Early Nutrition in Preterm Infants: Effects on Neurodevelopment and Cardiometabolic Health

1. Many nutritional interventions have proven benefits for growth in preterm infants.

2. Some, but not all, interventions to improve growth result in better neurodevelopmental outcomes.

3. Emerging evidence suggests that promoting more rapid early growth may have adverse consequences for future cardiometabolic health. These findings are important to incorporate when considering optimal targets for preterm infant growth.

1. Identify nutritional practices with demonstrated benefits to growth in preterm infants.

2. Appreciate that interventions to promote more rapid infant growth often benefit neurodevelopment, but may also have an adverse impact on cardiometabolic health.

3. Recognize critical periods for preterm infant nutrition and growth in relation to neurodevelopmental and cardiometabolic outcomes.

Preterm infants face specific nutritional challenges, primarily due to difficulties in meeting nutritional requirements during a period of expected rapid intrauterine growth. Because fetal life and infancy represent critical or sensitive periods in development, the preterm infant’s nutritional milieu has an important impact on subsequent health. The past several decades have seen major advances in nutritional support for preterm infants, most notably the routine use of specialized preterm formulas, fortification of breast milk, and parenteral nutrition. These interventions have translated into marked improvements in early growth, specifically weight gain, linear growth, and head growth. A subset of these interventions also promotes better neurodevelopment, highlighting the sensitivity of the developing brain to nutrition.

More recently, concerns have arisen that promoting more rapid growth in infancy may have adverse effects on cardiometabolic health, reflecting additional sensitivities of the developing infant to early nutrition. These concerns relate to David Barker’s work demonstrating that small size at birth—reflecting intrauterine growth restriction—is an important risk factor for the development of diseases such as hypertension, diabetes, and coronary heart disease in adulthood. (1) Moving beyond Barker’s original focus on the intrauterine period with potential relevance to the preterm infant, other researchers identified growth acceleration in infancy as an additional risk factor for later-life cardiometabolic disease. (2) It is now clear that preterm infants, regardless of their growth restriction status at birth, are at heightened risk for cardiometabolic disease, compared with their term counterparts. (3) The extent to which aspects of early growth and nutrition specific to the preterm infant contribute to this risk is now under study.

Most of the evidence linking early growth with later neurodevelopment or cardiometabolic outcomes arises from observational studies. Further evidence comes from a small number of randomized trials comparing the direct effect of specific practices on later outcomes. In this article, we discuss early growth and nutrition of the preterm infant, highlighting the potential tradeoffs that exist between enhancing neurodevelopment and minimizing the risk of later chronic diseases, such as obesity, type 2 diabetes, and hypertension. Balancing these considerations is imperative for optimal nutritional care of this high-risk population.

From the time of preterm birth through the first year, the infant brain undergoes rapid growth in size accompanied by major structural changes, processes that are highly sensitive to nutrition. (4) Preterm infants require specialized nutritional support during and after the neonatal hospitalization to match fetal nutrient accretion rates and support this rapid brain growth and development. In this section, we discuss effects of specific nutritional interventions on early growth and neurodevelopmental outcomes (Table).

Several historical interventional studies established the benefits to growth and neurodevelopment that are achieved by providing hospitalized preterm infants with more calories, protein, minerals, and micronutrients than are present in standard infant formula. One randomized, controlled trial conducted in the 1980s compared a specialized preterm formula with standard infant formula. (5) Formula was provided either as the sole diet or as a supplement to unfortified maternal breast milk. Infants receiving preterm formula gained weight more rapidly (difference of 2.5 g/kg per day over a median of 28 days in the study). Further, among infants receiving formula as their sole diet during their hospitalization, neurodevelopmental outcomes at age 18 months were better in those fed preterm formula, with cognitive scores approximately 1/3 standard deviation higher (not statistically significant) and motor scores approximately 1 standard deviation higher. A similarly designed trial by the same investigators compared preterm formula with unfortified donor breast milk, either as the sole diet or as a supplement. (6) As expected, infants fed preterm formula experienced faster weight gain, linear growth, and head growth during the intervention. However, contrary to the hypothesis that nutrient-enriched formula would be advantageous, neurodevelopment at age 18 months was no better in the infants who received the higher-nutrient preterm formula, (7) a finding discussed further in the “Breast Milk” section later in this article.

