Postnatal Growth Assessment and Prediction of Neurodevelopment and Long-Term Growth in Very Low Birth Weight Infants: A Nationwide Cohort Study in Korea

Background/Objectives: Extrauterine growth restriction (EUGR) is associated with high mortality and an increased incidence of poor neurodevelopmental outcomes in preterm infants. In this study, we aimed to compare the Intergrowth-21ST (IG-21ST) and Fenton charts in predicting long-term neurodevelopmental and anthropometric outcomes of very low birth weight (VLBW) infants. Methods: Data were collected from 2649 VLBW infants registered in the Korean Neonatal Network born between 240/7 and 316/7 weeks of gestational age from January 2013 to December 2017. Follow-up assessments were conducted at 18–24 months of age, corrected for prematurity. Multiple logistic regression analysis was performed to evaluate the association between EUGR and long-term outcomes. Results: Among the 2649 VLBW infants, 60.0% (1606/2649) and 36.9% (977/2649) were diagnosed as having EUGR defined by the Fenton chart (EUGRF) and by the IG-21ST chart (EUGRIG), respectively. The EUGRIG group exhibited a higher proportion of infants with cerebral palsy, neurodevelopmental impairment (NDI), and growth failure. In multiple logistic regression analysis, adjusted for risk factors for long-term outcome, the EUGRIG group showed higher risk of cerebral palsy (adjusted odds ratio [aOR], 1.66; 95% confidence interval [CI], 1.04–2.65), NDI (aOR, 2.09; 95% CI, 1.71–2.55), and growth failure (aOR, 1.57; 95% CI, 1.16–2.13). Infants with EUGRF tended to develop NDI (aOR, 1.29; 95%CI, 1.03–1.63) and experience growth failure (aOR, 2.44; 95% CI, 1.77–3.40). Conclusions: The IG-21ST chart demonstrated a more effective prediction of long-term neurodevelopmental outcomes, whereas the Fenton chart may be more suitable for predicting growth failure at 18–24 months.


Introduction
Despite improvements in the survival rate of preterm infants, those born very preterm still encounter an increased risk of adverse neurodevelopmental outcomes [1,2].Extrauterine growth restriction (EUGR) poses a universal problem in preterm infants and has been associated with elevated mortality rates and an increased incidence of unfavorable neurodevelopmental outcomes [3,4].Postnatal catch-up growth is a favorable predictor of cognitive function in term-born adolescents [5], recognizing the importance of optimal postnatal growth in determining later growth and neurodevelopmental outcomes [6].
Of the multiple factors associated with development of EUGR, birth weight is a very important contributor: very low birth weight (VLBW, birth weight [BW] < 1500 g) infants are at a higher risk of EUGR [7].Therefore, assessing and monitoring the optimal growth of VLBW infants is essential in neonatal intensive care.The goal of identifying EUGR is to address nutritional needs and optimize growth to prevent adverse neurodevelopmental outcomes.Additionally, overdiagnosis of EUGR should be avoided, as overfeeding preterm infants in the neonatal intensive care unit (NICU) can lead to obesity and cardiovascular disease later in life [8].Therefore, selecting an appropriate growth chart with adequate nutritional guidelines is important for identifying malnourished infants.
In practice, two growth standards are commonly used to monitor the postnatal growth of preterm infants.The Fenton preterm growth chart, revised in 2013, provides estimated fetal weight charts based on intrauterine growth and has been widely used as a reference [9].However, the Fenton chart is based on size-at-birth measurements, which can result in differences between actual postnatal growth and the growth indicated by the curve.More recently, the Preterm Postnatal Follow-up Study (PPFS) has established standards for postnatal growth in preterm infants [10].The Intergrowth-21 ST (IG-21 ST ) charts were developed from serial anthropometric measurements of preterm infants selected from the PPFS.The IG-21 ST charts are based on a longitudinal collection of preterm postnatal anthropometric data [10,11].A recent nationwide cohort study in South Korea demonstrated that EUGR is more prevalent based on the Fenton chart (EUGR F ) compared with the IG-21 ST chart (EUGR IG ), and EUGR IG is associated with worse clinical outcomes [12].Additionally, a single-center retrospective study in the US suggests that EUGR IG may have a stronger association with poor neurodevelopmental outcomes than EUGR F [13].Because of conceptual and methodological limitations and lack of studies on the efficacy of predicting long-term outcomes, determining the most appropriate growth chart remains a controversial issue for clinicians.Therefore, the current study aimed to compare the prevalence of EUGR defined by Fenton and IG-21 ST charts and to investigate the predictive power of both charts in neonatal long-term outcomes.

