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Preterm infants fed fortified human milk receive less protein than they need

Abstract

Objective:

The aim of this study was to compare the actual nutrient intakes observed in a previously reported study with assumed nutrient intakes based on the customary assumptions about the composition of human milk.

Study Design:

Fortified human milk is assumed to provide adequate amounts of nutrients for premature infants. This assumption holds if milk has the composition of milk expressed by mothers of premature infants during weeks 2 to 3 of lactation. The assumption does not necessarily hold for milk expressed after 2 to 3 weeks lactation. It also does not hold for donor milk, which is typically provided by mothers of term infants. The size of the disparity between assumed and actual nutrient intakes is not known. Actual nutrient intakes were available for 32 preterm infants participating in the study. Assumed nutrient intakes were calculated for these infants by substituting assumed nutrient concentrations for observed nutrient concentrations. Data were compared separately for each of the 3 study weeks.

Result:

Actual protein intakes were significantly and consistently lower than assumed protein intakes during each study week. The differences in mean intakes were large, ranging from 0.5 to 0.8 g kg−1 per day. Differences in energy intake were small and not consistently significant.

Conclusion:

Actual intakes of protein by preterm infants fed fortified human milk are substantially lower than assumed intakes. The discrepancy may in part explain why preterm infants frequently show postnatal growth failure.

Introduction

Human milk provides to preterm infants important protection against infection1, 2, 3 and necrotizing enterocolitis4, 5, 6, 7 and leads to better neurocognitive development.8, 9, 10, 11, 12 Therefore, it is the preferred feeding for preterm infants. However, human milk does not provide all the nutrients that preterm infants need, which is why human milk fed to preterm infants must be supplemented (fortified) with nutrients.13, 14 Commercially available fortifiers raise the nutrient levels of milk to levels that ensure adequate intakes of nutrients. In the case of protein, this is true only if human milk has the composition of milk expressed by mothers of preterm infants 2 to 3 weeks after delivery. Fortifiers are designed to raise the protein level of that specific milk to an adequate level. However, the protein concentration of preterm milk decreases with the duration of lactation below the 2 to 3 week level.13, 15, 16 Also, the protein concentration of banked donor milk, which is most often provided by mothers of term infants, is likely to be lower than that of milk of mothers of preterm infants.17 Hence, most human milk fed to preterm infants is likely to have an inadequately low protein concentration.

We hypothesized that the protein intakes actually received by preterm infants fed fortified human milk are less than intakes the infants are assumed to receive and that protein intakes of preterm infants are inadequate. Because the energy content of human milk is subject to less change with the duration of lactation than protein content, we hypothesized that actual energy intakes are similar to assumed energy intakes.

In the course of a recent study18 that tested a new method designed to ensure delivery of adequate amounts of nutrients to very low birthweight infants (adjustable fortification), the actual concentrations of protein and fat of human milk were determined. We now use this information to obtain estimates of the disparity between actual nutrient intakes and assumed nutrient intakes of preterm infants. The latter was calculated by assuming that milk had the composition of milk expressed by mothers of preterm infants during weeks 2 to 3 of lactation.

Methods

Study design and subjects

The original study18 was a prospective, randomized open-label trial comparing a new adjustable fortification regimen (ADJ) with a standard (fixed) fortification regimen (STD) in preterm infants. When the feeding volume reached 150 ml kg−1 per day, either full-strength STD fortification was continued or the infant was switched to the ADJ regimen. A total of 32 infants with birthweight between 600 and 1750 g and gestational age between 24 and 34 weeks completed at least 3 weeks of study.