Subsequently, a subset of children from both trials underwent cognitive testing and brain magnetic resonance imaging at 15 to 16 years of age. (5)(6) Grouping children according to early diet (“standard” nutrient diet consisting of donor breast milk or term formula vs “high” nutrient diet consisting of preterm formula) revealed that children in the high-nutrient group had higher verbal IQ scores and larger caudate size, beneficial effects of nutritional fortification that had persisted throughout childhood and into adolescence. (8)(9)(10) Despite substantial limitations, particularly the limited follow-up and post-hoc nature of many analyses, findings of these studies support the current practice of providing specialized, nutrient-enriched formula for hospitalized preterm infants.

Although historical studies demonstrated the lasting benefits of enriched preterm formula, they did not examine the role of breast milk fortification. This gap is important given (1) the specific health benefits of breast milk for preterm infants, and (2) the fact that while breast milk optimally meets nutritional needs for term infants, it does not meet protein and mineral requirements of preterm infants. Early studies focusing solely on protein fortification of breast milk demonstrated improved short-term growth. (11) More relevant to current practice, multicomponent breast milk fortifiers containing protein and other macro- and micronutrients (eg, minerals) also increased growth transiently during the neonatal hospitalization. (12) Only 1 study examined 18-month neurodevelopmental outcomes and found no difference between infants receiving breast milk with multicomponent fortifier and those receiving vitamin-fortified breast milk, but confidence intervals were wide and included potentially beneficial effects. (13) Taken together, these studies demonstrate the importance of protein supplementation of breast milk, particularly as part of a multicomponent fortifier that provides not just protein but also calories and other macro- and micronutrients, to support preterm infant growth. However, the impact of this approach on neurodevelopment remains uncertain.

Another important question is what to feed preterm infants when the mother’s own milk is in short supply or not available; alternatives include preterm formula or donor breast milk. Review of the trial comparing preterm formula with donor breast milk (discussed in the previous “Preterm Formula” section) provides some insight. (6) Infants fed donor breast milk gained weight more slowly than those fed preterm formula as their sole diet, suggesting relative undernutrition. However, developmental outcomes were equivalent at age 18 months, suggesting that there may be beneficial factors in breast milk itself that offset the harmful effects of relative undernutrition. This study was conducted before the routine use of multicomponent breast milk fortifiers. The question of whether fortified donor breast milk or preterm formula is superior in terms of early growth and/or neurodevelopment is the subject of the Donor Milk for Improved Neurodevelopmental Outcomes trial, currently under way. (14)

Given the time lag between birth and the establishment of full-volume, fortified enteral feedings, it is important to examine the role of parenteral nutrition in improving in-hospital growth, and potential benefits to neurodevelopment. One large observational study demonstrated that preterm infants who received more protein and energy in the first week after birth (98% in parenteral form) gained more weight and had better neurodevelopmental outcomes at 18 months of age. (15) In contrast, in another observational study, (16) extremely low-birthweight infants who received “adequate” (≥3 g/kg per day) parenteral protein by 5 days after birth had no better neurodevelopment at age 18 months than those receiving “inadequate” protein, despite better weight, length, and head circumference gains observed at NICU discharge. Four randomized trials of early (<24 hours after birth) protein administration reported an improved positive nitrogen balance. This practice appears to shorten the time to regain birthweight, but has little impact on linear or head growth; neurodevelopmental outcomes have not been reported. (17) Considering the amount of protein rather than the timing of protein administration, a randomized controlled trial (18) providing 4 g/kg per day versus 2.5 g/kg per day of protein parenterally over the first week after birth neither improved NICU growth nor affected neurodevelopment at 2 years. Taken together, these results suggest that despite potential benefits to early growth, current strategies to administer parenteral protein do not translate into clear neurodevelopmental benefits.