Materials and Methods
The Korean Neonatal Network (KNN) is a nationwide prospective registry of VLBW infants born in South Korea.The network encompassed 77 participating NICUs and covered more than 70% of all births of VLBW infants in South Korea [14].Each participating hospital's institutional review board (IRB) approved data collection for the KNN, and all data were regularly monitored by the KNN data management committee.All methods were performed in accordance with relevant guidelines and regulations.

Study Design and Data Collection
Among the registered population, infants with a gestational age (GA) between 24 0/7 and 31 6/7 weeks who were born in participating hospitals from 1 January 2013 to 31 December 2017 were eligible for inclusion.Moreover, infants who survived until NICU discharge and were followed up until 18-24 months of corrected age (CA) for prematurity at affiliated outpatient clinics were selected from the KNN registry for long-term outcome evaluation (Figure 1).
Maternal characteristics included maternal age, maternal hypertension, mode of delivery, histological chorioamnionitis, and antenatal steroid use.Neonatal variables encompassed GA at birth, BW, weight z-score at birth and discharge, 5-min Apgar score, and the sex of the infants."Small for gestational age" (SGA) was defined as BW under the 10th percentile for GA and sex, according to each growth chart.The evaluated short-term neonatal outcomes included respiratory distress syndrome (RDS), treatment for patent ductus arteriosus (PDA), moderate to severe bronchopulmonary dysplasia (BPD)) [15], and necrotizing enterocolitis (NEC) ≥ stage II [16].Severe brain injury was defined as an intraventricular hemorrhage exceeding grade 3 [17] or periventricular leukomalacia.Other outcome variables assessed included retinopathy of prematurity (ROP) [18], culture-proven sepsis in infants with clinical signs of infection, duration of parenteral nutrition, and length of NICU stay.

Definitions of EUGR
Gradients of z-scores for BW and weight at discharge were calculated using both the Fenton and IG-21 ST charts (https://intergrowth21.tghn.org/standards-tools/,accessed on 4 February 2022) [9,19,20].We defined decreased z-scores of weight >1 at discharge compared with the z-scores of weight at birth using the Fenton chart as EUGRF and the IG-21 ST chart as EUGRIG.

Long-Term Outcomes
The KNN follow-up protocol involved routine evaluations at 18-24 months CA for surviving infants at each participating hospital.All infants were asked to proactively visit the follow-up clinic and undergo a comprehensive assessment of growth and development.The evaluation utilized the Bayley scales of infant development, second edition (BSID-II); Bayley scales of infant and toddler development, third edition (BSID-III); and Korean developmental screening test (K-DST) for infants and children.Neurodevelopmental impairment (NDI) was defined based on meeting at least one of the following criteria: (1) BSID-II mental development index and/or BSID-II psychomotor development index score <70; (2) BSID-III cognitive composite score, language composite score, and/or motor composite score <85; and (3) K-DST score below -2 standard deviations, indicating NDI.Cerebral palsy (CP) was defined as the degree of functional impairment classified using the gross motor function classification system ≥2.In this study, growth failure was defined as a body weight measurement below the 10th percentile at follow-up assessment, following the World Health Organization child growth standard.

