Effect of standardized feeding protocol on nutrient supply and postnatal growth of preterm infants: A prospective study

1 Introduction

Infancy and early childhood are considered critical periods with a high risk of irreversible faltering in linear growth and cognitive deficits [1, 2]. Inappropriate nutrition (either over or under) during these critical periods contribute to significant morbidity and mortality [3]. Studies have shown that adequate supplies of nutrients during the first month of life contribute to a significantly higher intelligence quotient and reduced risk of cerebralpalsy [4].

The number of children born prematurely has increased substantially during the last decade’s worldwide [5]. These infants are strongly nutritionally challenged because of the interruption of maternal transfer and fetal accretion of nutrients. As a consequence of these deficits preterm infants have problems to achieve a growth trajectory similar to that of the last trimester [6].

Most very preterm infants experience major protein and energy deficits during neonatal intensive care unit hospitalization. Even protein and energy intake during the first week is associated with later developmental outcomes in the patients [7].

Neonatologists and other health professionals involved in neonatal care rely mainly on the assessment of growth patterns to determine whether or not nutrition support is adequate. Normal fetal growth for example, comprises a doubling in weight, from 30–36 weeks of gestation, alongside with remarkable tissue differentiation [8]. It remains a big challenge to match this quality and quantity of growth and development in infants whose nutrient supply via the umbilical cord has been prematurely interrupted. Major progress has been achieved in our understanding of meeting their nutritional needs, but surprisingly still a great deal of variability exists in clinical practice around the world, within countries and even between centers.

Preterm infants are not a homogenous population thus intake often needs to be individualized based on clinical condition and developmental stage [9]. Nutrient requirement estimates are intended for apparently otherwise “healthy” preterm infants. Unfortunately most very preterm infants (VPI) and extremely preterm infants (EPI) are sick, and therefore, their nutritional requirement cannot be simply estimated from needs of healthy neonates. Moreover scientific basis to estimate nutrient needs according to specific disease categories is lacking in mostcases [9].

Evidence based standardized feeding guidelines have been published by different organizations such as American Academy of Pediatrics (AAP) [10]. The Canadian Pediatric Society (CPS) [11], the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) [12, 13] and the Life Sciences Research office [14]. These guidelines cover either parenteral or enteral nutrition, requiring centers to define their own local combined parenteral/enteral nutritional support protocols. Nevertheless, implementation of these guidelines may reduce practice variation within a center. Development andimplementation of a standard feeding protocol based on these guidelines could improve postnatal growth and clinical outcomes [15].

Keeping this in view, we planned a prospective follow up study to evaluate nutrient supply and growth outcomes of preterm infants born <32 weeks in response to a standard feeding protocol. The main aim of the study was to analyze postnatal nutrient supply and growth patterns in response to nutritional support provided to very and extremely preterm infants during stay at NICU.

2 Methods

A prospective cohort study was conducted including preterm infants born <32 weeks entering the NICU during a 1-year-time period. Inclusion criteria was preterm birth (<32 weeks), and exclusion criteria were congenital malformations, metabolic disorders and surgical conditions.

Primary outcomes are the daily amount of each nutrient supply (protein, glucose, fat, energy and fluid) and secondary outcomes are the growth parameters (weight, length and head circumference). The parents of the study population gave consent for participation in the study and for the use of anonymized data for scientific research. The study was approved by the local Ethics Committee.

3 Results

During the observation period a total of 100 preterm infants (<32 weeks GA) were admitted at NICU-Children Hospital Graz. Infants were stratified according to gestational age: EPI born <28 weeks GA and VPI born≥28 to <32 weeks GA. Seventeen infants had to be excluded [transferred to surgery (n = 10); died (n = 7)] so 83 infants were included in analysis.

Basic characteristics of the total sample and the two groups of EPI (n = 27) and VPI (n = 56) are shown separately in Table 1. EPI compared to VPI stayed longer on parenteral nutrition (28.8 vs 9.3 days, p < 0.001), needed more time to reach full enteral nutrition (FEN) (21.0 vs 8.7days, p < 0.001), more frequently received postnatal steroids (37% vs 1.8%, p < 0.001), were ventilated for a longer time (19.1 vs 1.4 days p < 0.001), had less often the diagnosis IUGR (0% vs 17.9%, p < 0.001) and had a higher corrected age at discharge (p < 0.001).

The same standard feeding protocol based on 2005 and 2010 ESPGHAN guidelines was followed in both groups. Tables 2 and 3 give a detailed description of average weekly macronutrient (proteins, glucose and fat), fluid and energy supply. Nutrient supply was significantly different between the two groups, during the first 5 weeks of admission. Comparison beyond 5 weeks was not possible because mean length of stay in hospital for VPI was only 6.5 weeks.