The first months after discharge from the NICU represent a period of accelerated weight gain as infants “catch up” after relative growth restriction during their hospitalization. Many studies have focused on specialized formulas, whereas relatively fewer have examined strategies to fortify expressed breast milk. Typical study interventions of formula involve (1) “postdischarge” formula enriched with energy and nutrients at levels higher than standard term formula but lower than in-hospital preterm formula, or (2) continuation of energy- and nutrient-enriched in-hospital preterm formula. As reported in a recent systematic review, (19) several studies have demonstrated transient acceleration in growth, including head growth, with postdischarge energy- and nutrient-enriched formulas, with a suggestion that continued in-hospital preterm formula feeding may be of greater benefit than “postdischarge” formula. However, no clear evidence supports beneficial effects on neurodevelopment beyond 12 months of age. (20) Overall, nutrient fortification in formula-fed preterm infants after NICU discharge may transiently improve growth in early infancy to some extent, without consistent evidence for positive effects on neurodevelopment.

Regarding fortification of breast milk, 1 small (n = 39) study randomized infants to fortification of approximately half of the daily breast milk intake with a multicomponent human milk fortifier for 12 weeks after discharge versus no breast milk fortification. (21) Benefits were found in linear growth during the intervention period, and persisted to 1 year of age. Further, head growth improved in the subset of infants less than or equal to 1,250 g. No statistical differences in neurodevelopment were noted, though power was low. In contrast, a larger (n = 207), 4-center Danish study randomized infants to fortification of 1 breast milk feeding daily versus no fortification through 4 months’ corrected age. (22) Growth was no different by 12 months of age; neurodevelopmental outcomes were not reported. It is possible that more frequent fortification is required to demonstrate benefits to growth; further study is needed to determine neurodevelopmental effects, particularly considering the time burden on mothers of expressing and fortifying breast milk for infants after discharge from the neonatal unit. (22)(23)

Most studies of postdischarge nutrition have focused on an unselected group of preterm and/or low-birthweight infants. However, the benefits of enhanced nutrition may be greater for infants at high risk for neurodevelopmental impairments, as suggested by a randomized trial in which brain-injured preterm infants randomly assigned to receive 120% of the usually recommended energy and protein intake demonstrated better head growth and corticospinal tract axonal diameter at 1 year of age. (24) Those findings suggest the need for additional research to determine the optimal postdischarge diet for preterm infants with brain injury, who frequently experience oral feeding difficulties and may have unique caloric and nutrient requirements.

Given evidence that promoting more rapid growth in infancy is beneficial for later neurodevelopmental outcomes, it is important to ask whether there could be “too much of a good thing.” In other words, can excess nutrition lead to harmful effects? This concern is driven in part by animal studies (25) and observations in term human infant cohorts (26) demonstrating that prenatal and postnatal nutrition can program the risk for later obesity and related cardiometabolic diseases. This topic is especially relevant for preterm infants because they appear to be at heightened risk compared with their term peers. For example, preterm birth doubles the risk for later hypertension (3) and increases the risk of developing type 2 diabetes by up to 60%. (27) Despite being lighter and thinner at term-equivalent age (40 weeks’ postmenstrual age), preterm infants display higher body fat percentage (28) and have greater intra-abdominal fat, (29) differences that persist into adulthood. (30) Hypertension, diabetes, and increased abdominal fat are important risk factors for cardiovascular disease, though data on the risk of cardiovascular disease outcomes specifically attributable to preterm birth are mixed. (31)(32)(33) In the next section, we investigate aspects of nutritional care that might contribute to increased cardiometabolic risk in preterm infants, noting that data on this topic are relatively sparse compared with data on neurodevelopmental outcomes.