Statistical Analysis
Maternal and infant characteristics and neonatal outcomes were compared between the EUGR and non-EUGR groups using the Pearson chi-square test or Fisher's exact test for categorical variables and Student's t-test or the Mann-Whitney U test, as appropriate.Logistic regression analyses were performed to assess the association between EUGR and long-term outcomes.All variables found to be statistically significant in the univariate models were included in the analysis as potential confounders.Because of the multicollinearity between BW and GA, only GA was selected as a confounder.Furthermore, the

Definitions of EUGR
Gradients of z-scores for BW and weight at discharge were calculated using both the Fenton and IG-21 ST charts (https://intergrowth21.tghn.org/standards-tools/,accessed on 4 February 2022) [9,19,20].We defined decreased z-scores of weight >1 at discharge compared with the z-scores of weight at birth using the Fenton chart as EUGR F and the IG-21 ST chart as EUGR IG .

Long-Term Outcomes
The KNN follow-up protocol involved routine evaluations at 18-24 months CA for surviving infants at each participating hospital.All infants were asked to proactively visit the follow-up clinic and undergo a comprehensive assessment of growth and development.The evaluation utilized the Bayley scales of infant development, second edition (BSID-II); Bayley scales of infant and toddler development, third edition (BSID-III); and Korean developmental screening test (K-DST) for infants and children.Neurodevelopmental impairment (NDI) was defined based on meeting at least one of the following criteria: (1) BSID-II mental development index and/or BSID-II psychomotor development index score < 70; (2) BSID-III cognitive composite score, language composite score, and/or motor composite score < 85; and (3) K-DST score below -2 standard deviations, indicating NDI.Cerebral palsy (CP) was defined as the degree of functional impairment classified using the gross motor function classification system ≥ 2. In this study, growth failure was defined as a body weight measurement below the 10th percentile at follow-up assessment, following the World Health Organization child growth standard.

Statistical Analysis
Maternal and infant characteristics and neonatal outcomes were compared between the EUGR and non-EUGR groups using the Pearson chi-square test or Fisher's exact test for categorical variables and Student's t-test or the Mann-Whitney U test, as appropriate.Logistic regression analyses were performed to assess the association between EUGR and long-term outcomes.All variables found to be statistically significant in the univariate models were included in the analysis as potential confounders.Because of the multicollinearity between BW and GA, only GA was selected as a confounder.Furthermore, the sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and diagnostic odds ratio (DOR) of the EUGR IG and EUGR F were calculated for the long-term outcomes.Continuous variables are presented as medians and interquartile ranges (IQR), and categorical variables are expressed as frequencies and percentages.Statistical analyses were conducted using R software package version 4.3.0(R Foundation for Statistical Computing, Vienna, Austria) and SAS version 9.4 (SAS Institute, Cary, NC, USA).All tests were two-tailed, and p < 0.05 was considered significant.

Ethics Statement
The study protocol was reviewed and approved by the IRB of Yeouido St. Mary's Hospital (IRB no.SC21ZIDE0176) and the KNN Ethics Committee (2021-057).Data were prospectively entered into the KNN registry after obtaining written informed consent from parents.