Feedings

Most infants (83.3%) received parenteral nutrition starting soon after birth using central venous catheters. Feeding of unfortified mother's own milk or of donor milk from the hospital's milk bank was initiated during the first 3 days of life. Formula was not fed at any time. Addition of human milk fortifier (HMF) was initiated when feeding volume reached 90 ml kg−1 per day. The fortifier (FM 85; Nestlé, Italy) provided (per 100 ml of human milk) 0.8 g of protein in the form of hydrolyzed bovine whey proteins and 18 calories (from protein and maltodextrins) (Table 1). It was used at half strength (2.5 g per 100 ml of milk) for 2 to 4 days before it was increased to full strength (5 g per 100 ml). Infants assigned to the STD regimen received the standard amount of fortifier (5 g per 100 ml) throughout the study. In infants assigned to the ADJ regimen, adjustments of the level of fortification were made based on twice-weekly determinations of blood urea nitrogen (BUN). Every time the BUN was less than 9 mg per 100 ml, fortification was increased by one level. If the BUN was 9 to 14 mg per 100 ml, no change in fortification was made. Fortification level +1 was achieved by increasing the amount of HMF, and levels 2 and 3 by adding graded amounts of protein (Pro-Mix; Corpak MedSystems, Wheeling, IL, USA) in addition to HMF. Table 2 shows the amounts of HMF and Pro-Mix added at the different fortification levels as well as the amount of protein and calories added at each fortification level. A 24-h milk supply was prepared for each infant each morning by the addition of weighed amounts of HMF and of protein, if any. Aliquots of the prepared milk were removed on 2 days of each week, combined to form weekly pools and analyzed as described.18 The exact feeding volume, the level of fortification and the percentage of mother's own milk and donor milk were recorded daily.

Table 1 Nutrient composition of HMF and of supplemental protein (quantities added to 100 ml of milk) according to manufacturers
Table 2 Amount of HMF and protein supplement and assumed protein and energy content of preterm HM at the various fortification levels

Determination of assumed nutrient intakes

The protein content of HM was assumed to be 1.5 g per 100 ml, which is the reported protein content of preterm milk at 2 to 3 weeks of lactation,13, 15, 16 and energy content was assumed to be 67 kcal per 100 ml. To this were added the protein and energy from HMF and supplemental protein. Fat content was assumed to be 3.9 g per 100 ml. Assumed protein and energy intakes were calculated by multiplying protein and energy content by the recorded feeding volume.

Determination of actual nutrient intakes

The actual concentrations of protein and fat were determined and the energy content calculated for each study week as described.18 Actual protein and energy intakes were calculated by multiplying the determined protein and energy content by the recorded feeding volume.

Statistical analyses

Assumed and actual values were compared using paired t-tests. Statistical significance was set at the 5% level of probability. All statistical analyses were performed using the SPSS 14.0 program for Windows (SPSS, Inc., Chicago, IL). Unless indicated otherwise, the data are expressed as mean±s.d. values.

Results

The groups of infants (16 ADJ, 16 STD) were similar with regards to gestational age, Apgar scores, weight and head circumference and length at birth, and age and weight at study entry.18 In both groups, about 60% of milk was provided by the infants' own mothers and 40% was pasteurized donor milk from the hospital's milk bank. Mean fortification levels in the ADJ group increased significantly (P<0.001) over time, with mean levels being +0.9, +1.7 and +2.3, respectively, in successive study weeks. Intake volume was maintained around the target volume of 150 ml kg−1 per day in both groups.18 Stool output was similar in both groups (data not shown).

Assumed and actual milk composition

As Table 3 shows, the actual protein content of fortified milk was consistently lower than the assumed protein content. Differences in fat content and calculated energy density, although in the same direction as differences for protein, were on the whole quite small.

Table 3 Assumed and actual protein, fat and energy content of the fortified human milk and assumed and actual protein, energy intakes of the infants

Assumed and actual intakes of protein and energy

Actual protein intakes were consistently lower than assumed protein intakes (Table 3) throughout the study. The differences in protein intake were statistically significant and tended to be somewhat smaller in the STD group (difference in mean intakes 0.5 to 0.7 g kg−1 per day) than in the ADJ group (difference in mean intakes 0.8 g kg−1 per day). The range of differences among individual infants was −0.2 to 1.5 g kg−1 per day. In the STD group, mean actual protein intakes were consistently less than the requirement of 3.5 to 4.0 g kg−1 per day.18 Energy intakes, on the other hand, showed smaller differences between actual and assumed intakes, which were mostly not statistically significant (Table 3).