Several of the historical interventional studies discussed previously in relation to neurodevelopment also assessed long-term cardiometabolic outcomes (Table). A trial comparing unfortified donor breast milk with preterm formula followed 29% of the original participants for 13 to 16 years. Infants who received the lower-nutrient donor breast milk had small reductions in low-density lipoprotein (0.2 mmol/L), total cholesterol (0.3 mmol/L), and ratio of low- to high-density lipoprotein (14%), reflecting a more favorable lipid profile. (34) In addition, diastolic blood pressure was 3 mm Hg lower in the lower-nutrient donor breast milk group. (35) In contrast, a trial that compared standard formula with preterm formula found no substantial differences in lipid levels (34) or blood pressure at age 13 to 16 years. (35)(36) Given the low numbers of participants who completed follow-up, the investigators combined data from the 2 trials, demonstrating that infants fed a lower-nutrient diet (donor breast milk or term formula) had lower insulin resistance than those fed preterm formula. (25) Although limited, because of low follow-up rates and the post-hoc nature of many analyses, these trials suggest that promoting more rapid weight gain through nutritional fortification may lead to small increases in cardiometabolic risk factors, and that breast milk may be protective. However, contemporary studies are lacking and the impact of early diet on longer-term risk is unknown.

Because the accumulation of excess adiposity during infancy can lead to obesity and related complications later in life, it is important to determine the extent to which the postdischarge diet may influence these outcomes in preterm infants. Although weight gain alone does not convey information about accumulation of lean versus fat mass, simple techniques now exist to measure body composition directly. A few studies using these techniques offer preliminary insights into postdischarge diet and cardiometabolic health. In 1 study, preterm infants were randomized to either nutrient-enriched or standard formula from term-equivalent 6 months of age. (37) Weight and length were not different between the groups, but fat mass was lower in infants fed the nutrient-enriched formula; no follow-up beyond the intervention period was reported. Another study also randomized preterm infants to nutrient-enriched or standard formula at discharge and continued the study diet until age 6 months. (38) At 12 months of age, they found that nutrient-enriched formula led to proportionally greater gain in body fat compared with lean mass in boys. No differences were seen in girls. In addition, an observational study compared infants fed nutrient-enriched formula with historical controls fed standard formula until 6 months of age. (39) At age 24 months, infants fed the enriched formula had lower total fat mass and fasting insulin levels, indicating a more favorable metabolic profile overall. Taken together, these studies suggest a better cardiometabolic profile (lower relative adiposity and fasting insulin levels) in infants fed nutrient-enriched formula after discharge, but data are generally sparse and follow-up beyond 2 years of age is lacking.

A critical or sensitive period is a developmental window during which an organ is particularly susceptible to environmental influences. Critical periods typically occur during times of rapid growth and development. Because early exposures have long-term effects on the developing brain and on cardiovascular function and metabolism, fetal life and infancy are considered critical periods in the development of these organ systems.

For the preterm infant, the period of time from birth until term-equivalent age aligns developmentally with the third trimester of gestation for a fetus, with brain development involving processes such as cortical folding and gyrification, axonal development, and neuronal proliferation and migration. (4) After reaching a term-equivalent age, brain development is more similar to that of a term newborn, with processes such as myelination and microstructural cortical maturation predominating. (4) In terms of the cardiovascular system and metabolism, intrauterine growth restriction of the fetus induced by maternal undernutrition during pregnancy leads to offspring with elevated blood pressure, insulin resistance, and increased adiposity in animal models. (40) Conversely, overnutrition and excess weight gain after reaching term-equivalent age predicts later obesity and higher blood pressure in both animal models (25) and human infants. (26)(41)

In this section, we examine potential critical periods for effects of nutrition on neurodevelopment and cardiometabolic health in preterm infants. Identifying specific time windows during which nutrition affects these outcomes has important implications for tailoring nutritional interventions in the NICU and the home environment.