Clinical Characteristics of Study Population
A total of 9969 VLBW infants were registered in the KNN registry during the study period.Of these, 4623 infants were excluded for the following reasons: congenital anomalies (n = 207), multiple gestations (n = 3383), not discharged until postmenstrual age 50 weeks (n = 276), and death before discharge (n = 757).Among the 5346 infants, 2697 were excluded after discharge due to post-discharge death (n = 18), loss to follow-up (n = 2660), and insufficient follow-up data (n = 19).Finally, 2649 infants were included in the analyses, and their information was available for the CA of 18-24 months visit (Figure 1).
Characteristics of the study population are summarized in Table 1.Based on the Fenton chart, EUGR was more prevalent: 1606/2649 (60.6%) infants were diagnosed as defined by EUGR F and 977/2649 (36.9%) as defined by EUGR IG .Significant differences were observed in maternal and neonatal characteristics across EUGR definitions.In both classifications, a higher proportion of infants with maternal hypertensive disorders was found in the non-EUGR group, whereas maternal chorioamnionitis was more prevalent in the EUGR group.Differences in the mode of delivery were significant only according to the IG-21 ST definition.Infants with EUGR were born at an earlier GA than non-EUGR infants in both charts.The median (IQR) GA at birth was 27.3 (26.0-28.7)weeks for infants with EUGR IG and 29.0 (27.6-30.1)weeks for non-EUGR IG infants.In the case of the Fenton definition, the median GA at birth was 27.9 (26.4-29.4)weeks for infants with EUGR F , and 29.1 (27.7-30.3)weeks for non-EUGR F infants.In both classifications, the median (IQR) BW of infants in the EUGR group was lower than that in the non-EUGR group: 1030 g (850-1240) for EUGR F , 1140 g (940-1300) for non-EUGR F , 1000 g (840-1210) for EUGR IG , and 1120 g (900-1300) for non-EUGR IG .According to the IG-21 ST definition, a higher proportion of male infants was observed in the EUGR IG group than in the non-EUGR IG group; however, no significant differences were noted in the Fenton classification.When each chart was used to evaluate SGA at birth, the proportion of infants with SGA was not significantly different between the EUGR F and non-EUGR F groups.However, the proportion of SGA infants was significantly higher in the non-EUGR IG group than in the EUGR IG group according to both the Fenton and IG-21 ST criteria.
According to the IG-21 ST classification, moderate to severe BPD was more frequent in EUGR IG infants compared with non-EUGR IG infants; however, no significant differences were found between the EUGR F and non-EUGR F groups.Except for moderate to severe BPD, other neonatal morbidities, including RDS, treated PDA, NEC, severe brain injury, ROP, and sepsis, occurred more frequently in the EUGR group than in the non-EUGR group in both charts.In both classifications, infants with EUGR required a longer duration of parenteral nutrition and experienced longer hospitalization periods than non-EUGR infants.

Diagnostic Effectiveness of EUGR F and EUGR IG
To diagnose long-term outcomes, the EUGR F showed a higher sensitivity than the EUGR IG ; however, the specificities were higher in the EUGR IG than in the EUGR F .The DORs for CP, NDI, and growth failure were greater than 1 for EUGR IG and EUGR F .For CP, the EUGR IG had a higher DOR than the EUGR F (1.73 vs. 1.40, respectively).Similarly, for NDI, the DOR of the EUGR IG was higher than that of the EUGR F (2.08 vs. 1.59, respectively).Conversely, for growth failure, the DOR of the EUGR IG was lower than that of the EUGR F (1.77 vs. 2.46, respectively) (Table 3).

Discussion
To date, this is the first study to analyze two growth standards to evaluate EUGR and long-term outcome using large nationwide population.This study makes a significant contribution to the literature, as postnatal growth plays an important role in determining long-term outcomes for preterm infants.It emphasizes the need to properly utilize tools to evaluate postnatal growth.Our study has several notable findings.First, EUGR was more prevalent based on the Fenton chart.Second, EUGR IG was a better predictor than EUGR F for CP or NDI, and EUGR F was a better predictor compared with EUGR IG for growth failure at 18-24 months of CA.

