risk of costly and handicapping morbidities in premature infants. The mechanisms by which human milk provides this protection are varied and synergistic, and appear to change over the course of the NICU stay. The fact that these mechanisms include specific human milk components that are not present in the milk of other mammals means that human milk from the infant's mother cannot be replaced by commercial infant or donor human milk, and the feeding of human milk should be a NICU priority. Recent evidence suggests that the impact of human milk on improving infant health outcomes and reducing the risk of prematurity-specific morbidities is linked to specific critical exposure periods in the post-birth period during which the exclusive use of human milk and the avoidance of commercial formula may be most important. Similarly, there are other periods when high doses, but not necessarily exclusive use of human milk, may be important. This article reviews the concept of "dose and exposure period" for human milk feeding in the NICU to precisely measure and benchmark the amount and timing of human milk use in the NICU. The critical exposure periods when exclusive or high doses of human milk appear to have the greatest impact on specific morbidities are reviewed. Finally, the current best practices for the use of human milk during and after the NICU stay for premature infants are summarized.
Article
Base deficit and serum lactate concentrations may be important prognostic indicators in preterm infants. We sought to (1) determine the relationship between day 1 serum lactate values and base deficit and (2) determine the relationship between day 1 biochemical parameters and adverse outcome in preterm infants <32 weeks. This was a retrospective study of all patients less than 32 weeks gestation admitted to neonatal intensive care unit over a 6-month period. All blood gases performed during the first 24 h post delivery were analysed. Adverse outcome was defined as death, severe (grade 3 or 4) intraventricular haemorrhage or periventricular leukomalaica on cranial ultrasonography. Patients were excluded if there was a known lethal malformation or cardiac defect. Seventy-two infants had a total of 473 lactate levels performed in the first 24 h. Mean (SD) gestational age was 29 (2.3) weeks, mean (SD) birth weight 1.28 (0.42) kg. Mean (SD) lactate values in first 6 h was 4.63 (3.69), at 12 h 3.08 (2.6), at 18 h 2.47 (2.68) and 2.08 (2.74) mmol/l at 24 h. There was a strong correlation between lactate values and base deficit values (R value 0.8, p < 0.01). Mean base deficit values at 6 h were 5.9 (4.5), at 12 h 3.8 (3.9), at 18 h 3.6 (3.1) and at 24 h 4.1 (3.8) mmol/l. A single lactate value greater than 5.6 mmol/l had a sensitivity of 100% and specificity of 85% of identifying adverse outcome. Persistently elevated or worsening lactates were associated with adverse outcome. There is a strong correlation between lactate values and base deficit on day 1 of life. Serial lactate measurements greater than 5.6 mmol/l predict adverse outcome and may aid the clinician in bedside decision making.
Article
The first feed of breast milk given to a group of 12 term infants was previously shown to increase the levels of blood glucose and plasma insulin, growth hormone (GH), gastrin, and enteroglucagon. We have now studied the effects of the first feed of breast milk in two similar groups of preterm infants, to compare the results with those obtained for the term infant. One group of 8 preterm infants received a bolus (2.5 ml/kg) of breast milk via a nasogastric tube; the other group of 5 infants received a continuous intragastric infusion (2.5 ml/kg per hour) of breast milk. No change occurred in the concentrations of blood glucose, lactate, pyruvate, or ketone bodies, or in plasma insulin, GH, pancreatic glucagon, or enteroglucagon in either the 'bolus fed' or the 'infusion fed' group of preterm infants. Thus the marked metabolic and endocrine changes in term infants after the first feed do not occur in preterm infants with standard methods of feeding.
Article
Results of a comprehensive longitudinal study comparing the effects of feeding healthy preterm infants with human milk or a specially adapted formula designed for the preterm infant are reported. 10 healthy infants were given human milk from birth, and 9 similar infants were given a formula which contained 80 kcal, 1.8 g protein, and 4.5 g fat per 100 ml. Anthropometric measurements were made weekly as were routine haematological and biochemical variables together with plasma amino acid and gastrointestinal regulatory peptide levels and metabolic fuel concentrations. Infants receiving the formula demonstrated a significantly greater growth velocity compared with infants receiving human milk. There were no significant differences between the two groups in routine haematological or biochemical variables measured nor in plasma insulin or blood glucose, lactate, pyruvate, or ketone body concentrations. Plasma amino acid profiles, however, did demonstrate some significant differences between the two groups with higher methionine and threonine levels in the formula-fed infants. Plasma motilin, enteroglucagon, neurotensin, cholecystokinin, gastric inhibiting polypeptide, and pancreatic polypeptide levels all demonstrated significant postnatal surges, with significant differences between the two groups in plasma gastric inhibiting polypeptide and pancreatic polypeptide concentrations.
Article
Investigations on the effect of colostrum feeding in 1–4-day-old newborn infants on serum proteins and their immunoglobulins were carried out. The values for serum total proteins, albumin and gamma globulins are higher in colostrum-fed infants than the artificially fed group. Immunoglobulin G and immunoglobulin A levels were significantly higher, while immunoglobulin M level was only slightly elevated in the former group. On the other hand, serum total proteins as well as albumin and gamma globulins levels were decreased in lactating compared with non-lactating females, while the alpha and beta globulins levels were higher for lactating than controls. For individual immunoglobulins; IgG level was lower and IgA, IgM levels were higher for lactating than non-lactating females.