Interventional studies discussed earlier in this article demonstrate a sustained effect of diet during the neonatal hospitalization on neurodevelopment, suggesting that the time from preterm birth to term-equivalent age is a critical period for neurodevelopment. Observational studies provide further supporting evidence, with several studies in diverse populations showing that more rapid weight gain during the neonatal hospitalization predicts better cognitive and motor outcomes. (42)(43)(44) As the developing brain appears to be highly sensitive to nutrition from preterm birth to term-equivalent age, targeted improvements in nutritional care during this period are likely to benefit neurodevelopmental outcomes.

As noted before, small differences in lipid profiles and insulin resistance were detectable in adolescence after exposure to fortified diets during the neonatal hospitalization. (25)(34)(35) Further, an observational study found that greater weight gain from birth to 2 weeks of age, but not from 2 weeks of age through NICU discharge, was associated with insulin resistance in adolescence, potentially pinpointing the earliest weeks after preterm birth as the most important for later insulin resistance. (25) However, the suggestion that greater weight gain from preterm birth to term-equivalent age leads to heightened cardiometabolic risk contrasts with animal data demonstrating that fetal undernutrition is associated with a greater cardiometabolic risk. (40) More data from preterm infant populations are needed to elucidate the true magnitude and direction of nutritional effects from preterm birth to term-equivalent age on cardiometabolic outcomes.

In addition to the interventional studies discussed before, which generally do not demonstrate neurodevelopmental benefits of nutrient-enriched diets after term-equivalent age, several observational studies have examined relationships of growth after reaching term-equivalent age with neurodevelopmental and cardiometabolic outcomes. In our work, more rapid linear growth or weight gain in the first year after reaching term-equivalent age were associated with slightly better neurodevelopmental outcomes at age 18 months, (44) 8 years, and 18 years. (27)(45) The same studies revealed that increasing weight out of proportion to linear growth (gain in weight-for-length or body mass index) did not appear to be beneficial for neurodevelopment, but was linked with a higher risk of obesity (27) and higher systolic blood pressure. (45) These findings highlight the potential importance of adiposity gain compared with accrual of lean mass, which could be investigated using direct measures of body composition, as discussed before. Two additional observational studies also described links between faster weight gain from term-equivalent age to 3 months and greater adiposity in young adulthood, but did not examine weight gain in relation to infant length. (46)(47) Overall, more rapid weight gain after term-equivalent age appears to be associated with small benefits to neurodevelopment and with increased cardiometabolic risk. Excess weight gain out of proportion to linear growth during this time may reflect accumulation of fat, appears not to confer any benefit, and may be harmful.

Nutritional interventions during the neonatal hospitalization and after discharge are effective at increasing growth in preterm infants. Some interventions also have important effects on subsequent neurodevelopment and cardiometabolic health. An optimal nutritional strategy would result in improved neurodevelopmental outcomes without increasing cardiometabolic risks. A tension exists when interventions that improve outcomes in one area have detrimental effects in another: specifically, promoting rapid weight gain in early infancy is beneficial for neurodevelopmental outcomes but may lead to poorer cardiometabolic health. Understanding the critical developmental periods is helpful for targeting nutritional interventions. For example, avoiding excess weight gain after neonatal discharge may improve cardiovascular health without sacrificing the neurodevelopmental benefits of enhanced nutrition that can be accrued during the neonatal hospitalization. Improved data would be helpful to determine the magnitude of cardiometabolic effects, which currently appears to be small in relation to neurodevelopmental benefits. It is possible that clinicians and patients would be willing to accept small cardiometabolic risks in exchange for larger improvements in neurodevelopment. As a start, we agree with other authors (48) that, moving forward, investigations of new nutritional interventions should assess effects not just on growth and neurodevelopment, but also on relevant measures of cardiometabolic health.

Drs Kunz and Bell contributed equally to the article.