Difference between EUGR F and EUGR IG
EUGR is a common phenomenon in preterm infants during their NICU stay.The Vermont Oxford Network study reported that EUGR, defined as weight below the 10th percentile according to the Fenton chart, occurred in half of VLBW infants [21].Similar to our study, EUGR defined by dynamic changes in z-scores is a widely accepted criterion.A study using the Fenton chart reported the prevalence of EUGR during NICU admission in preterm infants born at a GA of 22-32 weeks as 38-47% [22,23].In our study population, the incidence of EUGR F and EUGR IG were 60.6% (1606/2649) and 36.9%(977/2649), respectively.These results are in line with previous studies comparing various growth charts; EUGR for weight was less prevalent with the IG-21 ST charts compared with the Fenton chart [12,[24][25][26].This difference may be expected because the Fenton chart might overestimate anthropometric data compared with the IG-21 ST chart.The Fenton chart is based on size-at-birth measurements for preterm infants, whereas the IG-21 ST chart is based on actual postnatal growth in preterm infants who experience a different environment and metabolic responses than fetuses in the intrauterine environment.As a result, more infants were diagnosed by EUGR F than by EUGR IG .

Factors Associated with EUGR
In the current study, the proportion of infants with a maternal historical chorioamnionitis was significantly higher in the EUGR group than in the non-EUGR group, according to both definitions.In preterm infants, antenatal exposure to chorioamnionitis is associated with an increased risk of in-hospital morbidities [27].These morbidities might represent conditions that disrupt nutrition potentially affecting postnatal growth.The results of our study, which assessed neonatal outcomes, also support this hypothesis.Infants in the both EUGR groups showed a significantly higher incidence of neonatal morbidities.
The most important factors related to EUGR are prematurity [28,29], and enteral nutritional support [30].We also found that infants in the both EUGR groups were not only more immature but also had lower BWs than those in the non-EUGR.The growth of preterm infants is a developmental process; feeding intolerance, and/or difficulties in digesting decrease as infants mature [31].

Efficient Prediction for Long-Term Outcomes
Analyses of long-term outcomes are required to evaluate the appropriateness of growth charts in defining EUGR.In a retrospective cohort study in Taiwan, Chien et al. reported that EUGR is significantly associated with cognitive function at 24 months of CA for prematurity [32].Zozaya et al. found that a low-weight z-score is associated with poor BSID score at 24 months of CA for prematurity in an Italian preterm cohort [33].Our findings revealed a higher incidence of infants diagnosed with CP, NDI, and growth failure in the EUGR group at 18-24 months CA compared with the non-EUGR group, based on both definitions.Interestingly, the differences were observed between the growth charts in predicting long-term outcomes.After adjusting for confounding factors, infants diagnosed by EUGR IG at the newborn period had a 1.66 times higher risk of developing CP and a 2.09 times higher risk of developing NDI than infants without EUGR IG .Although the aOR of the EUGR F for NDI reached statistical significance, it was lower than that of the EUGR IG (1.29 and 2.09, respectively).Furthermore, the DOR of the EUGR IG was higher than that of the EUGR F when CP or NDI were analyzed, with higher DORs indicating better test performance [34].It could be argued that for predicting neurodevelopmental outcomes such as CP or NDI, the IG-21 ST chart is more appropriate than the Fenton chart.Meanwhile, the aOR of growth failure calculated in EUGR F was higher than that of the EUGR IG (2.44 and 1.57, respectively).These were in line with previous studies.Yitayew et al. compared the Fenton and IG-21 ST growth charts and found that weight-based EUGR IG may be more strongly associated with poor neurodevelopmental outcomes than EUGR F [13].Lan et al. reported that the IG-21 ST growth chart is not superior to the Fenton chart for assessing preterm growth based on a Chinese retrospective cohort study [35].Also, recently, Italian researchers compared the Italian Neonatal Study Charts and IG-21 ST growth charts and found that EUGR IG could predict neurodevelopmental outcomes in preterm infants more frequently [36].
Due to poor diagnostic effectiveness in terms of sensitivity and/or specificity for both EUGR definitions, it is not a suitable method for predicting long-tern outcomes in clinical practice.The definition of EUGR is primarily based on the physical growth status of infants and is not designed to evaluate neurodevelopment.However, because EUGR is determined through a simple method using easy, noninvasive weight measurements, both EUGR IG and EUGR F could serve as simple indicators useful to clinicians in their everyday practice.When infants are classified as EUGR, neonatologist should be alerted to potential concerns about poor long-term outcomes.Emphasizing early evaluation and intervention for EUGR is crucial when caring for preterm infants.
The strength of our study lies in the utilization of data from a population-based national cohort registry, encompassing approximately 70% of VLBW infants in Korea [14].The registry maintains a complete data-monitoring system to improve data quality [37].However, our study is not without limitations.First, we solely focused on weight-based EUGR for the outcome analysis.Second, both the Fenton and IG-21 ST charts may not entirely reflect the specific growth patterns of Korean infants due to potential influences from environmental factors and ethnicity.

