Strategies in Neonatal Care to Promote Growth and Neurodevelopment of the Preterm Infant

Abstract

Recommendations for nutrition of very preterm and very low birth weight infants have developed over time with our understanding of the requirements of preterm babies and the awareness of widespread poor postnatal growth. In general, the trend has been towards enhancing nutrition, but more recent recommendations have begun to raise questions with respect to the potential for high and early nutritional intakes, particularly of protein, to carry risks such as refeeding syndrome. However, large gaps in our knowledge remain for both macro- and micronutrient requirements to support optimal growth and how nutrition and growth relate to important long-term outcomes. Closing these knowledge gaps has been hampered by inconsistent reporting of nutrition intakes and growth parameters, small trials with short-term outcomes and the use of a variety of different methods of monitoring growth. The challenge now is for future research to address these issues through consensus building around the important questions that need to be answered, how to report data from neonatal nutritional trials and whether large trials answering important questions can take place through development of consortia that undertake similar trials in multiple jurisdictions with agreements to share data. 
  
Supporting growth of preterm newborns, particularly those born very or extremely preterm, through regular monitoring on growth charts and careful attention to their nutrition is consistent with all pediatric practice, measuring growth of all children as surveillance for failure to thrive, malnutrition, or stunting. Why then, do we still not understand what the optimal growth trajectory is for these vulnerable babies nor have consensus on how we should measure them? Until recently, the generally accepted recommendation was that preterm babies should grow along a trajectory similar to that of the fetus. Yet we know that preterm babies, as a population, are born growth-restricted compared with their gestational-age-matched intrauterine peers who go on to be born at term. We use weight as a proxy for growth and we plot growth on cross-sectional charts of birth weight. The driver for promoting growth is that better in-hospital growth is associated with better neurodevelopmental outcome. The assumption follows that better nutrition will lead to better growth and, therefore, better neu- rodevelopmental outcomes, but high-quality evidence to support this assumption is lacking.

Measuring Growth

Weight is a measure of mass, not of growth. Increases in mass can be due to true growth of lean mass or accumulation of fluid or other tissue, such as fat or path-ological tissue. To assess growth requires measurement of length (in babies, rather than height). In babies, head circumference correlates well with brain growth, so measurement of head circumference also is a useful measure, although the potential impact of short-term changes due to molding of head shape from lying position or from equipment used to secure continuous positive airway pressure systems needs to be borne in mind. There are numerous length boards and neonatometers now available that fit easily into incubators and nonstretch head circumference tapes that make measurement of length and head circumference on a regular basis (e.g., weekly) relatively straightforward. Regular measurement of all three parameters should be routine practice in neonatal intensive care and smooths out the inevitable inaccuracies due to the challenges that exist in measuring sick preterm infants reliably and consistently. More precise measurement of linear growth, accurate to a magnitude of change similar to 1-2 days' linear growth, can be obtained for research purposes using a knemom- eter [1].

Monitoring Growth

When plotting preterm babies' size at birth on cross-sectional growth charts, the distribution approximates a Gaussian distribution, but when plotted on fetal growth charts the distribution is skewed to the left, demonstrating that, as a population, preterm babies are growth restricted [2]. Fetal growth trajectory is associated with gestation length [3]. However, fetal ultrasound charts do not in-clude length or head circumference, meaning they are not useful for the postnatal monitoring of growth.

Thus, postnatal growth needs to be measured on postnatal growth charts. Most of these are cross-sectional charts based on the birth weight of babies across the gestational age spectrum. The INTERGROWTH-21st consortium has published postnatal longitudinal growth charts for “healthy” preterm babies, but includes only 201 babies, 12 of whom were born very preterm (27-32 weeks' gestation, with none below 27 weeks) [4]. Large numbers of different birth weight centile charts for preterm babies are available and are used in reporting growth outcomes [5]. This makes comparing growth across studies very challenging, as the same baby plotted on different charts could be interpreted as having very different outcomes. For example, a baby born at 27 weeks with a birth weight that sits on the 10th per-centile on the UK-WHO growth charts and who then grows along the 10th percen-tile on the UK-WHO growth charts (with a z-score change of zero from birth to term-corrected age) will demonstrate a decrease of approximately one z-score when plotted on the Fenton growth charts and a drop of 1.2 standard deviations on the INTERGROWTH-21st postnatal growth charts (Fig. 1). An alternative to describing postnatal growth according to z-score change, at least until there is con-sensus on which chart should be used, is to describe the actual change in growth as an incremental change, for example grams per day or grams per kilogram per day. The latter is more robust, taking into account the size of the baby (similar incre-mental growth can be calculated for length and head circumference), but does not account for different growth velocities across the gestational age spectrum nor for sex. There remains debate about how best incremental change in growth should be calculated [5, 6]. Given the fact that all babies lose weight after birth (see below), should birth weight be used as a reference point, the minimum weight before weight-gain starts again or a fixed point in time when babies are expected to have stabilized their weight [7] ? All of the above have been proposed, and there are rea-sonable arguments for each, but clearly the reference point taken will impact upon the assessment of subsequent growth trajectory and, therefore, potentially the identification of faltering postnatal growth. Once a reference has been determined, there also are differences in the method used to calculate growth velocity, the three most common being: net weight gain over time interval divided by the time interval and starting weight; net weight gain over time interval divided by the time interval and the mean of starting weight and weight at the time of interest, and an exponential method. These different methods can result in substantial differences in estimated weight gain in g X kg-1 X day-1 with potential impact on nutritional decisions [5, 6].