By the 5th week of life 100% of VPI and 54% of EPI were receiving full enteral nutrition (FEN). The remaining 46% of EPI were receiving a combination of enteral and parenteral feeds. 61% of VPI and 88% of EPI were exclusively receiving human milk. As mentioned earlier EPI reached FEN later than VPI (Table 1) so as a consequence fortification was also started significantly later 15 th day of life vs 10th day of life respectively.

In our population of EPI and VPI, following a standardized unit specific feeding protocol led to significant differences in various growth parameters and actual nutrient supply between the 2 groups. Similar to our findings, Embleton et al., (2001) conducted a study to analyze factors related to postnatal malnutrition and growth retardation. They reported that 45% of growth variation was related to nutritional intake and 7% was related to birth weight but other 45% growth variation was unexplainable [19]. This raises the question whether nutritional support alone is sufficient to produce optimized growth outcomes or not. Overall care practices might also need to be adjusted according to individual cases. Gestational age at birth is one of the important contributors towards achievement of better growth outcomes, [20] but nutritional and medical care during the hospital stay can also play a vital role [21–23]. VPI and EPI experience a variety of challenges in extra uterine environment. For example early onset of sepsis, infant respiratory distress syndrome (IRDS), bronchopulmonary dysplasia (BPD) and intraventricular hemorrhage (IVH) etc. [24], which determine their nutritional requirements and can be different from healthy neonates. The results of present study show that EPI received parenteral nutrition longer than VPI, and they reached FEN later as well. EPI also remained on ventilator for a longer duration which reflects these infants experienced more breathing problems as compared to late preterm infants. Recently a study reported that parenteral nutrition can have additive effect on prolonged oxidative stress and increased risk of BPD in EPI [25]. Thus, enteral feeding has to be regarded as extremely important. When we analyzed the reasons for the differences in nutrient supply in our study population, it became evident, that it was most pronounced in week 2 and 3 and that the main difference was in the amount of fortification of enteral feeding. There were no differences in the volume intake between both groups, but EPI group reached FEN later and this led to delayed initiation of fortification of feeds resulting in compromised protein and energy supply. The feeding intolerance is one of the major problems in nutritional management of preterm infants who are born less than 28 weeks [26]. There are numerous factors that influence feeding tolerance for example intestinal motility, gastric emptying, stool output, digestive enzymes, type of milk, rapidity of feeding, volume of feeding, concentration of milk, concomitant medications, and medical conditions. Clinical decision-making to initiate, advance or discontinue feedings can be directly related to infant’s ability to tolerate enteral feeds. Therefore, feeding intolerance could be a primary determinant of the prolonged duration of parenteral nutrition and hospitalization [27].

Nutritional supply during early infancy can either help to sustain metabolic capacity or can develop metabolic load. Interpreting our results in light of the amounts of nutrient intake currently recommended by ESPGHAN for preterm infants, [12, 13] overall initiation of macronutrients fell just below the guidelines in the first week of life, but EPI received significantly lower amounts of nutrients than VPI later during the next 5 weeks.

According to ESPGHAN recommendations a reasonable intake of energy is 110 to 135 kcal kg ^- 1 day ^- 1 and therefore our study group was provided sufficient energy. The lower intake levels during the first days of life fit to the recommendations of the AAP defining in more detail this important vulnerable nutritious phase in preterm infants [10, 28].

The ESPGHAN- recommendations generally recommend starting protein supply within 24 hours after birth at 1.5–3.0 g/kg/day with daily advancement to reach the goal of 3.5–4.0 g/kg/day for parenteral supply [13]. Whereas for enteral supply the recommended range of protein intake is 3.5–4.0 g/kg/d for infants with birth weight of 1000–1800 g and 4.0–4.6 g/kg/d for infants with birth weight up to 1000 g [12]. In our cohort, mean protein supply was 2.4 g/kg/d in both groups in week 1 and reached a maximum protein supply of 3.73 g/kg/d during first 5 weeks. In the first 5 weeks of life the switching from or combination of parenteral and enteral nutrition is a very challenging task. In our cohort the maximum protein intake goal was not reached according to ESPGHAN and AAP guidelines.Recommended intakes of protein for EPI (with mean birth weight <1000 g) were achieved following standard feeding protocol after 3 weeks of life according to AAP (3.5–4.4 g·kg ^- 1·day ^- 1) [10]. Energy supply was significantly lower in EPI compared to VPI. This shortfall of protein and energy can lead to growth deficits by term gestation. On the other hand results from recent studies suggest caution in the use of high rates of protein infusions in preterm babies, particularly in those who are sick, metabolically unstable early after birth [29]. Studies related to nutritional management of preterm infants indicate that optimized growth rates cannot be achieved with inadequate supplies of protein and energy [7]. To prevent the protein and energy deficit, it is suggested that during this critical period, on one hand prompt initiation of parenteral amino acids should be initiated with 3.0 g/kg/d within hours after birth and advanced to 4.0 g/kg/day and on other hand fortification should be initiated earlier at least when enteral volume of 80–100 ml/kg/d is achieved [29–31]. Some studies most recently suggest introduction of fortification even earlier [32, 33].

