Enteral feeding advancement and growth until 5 years in extremely preterm infants

Intensive nutritional support for preterm infants improves growth and thereby potentially neurodevelopment [1‐3]. Therefore, most pediatric societies recommend that postnatal growth in the NICU should match that observed in utero [4].

Reaching this goal may require intensified enteral nutrition and faster feeding advancements, thereby also reducing time with intravenous access and parenteral nutrition, and the risk of sepsis and cholestasis [5]. The optimal rate of enteral feeding advancements in preterm infants is yet unknown, but available data suggest that advancing enteral feeding volumes at daily increments of 30–40 ml/kg does not increase the risk of necrotizing enterocolitis (NEC) or death even in very preterm or growth-restricted infants [5‐8].

Especially after rapid advancement of enteral feeding volumes, there is concern that preterm infants’ growth could be impaired by the variability in protein and energy content of human milk or insufficient enteral macronutrient absorption immediately after birth [9]. In a recent large randomized trial involving 2804 preterm infants, no difference could be found in developmentally intact survival at 24 months with a strategy of advancing milk feeding volumes in daily increments of 30 ml/kg as compared to 18 ml/kg [7]. However, long-term data on growth in later childhood and metabolic outcome of premature infants after accelerated enteral feeding advancement are sparse.

We studied the effect of accelerated enteral feeding advancements in infants born at < 32 wk. gestation or with birth weights < 1500 g [8]. Time to full enteral feeds was significantly shorter in the cohort with faster advancement of enteral feeding volumes (6 vs. 8 days), while NEC rates were similar (3.3 vs. 2.7%). In contrast to published data reporting extrauterine growth restriction among most very preterm infants [10‐14], both study cohorts continued to grow along their intrauterine percentiles. Better head circumference growth in the cohort with slower enteral feeding advancement was associated with higher parenteral protein administration in the first postnatal week [8].

We now aimed to investigate the effects of accelerated enteral feeding advancements on growth between hospital discharge and age 5 years in extremely preterm or extremely low birth weight infants previously described including details on postnatal nutrition [8].

The aims of this study were to analyze and describe growth in extremely preterm infants during the first 5 years after birth following accelerated enteral feeding advancement and in-hospital weight gain as in utero, and to investigate factors potentially influencing anthropometric data until 5 years of age. Median postnatal age at full feeds (defined as ≥140 ml/kg/d administered for 24 consecutive hours) was 9 days and 7 days in these extremely preterm or extremely low birth weight infants.

Overall, no differences in growth pattern up to 5 years of age were found between the two cohorts with different feeding regimens. Compared to the reference population, the preterm infants studied here had a significantly lower SDS_W, SDS_L and SDS_HC at birth. There were no differences in SDS_W between the two cohorts throughout the observational period. In Cohort 1, with slower daily feeding increments and higher parenteral protein intake during the first postnatal week, a better early postnatal head circumference growth was observed until discharge [8]. At age 5 years, this difference in head circumference and in change in SDS_HC was no longer evident. Nevertheless, cumulative parenteral protein intake after birth remained significantly associated with SDS_HC at 5 years in multiple linear regression analysis and SDS_HC progressively decreased up to age 5 years. As a consequence of this finding we have increased parenteral protein supplementation during the postnatal transition to full enteral feeds, but additional nutritional interventions (e.g., supplementation with choline and polyunsaturated fatty acids) should also be considered [17‐20]. Catch-up growth occurred only for SDS_L in both cohorts, showing values within the reference range at age 5 years.

A Swedish follow-up study of 83 extremely preterm infants came to similar results: weight showed a sharp decrease in z-scores from birth to 3 months’ corrected age, followed by catch-up growth up to age 11 years, but weight remained lower than in term-born controls (mean (SD) z score: at birth − 0.57 (0.98), at due date − 1.62 (0.76), at 3 months − 2.27 (1.38), at 5 years − 0.77 (1.35) and at 11 years − 0.15 (1.22)) [21]. Z-scores for height decreased up to 3 months corrected age (− 2.24 (1.32)), followed by catch-up growth up to 11 years (− 0.53 (1.08). Head circumference also showed no catch-up growth and remained significantly lower than in control participants at all ages, mean z-Score_HC at birth was − 1.30 (0.71) and − 1.11 (1.06) at 11 years of age.