Compounding the interpretation of postnatal growth is the tendency to use the term “extrauterine growth failure” to mean a baby's position on a growth chart at a particular point in time, for example, a baby below the 10th percentile at 36 weeks' postmenstrual age or at term-corrected age [8]. This, clearly, is a nonsense as an individual's position on the chart will be determined in a large part by the starting position of that individual and growth faltering is predicated upon a change in velocity, not on a static point in time. A baby born at or below the 10th percentile and who is just below the 10th percentile at term-corrected age is likely to have had perfectly adequate growth.
Furthermore, all babies lose weight after birth due to loss of extracellular fluid, and Rochow et al. [9] have demonstrated that, when plotted on the Fenton growth charts, this loss appears to stabilize at approximately -0.8 standard deviation (z) scores regardless of gestation. However, of note is that for very pre term babies, one standard deviation around the mean extends from a weight loss of approximately -0.4 to -1.2 z-scores, indicating that 17% of very preterm babies have a decrease in z-score for weight of greater than -1.2. Shifts in fluid and the effects of molding may also affect head circumference measurements after birth, and there is some evidence to indicate that linear growth also slows around birth, at least following vaginal birth, but these changes have not been quantified reliably for preterm babies and may be relatively greater than for term birth due to the stress associated with preterm birth [10].

To advance our ability to interpret growth of preterm babies and the impact of different growth trajectories on important outcomes, it is essential to be able to compare results of different research. To be able to do so, we need consensus on, at a minimum, the following: growth charts to be used for plotting growth; method of calculating postnatal growth velocity; the definition of postnatal faltering growth, and the growth variables to be reported.

Growth and Long-Term Outcome

The underlying reason for monitoring postnatal growth is to ensure that growth is adequate to support optimal neurodevelopment without adverse effects, such as excess accumulation of fat or later increased risk of adverse metabolic outcomes. For example, in preterm babies more rapid linear growth between term- corrected age and 4 months has been associated with decreased odds at age 8 years of an intelligence quotient more than one standard deviation below the mean (odds ratio [OR] and 95% confidence intervals [CI] 0.82 [0.70-0.96] per 1 z-score increase in linear growth), but increased odds of overweight or obesity (OR 1.27 [1.05-1.53]) [11].

Most studies report a positive association between in-hospital growth of ex-tremely preterm babies and long-term neurodevelopmental outcome (for example, see [12]), but this does not imply causation. Preterm babies that have a straightforward course are likely to both grow better and to have better neuro- developmental outcomes. As might be expected from the discussion above, the association between growth and outcome will depend upon the methods of de-termining growth and the definitions used to define adequate growth or growth faltering. Recent data from follow-up of a randomized controlled trial indicate that poor postnatal growth, defined as a decline in growth trajectory above a threshold, determined using fetal growth charts (that is, those using cross-sectional data from size at birth) may be a better predictor of poor neurodevelop- mental outcomes than poor postnatal growth determined using the longitudinal INTERGROWTH charts [13], but more data are needed.

Nutrition, Growth and Long-Term Outcome

In fetal life, growth is determined by nutrition; after birth, growth is determined by genes providing nutrition is sufficient. Multiple components of nutrition are required to support brain growth and development (Fig. 2). Breast milk compo-sition is highly variable, but when given at 150 mL X kg-1 X day-1, a common upper limit for enteral feeds, the macronutrient content, particularly of protein, is unlikely to be sufficient to support adequate growth. Additional macronutrients are, therefore, often provided as supplements to breast milk, either as mul-ticomponent fortifiers or as single macronutrient supplements. Cochrane meta-analyses suggest that these do result in increased in-hospital growth, including linear and head circumference growth, but the quality of evidence is low, and there are no data on long-term outcomes [14, 15]. Recent meta-analyses of trials that have provided nutritional supplementation (including enriched infant formula) to babies born preterm or small-for-gestational-age found that in toddlers (<3 years of age; 29-31 trials, 2,797-2,924 toddlers) supplementation increased weight (mean difference [95% confidence intervals (CI)] 0.16 [0.01-0.30] kg), and length/height (mean difference 0.44 [0.10-0.77] cm), but not head circumference (mean difference 0.15 [-0.03 to 0.33] cm), with a subgroup analysis of 2 trials (173 boys, 159 girls) finding an effect in boys but not girls [16]. There were no consistent effects through later childhood, adolescence, or in adulthood. Similarly, there were no effects on cognitive scores or cognitive impairment (21 trials, 3,680 infants), although once again subgroup analyses suggested that toddler boys, but not girls, may have small benefits in cognitive scores [17]. There also were no effects on motor scores, although fewer supplemented children had motor impairment (relative risk [RR] 0.76 [0.62-0.94]) [17]. These possible effects on cognitive scores in boys and for motor impairment did not persist through to childhood, although the number of children included is much smaller. The meta-analysis concluded that overall quality of evidence is low to very low; an individual participant data meta-analysis is underway [18].



