**4. Discussion**

This is the first large study showing the longitudinal growth and developmental patterns of children born with low birth weight in Korea. LBW infants are subject to a significant burden of morbidities, such as postnatal growth failure and neurodevelopmental impairments. However, extreme preterm infants have been the primary focus of the research over the years. In this study, longitudinal growth outcome in LBW infants from birth to 60 months was shown using nationwide population-based health check-up data. We confirmed an association between poor post-natal growth and developmental delay, both of which are persisting on long term follow-up, especially among LBW infants.

Our findings are consistent with those of previous international studies, which reported that a lot of preterm infants born lighter and shorter than full-term infants remain growth-restricted beyond the catch-up period [14]. We found that some degree of catch-up growth did occur with time; however, the difference remained until 60 months of age compared to the infants with 2500–4500 g. As shown in Figure 1, the smaller birth-weight group showed lower catch-up growth even at 60 months. Mean weight, height, and HC percentiles were persistently below 40 percent among LBW infants, as well as VLBW infants. Among children with poor growth, there is a decreasing trend in the incidence of poor growth until the 36 months of age, which then showed a stable or slightly increasing trend in the 48- and 60-months of age. Relatively poor growth can be seen in more preterm infants due to limitation of chronologic age up to 3 years of age; however, the difference in growth has persisted from 3 to 6 years old. Poor growth is still a serious problem in preterm infants, although there is an increase in survival and morbidity free survival in Korea. Therefore, close check-ups and support for catch-up growth until school age should be provided for preterm infants, as well.

Both the severity and duration of the growth retardation are related to the degree of prematurity of an infant [15]. We found the smaller the birth weight, the lower the mean growth percentiles, and the higher the incidence of poor growth. SGA children have a higher risk of growth failure throughout the follow-up period [16]. A 6-year follow-up study of very preterm infants showed the catch-up growth was mostly achieved before 2 months of age; however, it was continued until 6 years of age in SGA infants [17]. There have been reports of risk factors for growth failure that persist even after the catch-up period, and there are reports that SGA infants and more premature infants with morbidities are more vulnerable to growth failure [18–20]. In this study, SGA infants showed a higher risk for growth failure at 60 months of age than non-SGA infants did. In terms of height, most infants born SGA can catch-up by 2 years but around 15 % of them cannot achieve catch-up growth and remain short-heighted in adulthood. [19,21].

Children with poor growth have greater neurodevelopmental functioning problems than those with normal growth [22]. A nationwide Japanese population-based study analyzed the association of SGA infants with poor postnatal growth at 2 years of age with neurobehavioral development both at 5.5 and 8 years of age and reported that the findings warranted early detection and intervention for attention problems among these group [23]. Consistent with the other study, this research found that, children born with smaller birth weight showed poorer developmental results, and children with weight, height, HC less than 10th percentile at 60 months of age also showed higher incidence of the poor development, confirming growth is related to neurodevelopmental functioning.

Early postnatal growth is positively related to neurodevelopmental outcomes, especially Intelligence Quotient [22]; Postnatal growth rate of infants with intrauterine growth restriction has been associated with later cognitive outcomes, specifically Pylipow et al. reported that growth in the first 4 postnatal months is a risk factor for cognitive outcome at age 7 years [24]. Neurodevelopmental score at 8 year was related to weight, height, and HC at 8 years [25]. We confirmed the mean percentile of weight, height, and HC at 60 months of age were correlated with the mean growth percentile of 6 months of age. Therefore, close monitoring from early infant period and proper intervention for growth are important.

Previous studies reported that growth restriction was more common in preterm infants but recent studies have shown positive reports of catch-up growth through nutritional support and quality improvement [26]. Small for gestational age infants with less than 28 week's gestation had appropriate catch-up growth at term, improved with postnatal nutrition and care [27]. Early HC growth failure in very preterm infants can be improved by optimizing parenteral nutrition [28]. Although an aggressive nutritional strategy including using human milk fortifier or preterm formula, and high amino acid composition of parenteral nutrition were adopted in Korea, in this study we confirmed postnatal growth impairment is common in LBW infants, and catch-up growth may be delayed and incomplete in some.

Children who fail to achieve catch up growth within 2 years of life remain short after childhood so an early initiation of growth hormone treatment was recommended by previous research [29,30]. The length Z and changes of scores at 12 months of corrected age may be correlated with catch-up height at 3 years and so it is useful for earlier initiation of growth hormone treatment in VLBW infants [31]. We found that the infants with a height below 10th percentile at 60 months of age were more numerous in VLBW (25%) group than in LBW (14%) or 2500–4500 g (5%) group. At 60 months of age, the mean percentile of height had correlations with the mean height percentile of 6 months of age.

The main strength of this study was that it was a nationwide study with a large population and it was able to report an association between growth and neurodevelopmental outcomes overtime. A total of 99% of eligible infants participated in the national health screening program for infants and children, so these results are an accurate representation of the growth of the infant population in Korea. These nationwide data accounts for all infants, including LBW but not VLBW infants, who participated in health check-ups during the first five years of life in addition to the infants weighing 2500–4500 g infants as a reference.

There are some limitations to this study. Since weight is the most important factor in the growth assessment of newborns and infants, this study design was analyzed based only on birth weight. Because birth weight is usually related with gestation, and SGA status can make some discrepancy, we just display the infants dividing birth weight rather than gestational age. Poor growth was defined as weight, height, and HC individually below

the 10th percentile. VLBW infants accounted for 0.7% of total birth infants in this cohort, which is a very small proportion. Preterm infants with intraventricular hemorrhage or post-hemorrhagic hydrocephalus have larger HC but the effect isn't considered due to a small population. There are many factors having affecting on growth including nutrition and co-morbidities, but we lack detailed data that may provide information on important confounders. For the integrity of data on growth in preterm infants, we included the growth parameter at only postnatal age, but not the corrected age.

#### **5. Conclusions**

This Korean population-based study showed that a significant number of LBW infants did not achieve catch up growth even at 60 months of age. Close monitoring of appropriate weight gain, nutritional intervention, and early intervention programs will be needed for improving children's growth and developmental outcomes. Our findings provide guidance for developing a nationwide follow-up program for infants with perinatal risk factors.

**Author Contributions:** Conceptualization, S.M.L. and S.J.Y.; methodology, S.M.L. and S.J.Y.; validation, J.L. and J.H.H.; formal analysis, S.M.L. and S.J.Y.; writing—original draft preparation, S.M.L. and S.J.Y.; writing—review and editing, J.L., J.H.H., J.E.S., H.S.E., M.S.P. and K.I.P.; supervision, S.M.L. and M.S.P. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of Gangnam Severance Hospital (IRB No. 3-2019-0147).

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** The authors thank MID (Medical Illustration & Design) for helping to design Figure 3.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


International Journal of *Environmental Research and Public Health*