Mean glucose supply during the first week of life mostly reflects intravenous glucose infusions for all preterm infants but EPI mostly receive parenteral nutrition for a longer time. Glucose infusion rate is recommended to start with 4–8 mg/kg/min with maximum increase up to 10 mg/kg/min (14.4 g/kg/d) [13]. For enteral nutrition 11.6–13.2 g/kg/d glucose supply is recommended [12]. In our cohort, mean glucose supply was initially offered with 7.66 g/kg/d to EPI and 8.12 g/kg/d to VPI which increased progressively to 16 g/kg/d for EPI and 14.4 g/kg/d for VPI at week 5. EPI were receiving significantly less glucose supply during week 2 and 3, but in week 5 EPI were receiving significantly higher glucose supply compared to VPI. Both groups exceeded the upper limits of ESPGHAN recommendations in regard to glucose supply in week 5. This increased supply of glucose was continued during week 6, 7, 8 and 9 for EPI (data is not shown here). Increased supply of glucose can be the consequence of two clinical practices. Most preterm infants who are unstable and stressed are fed too aggressively with intravenous dextrose [34] or mother milk fortification can end up providing higher glucose supply. In our cohort 88% of EPI were receiving fortified mother milk, which may have led to higher glucose supply. Hence our results suggest that glucose intake should be closely observed during FEN phase. There is need to monitor mother milk fortification very carefully. This point needs to be evaluated in future studies to answer the question whether the composition of mother milk fortifiers need to be modified in order to stay within ESPGHAN/AAP recommendations.

Mean fat supply g/kg/d is recommended at 0.5–1.0 g/kg/d on the first day with incremental advancement to a goal of 3.0–4.0 g/kg/d at the end of week 1 for parenteral nutrition, [13] whereas for enteral nutrition fat intake is recommended to be 4.8–6.6 g/kg/d [12]. Results of our study showed that mean fat supply (g/kg/d) in both groups was in the range of ESPGHAN recommendations, however EPI were receiving significantly less than VPI during first 5 weeks of life. Early and aggressive initiation of intravenous lipids seems to be safe and effective. Extremely preterm infants can tolerate higher amounts of fats, but it is necessary to determine whether higher fat supply is required or not, because provision of additional energy in form of fat promotes more fat mass. Although the rate of weight gain during stay at NICU is directly proportional to absolute intake of protein and energy, the relative composition of the weight gained depends on protein-energy ratio of the diet [35].

The limitation of this study is missing data on additional care conditions maybe influencing nutritive supply. However, according to the presented data we conclude that, a standardized protocol, based on evidence-based recommendations can facilitate adequate nutrient delivery and growth outcomes in very preterm infants. In this cohort very preterm infants could receive nutrient intakes close to recommendations [10, 13] and their weight for age Z-scores of week 1 were achieved at discharge. Despite better nutrient supply, 19% of these infants were below 10th percentile at discharge. As mentioned earlier, our results suggest that extra uterine growth retardation (EUGR) may be unavoidable in some infants. Similar to our results, it has been reported earlier on postnatal growth retardation to be an inevitable outcome that cannot be prevented with current recommended nutrient supplies for preterminfants [19].

In EPI significantly more infants, 37% were below the 10th percentile of weight at discharge. Although nutritional support in NICU and post discharge has been improved, still extremely immature survivors continue to suffer postnatal growth deficits [19, 35]. A similar study reported extra uterine growth restriction remained high in extremely premature infants [36]. Further research is needed to define the strategies to improve nutritional support of preterm infants; particularly extremely preterm infants, because immediately after preterm birth, infant is different from fetus and extent of prematurity seems to have strong impact on postnatal growth. Therefore, EPI should not be expected to follow fetal growth pattern and there is need to establish separate growth standards for this vulnerable group.

6 Conclusion

After implementation of a standardized feeding protocol, WAZ scores in both groups remained below zero during observation period. At discharge all anthropometric Z scores were significantly lower in EPI group.

Of interest is the fact that nutritional care practices for these diverse groups need more attention and particularly extremely preterm infants should be provided aggressive parenteral nutrition during first 3 weeks of life if significant progress in enteral intake is not achieved. If enteral feeds are tolerated well, fortification should be initiated when 100 ml/kg/d enteral volume is achieved. Moreover, the use of mother milk fortifier resulted in glucose intake above the ESPGHAN/AAP recommendations –this needs to be evaluated in future studies.

Conflicts of Interest and Source of Funding

Khan Z received a scholarship for her Doctoral Studies from Higher Education Commission (HEC) Pakistan and OeAD.

For the remaining authors, there is nothing to declare.