In this study, we demonstrated that more babies are identified as having EUGR when using Fenton growth standards as compared to Intergrowth-21, but a return to their birth weight z-score was achieved by the second follow-up clinic visit around 86 weeks PMA. Babies who were human milk fed after discharge from the NICU had slower CUG, but higher Bayley-III scores at 24 months of age.
Horbar et al. demonstrated that postnatal growth failure and severe postnatal growth failure decreased from 2000 to 2013 in North American hospitals in the Vermont Oxford Network (13). However, growth failure in preterm infants during NICU hospitalization remains a serious problem, with a reported incidence ranging from 30 to 60% (6, 14, 15). Our study demonstrated that use of postnatal growth standards based on the assumption that postnatal growth should mimic intrauterine growth (Fenton standard) resulted in a higher prevalence of EUGR than when infants were plotted on a growth standard derived from the actual growth of healthy preterm infants monitored longitudinally after birth (Intergrowth-21 standard); this aligns with previous studies which showed EUGR was less prevalent when Intergrowth-21 was used (16–19). EUGR defined by Intergrowth-21 categorizes infants with adverse clinical courses more elaborately (19), such that weight-based growth failure may be more strongly associated with poor neurodevelopmental outcomes at 12 and 24 months of age than Fenton (16).
Accurate monitoring of preterm infant growth is critical in guiding nutritional protocols. Nutrition delivery that exceeds infants’ actual needs may cause unintended harm, including an increased risk for cardiovascular disease, obesity and metabolic syndrome later in life (20–24). One potential advantage of the preferential use of Intergrowth-21 is less erroneous identification of EUGR, and thereby less risk of overfeeding. Moreover, longitudinal monitoring after discharge is possible on the same growth curve up to 64 weeks PMA, making growth monitoring during the transition from inpatient to outpatient care seamless. An important limitation of the Intergrowth-21 growth standards is that few babies born before 33 weeks’ gestation could be included, as it was difficult to identify healthy babies with decreasing gestational age at birth. Therefore, data was derived using a very small cohort of preterm infants at 33–37 weeks gestational age (8, 9) that were later supplemented with measurements from 408 neonates who had been previously excluded (infants born at 24–33 weeks gestational age to mothers with some risk factors for fetal growth restriction) (25). Therefore, no z-scores were available for size at birth for gestational ages less than 24 weeks and we excluded these infants from our study.
The literature suggests that preterm infants fed an exclusive human milk diet experience slower growth compared to those receiving preterm formula, which places them at greater risk for developing EUGR (26–28). Ehrenkranz et al. demonstrated that extremely low birth weight (ELBW) infants with slower growth velocity in the NICU exhibited poorer neurocognitive outcomes at 18–22 months corrected age (29). However, it is worth noting that preterm infants fed human milk demonstrate improved neurodevelopmental outcomes in comparison to those fed preterm formula (30–32). We found that human milk feeding had a positive impact on cognitive, language and motor developmental outcomes at 24 months of age, despite lower weight z-scores after NICU discharge, which is in alignment with Rahman et al. who found that EUGR in ELBW infants fed an exclusive human milk diet did not negatively impact neurodevelopment at 24 months (33).
Few studies have examined the progression of weight z-scores after NICU discharge. We found that infants born between 24 and 32 weeks GA had a return to their birth weight z-score by the time of their second NICU follow up clinic visit.
McGowan et al. found that infants with ≥ 2 medical morbidities had lower Bayley scores at 2 years of age (34). Our study showed that having a history of IVH grade III or IV, ROP treatment and BPD, being male, needing occupational therapy, and having more severe EUGR were all associated with lower Bayley-III scores at two years of age. In addition to human milk feeding, higher Bayley-III scores were also associated with increasing GA, and private insurance. Similarly, previous studies showed an association of economic vulnerability with an increased risk of adverse neurodevelopmental outcomes at 2 and 5 years of age (35).
Our study had several important limitations. The study reviewed data obtained from patients before and during the Covid-19 pandemic. In 2020 and 2021, many fewer follow-up visits were conducted in person. Our study may furthermore be biased towards those patients whose parents are presumably more compliant to medical recommendations and not lost to follow up. Telehealth visits could not collect anthropomorphic measurements or perform detailed neurodevelopmental testing. We cannot know what impact stay-at-home policies and social distancing had on the social and learning environments of these infants and toddlers. Many children spent more time at home with close relatives and less time in daycare and school settings; the downstream effects of these differences in socialization on their neurodevelopment is not yet known.
While we did not assess the protein content of nutrition during the NICU hospitalization, improved change in weight z-score between the first and second follow up visits was significantly associated with TPN duration, suggesting that higher protein delivery early in life might be beneficial for later CUG. Interestingly, Stephens et al. found that increased first-week protein and energy intakes in extremely low birth weight infants were associated with higher Mental Development Index at 18 months of life (36). Furthermore, we were not able to determine if a mother was nursing her infant directly or bottle-feeding expressed human milk and relied on mothers’ reports of feeding type, amount and frequency. Unfortunately, it was also not recorded in the patients’ chart when the mothers switched from one feeding type to another.
Despite these limitations, and although infants had decreased weight gain from 36 weeks PMA to the first NICU follow up visit when they were receiving human milk as opposed to formula, our results suggest that human milk feeding practices may play an important role in language, motor and cognitive developmental outcomes for preterm infants. The identification of risk factors such as BPD, IVH, need for ROP treatment and male gender may help clinicians target interventions and support to infants at higher risk for developmental delays. We conclude that formula feeding at the expense of human milk feeding in the interest of improved CUG for babies identified as EUGR on Fenton growth curves may lead to unnecessary overfeeding and may instead contribute to lower Bayley scores at two years of age.