Similarly, a meta-analysis of trials investigating higher versus lower parenteral amino acid intakes in preterm babies found a reduction in postnatal growth failure (defined as weight <10th percentile at discharge, RR 0.74 [0.56-0.97]) but insufficient evidence to assess impact on long-term neurodevelopmental outcomes [19]. Quality of evidence was very low, and there are several more recent trials not included in this meta-analysis.

In summary, trials of enhanced nutrition, or of nutritional supplementation, in preterm and small-for-gestational-age babies have, in general, focused on short-term outcomes, are mostly of small size, and provide low-quality evidence, with very few trials addressing outcomes that are truly important, such as survival free from neurodisability or childhood metabolic/cardiovascular health as the primary outcome.

Concerns also have been raised that providing enhanced nutrition to sick, preterm babies may be harmful [20]. Although most studies have found a positive association between nutrition and growth, some have reported decreased measures of growth [21, 22]. A further potential concern of enhanced nutrition is the risk of refeeding syndrome, a biochemical disturbance characterized by hypophosphatemia, hypokalemia, and hypercalcemia, which may arise upon refeeding malnourished individuals [23, 24]. As discussed above, as a population preterm babies are growth restricted, and many may have been exposed to relative undernutrition due to placental dysfunction. Refeeding syndrome has been reported to occur in a significant proportion of extremely preterm babies, to be associated with nutritional intakes, and with clinical outcomes [24]. However, refeeding syndrome appears to be more complex than simply being related to higher protein and energy intakes as, in a large, multicenter, prospective cohort study, the incidence of refeeding syndrome varied widely amongst centers, and some centers with higher protein and energy intakes reported lower incidences of refeeding syndrome [24].

In general, the current approach is to provide nutrition, particularly enteral nutrition, early to extremely preterm infants because of their minimal stores, rapid growth phase and to avoid an accumulating nitrogen deficit. However, findings from the PEPaNIC randomized trial in pediatric intensive care units [25], which compared withholding parenteral nutrition (PN) for 1 week with early (before 24-48 h) initiation of PN, raised concerns about whether early provision of PN is appropriate in preterm babies. A preplanned secondary subgroup analysis of the PEPaNIC trial of critically ill term neonates (n = 209) in pediatric intensive care found that late initiation increased the likelihood of live discharge from pediatric intensive care (hazard ratio 1.61 [1.19-2.20]) [26]. In neonates aged up to 1 week (n = 145), the risk of infection was reduced with late initiation of PN (adjusted odds ratio 0.36 [0.15-0.83]) [26]. At 2-year follow-up of the whole PEPaNIC cohort (mean age at follow-up approximately 6 years), executive function as reported by the parent or caregiver was reported to be improved in children who had received late initiation of PN [27].

There has been extensive commentary on the PEPaNIC trial and its implica-tions for preterm babies given that there were no preterm babies included in the trial. A key concern is the provision of energy intakes in excess of recommenda-tions in the early group and substantially higher than in the late group. Overfeeding is potentially harmful, and there were no reports of biochemistry data, meaning it is not possible to determine whether refeeding syndrome in the early group was a significant factor. The PEPaNIC trial findings therefore need to inform future research in preterm infants, rather than influencing current practice. Results from the ProVIDe trial, a multicenter, triple-blind randomized controlled trial of an additional 1 g X d-1 of amino acids for the first 5 days after birth on survival free from neurodisability at 2 years of age [28] should provide valuable information on whether similar risks of enhanced early nutrition may apply to extremely preterm babies.

Conclusions

Nutrition for very preterm babies is a universal, relatively simple, and inexpensive part of their care, yet we still do not understand what a package of nutritional support that will provide optimal long-term outcomes looks like. Progress has been hampered by small trials, often with methodological weaknesses, with short-term outcomes and inconsistency of reporting of key outcomes of interest.

Future research should identify priorities for research that need to be developed through a robust prioritization framework including families, standardization of reporting through the development of Core Outcome and Minimal Reporting Sets for nutritional studies in preterm infants, and the development of international consortia to undertake trials that, when combined through meta-analysis and, ideally, individual participant data meta-analysis, are large enough to address important outcomes.

Conflict of Interest Statement

Professor Frank Bloomfield is Director of the Liggins Institute at the University of Auckland. Dr. Barbara Cormack is a Nestlé Nutrition Institute Oceania Paediatric Advisory Board Member.

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