Contrary to our and the Swedish findings, many studies reported that preterm infants with postnatal growth retardation up to discharge regain weight in the following months, with catch up to their peers by the time of reaching school age [10, 21].

As currently recommended [4], both study cohorts matched in-utero weight gain during their stay in the NICU with a delta-SDS_W from birth to discharge of close to zero; likewise the change in SDS_W from birth to age 5 years was close to zero. The SDS_BMI at age 5 years was significantly lower than at discharge and lower than that of the reference population, but again not different between cohorts. Presumably, there were no differences in growth pattern up to age 5 years between the two cohorts because time to establish full enteral feeds was similarly short and cumulative protein intake until d28 was similarly high and higher than in most previous studies reporting increased weight gain with increased protein intake [1, 11]. Recently published randomized controlled trials on the effect of increased protein supplementation on growth of very preterm infants have shown that increasing protein intake by 0.6 g/kg/d to an intake of 4.3 g/kg/d does not further promote growth until discharge, possibly due to a ceiling effect [22, 23].

In contrast to our findings, most studies report that preterm infants fail to achieve near in-utero weight gain during their NICU stay [10‐12, 21, 24]. A number of studies demonstrated an association between impaired postnatal growth in preterm infants and neurodevelopmental disabilities, hence the importance of early and adequate nutrition in this period of rapid growth [1‐3].

Beyond neurocognitive development, it has been suspected that disturbances in intrauterine growth can have long-term effects on adult health, e.g., an increased risk for hypertension and insulin resistance, likely based on mechanisms of fetal programming and epigenetics [25, 26]. However, it is unclear whether extrauterine growth restriction in preterm infants has similar effects as fetal growth restriction [24, 27, 28]. For example, a higher prevalence of insulin resistance and glucose intolerance and increased systolic blood pressure have been described in 163 very low birth weight (VLBW) infants at age 18–27 years compared to young adults who were born at term [24]. In that study, extrauterine/postnatal weight gain was poor and mean SDS change from birth to term − 1.4 ± 1.32, very different from our observations. In a randomized study including 50 VLBW infants, a significant improvement in postnatal growth without Z-score loss from birth to 36 weeks corrected age was found with increased compared to standard nutrient supply [29]. In that study, adiponectin concentrations at 5 months corrected age were higher with increased nutrient supply and this correlated positively with early weight gain, where increased adiponectin levels are generally associated with a lower risk of obesity and metabolic syndrome in children [29, 30]. Early nutrition and growth may therefore influence metabolic markers in infancy and early childhood. The long-term metabolic effects of an in-hospital growth pattern mimicking intrauterine growth on cardiovascular and metabolic health require further study.

Limitations of our study include its retrospective and single-center design and up to 35% loss to follow-up until age 5 years. Potentially, the latter could introduce attrition bias and thus affect the validity of our observations, however, mean GA at birth of those followed to age 5 years and of the initial cohorts were similar. For this study, we deliberately did not contact parents whose children had already died before age 5 years, consequently our data only apply to infants who survive to 5 years. Furthermore, this study is obviously limited to survivors, the growth data of the sickest preterm infants, who died before discharge, have not been included. Although this is a retrospective cohort study in two periods 3–4 years apart, there were no significant changes in management between the two cohorts described, apart from modifying the feeding protocol. Remarkably, however, in cohort 1 the proportion of multiple births and gestational age were lower than in cohort 2, although we did not find an explanation for this increase.

Strengths include our well-described nutritional regimen and detailed information on nutritional support during the first 28 postnatal days, and that both cohorts included an unselected population of extremely low birth weight (ELBW) infants with intensified and very early enteral nutrition resulting in an early postnatal growth along their intrauterine percentiles during their NICU stay.

Both cohorts attained full enteral feeds much earlier than previously reported and weight gain as in utero was achieved. There was no significant difference in anthropometric parameters after discharge between both cohorts, but there was catch-up for SDS length/height from discharge to age 5 years. SDS weight and SDS BMI at age 5 years remained lower than in the reference population, SDS weight decreased from discharge to about 10–12 months and returned to birth values at age 5 years. SDS head circumference decreased from birth to 5 years, thus higher parenteral protein supplementation may be necessary during transition to full enteral feeds.

In summary, there is no evidence of an increased risk of obesity up to age 5 years following intensified nutritional support with rapid enteral feeding advancement and percentile-parallel weight gain during their NICU stay. Further follow up into adulthood is desirable.