Discussion

In clinical practice, food intake is almost always quantified on the basis of caloric intake. Preterm infants are no exception in this regard. This practice tacitly assumes that intakes of all nutrients are adequate when caloric intake is adequate. This assumption is valid under many circumstances, but in preterm infants fed human milk the assumption is very often not valid. The main reason is that the composition of human milk, in particular its protein content, is changing with the duration of lactation. Because the actual composition of human milk is never known, the clinician makes assumptions regarding its nutrient content. The caloric density of expressed preterm human milk, although varying from pumping to pumping due to variation in fat content, on average differs little from the caloric density of term human milk, and the caloric density does not change much with the duration of lactation. Assuming that expressed preterm milk has the caloric density of term milk (670 kcal l−1) therefore is reasonable. Protein content of preterm milk, on the other hand, changes with the duration of lactation and is higher in expressed preterm milk than in term milk.17, 19, 20 For the purpose of arriving at a suitable protein level in fortifiers, manufacturers of HMFs have assumed expressed preterm milk to have the typical protein content observed at 2 to 3 weeks of lactation (15 g l−1). Although this is a reasonable assumption to make on the part of the manufacturer, the clinician's tacit assumption that all expressed preterm milk has this protein concentration is not justified. And it is certainly not justified to make this assumption with regard to donor milk, which is predominantly provided by mothers of term infants and has a protein concentration of 8 to 9 g l−1.17 Hence, the assumption that protein intakes are adequate when energy intakes are adequate usually does not apply to preterm infants fed human milk. On the basis of what is known about the protein content of expressed preterm milk and donor milk, we predicted that the actual protein intakes would be on average less than assumed intakes and therefore would be less than adequate.

The present study has confirmed this prediction. Actual protein intakes were indeed found to be less than assumed intakes and were found to be considerably less than adequate. It was somewhat surprising that the size of the discrepancy was relatively constant with advancing age of infants. Perhaps this suggests that the protein content of expressed milk had reached its nadir by the time the infants entered the study.

When growth of preterm infants lags behind expected growth (that is, growth like the fetus), it is almost always protein that is limiting growth.21, 22, 23 Energy, on the other hand, provided that intakes are at least 90 to 100 kcal kg−1 per day, is seldom limiting for growth. Therefore, the inadequate levels of actual protein intakes observed in the present study offer an explanation of why preterm infants fail to grow adequately in spite of receiving adequate energy intakes. Postnatal growth failure is strongly associated with suboptimal neurocognitive outcome.24 The lower intakes of energy (Table 3), on the other hand, would explain only small differences in weight gain. On the basis of the study by Kashyap et al.,25 the observed differences in energy intake would explain differences in weight gain of only 0.88, 1.68 and 1.38 g kg−1 per day, respectively, during weeks 1, 2 and 3.

The constancy of the discrepancy between actual and assumed protein intakes suggests that protein intakes could be raised to adequate levels by the relatively simple measure of increasing by a fixed amount the amount of protein added to human milk. That amount would need to be such that all milk, including milk with the lowest protein content, attains an adequate protein level. Milk with a relatively high protein content would of necessity attain a protein level somewhat in excess of an adequate level. Whether such a moderate excess is indeed harmless, as is expected, would have to be ascertained in appropriately designed studies.

At present only the method of adjustable fortification18 offers the possibility of overcoming the inadequately low protein content of human milk fed to preterm infants. This method has been shown to be effective. Whether addition of a fixed amount of protein is as effective in attaining adequate protein intakes as adjustable fortification is not known and needs to be tested. But until all preterm infants receive adequate protein intakes by one method or another, preterm infants will continue to grow suboptimally, with all the adverse consequences that slow growth entails.

Conflict of interest

The authors declare no conflict of interest.

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Arslanoglu, S., Moro, G. & Ziegler, E. Preterm infants fed fortified human milk receive less protein than they need. J Perinatol 29, 489–492 (2009). https://doi.org/10.1038/jp.2009.50

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Keywords

  • human milk fortification
  • adjustable fortification
  • protein intake
  • breast milk fortification
  • neonatal nutrition
  • preterm

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