Conclusions
In conclusion, this retrospective study investigated the association between long-term growth and neurodevelopmental outcomes and EUGR as defined by either the Fenton or IG-21 ST chart in VLBW infants.We found that a higher proportion of CP and NDI at 18-24 months CA was associated with EUGR IG compared to EUGR F .Additionally, EUGR IG demonstrated a higher DOR and negative predictive value, suggesting better diagnostic performance in predicting CP or NDI, compared to EUGR F .Conversely, EUGR F exhibited a higher DOR and negative predictive value, indicating better diagnostic performance in predicting growth failure, compared to EUGR IG .The IG-21 ST chart may be more useful for predicting long-term neonatal neurodevelopmental outcomes, and the Fenton chart may be more suitable for predicting growth failure.Meticulous growth monitoring should be consistently implemented throughout the NICU hospitalization of preterm infants.Further studies are needed to investigate the long-term neurodevelopmental outcomes of EUGR preterm infants beyond 24 months of age.Additionally, consideration of the future metabolic risk of overgrowth problems will be helpful in determining the "gold standard" chart for assessing growth in NICU.Informed Consent Statement: Data were prospectively entered into the KNN registry after written informed parental consent was obtained.

Data Availability Statement:
The data that support the findings of this study are available from the KNN, but restrictions apply to the availability of these data, which were used under license for the current study and are not publicly available.

Author
Contributions: Conceptualization, S.Y.K.; Data curation, M.S.K. and J.S.; Formal analysis, M.S.K.; Funding acquisition, S.Y.K.; Writing-original draft, M.S.K. and J.W.K.; Writing-review and editing, S.Y.K.All authors have read and agreed to the published version of the manuscript.Funding: This research was supported by the National Research Foundation of Korea (NRF), funded by the Korea government (Ministry of Science and ICT) (RS-2023-00279932).The funder had no role in the study, including the design, data collection, analysis, interpretation of data, or writing of the manuscript.Institutional Review Board Statement:The study protocol was reviewed and approved by the IRB of Yeouido St. Mary's Hospital (IRB no.SC21ZIDE0176) and the KNN Ethics Committee (2021-057).

Table 1 .
Clinical characteristics of study population according to EUGR.
Values are expressed as median (interquartile range[IQR]) or number (percentage).a p values were calculated by comparing EUGR F and non-EUGR F infants and b p values by comparing EUGR IG and non-EUGR IG infants.Abbreviations: AS, Apgar score; BPD, bronchopulmonary dysplasia; EUGR F , extrauterine growth restriction defined by Fenton chart; EUGR IG , extrauterine growth restriction defined by IG-21 ST chart; HTN, hypertension; IG-21 ST , intergrowth-21st; PDA, patent ductus arteriosus; PN, parenteral nutrition; SGA F , small for gestational age by Fenton chart; SGA IG , small for gestational age by IG-21 ST .

Table 2 .
Logistic regression analyses for the relationship between EUGR and long-term outcomes.The ORs and aORs were calculated using non-EUGR IG or non-EUGR F as a reference.aOR is adjusted for the variables that were significantly associated with neonatal outcome in univariate analysis.a There were 690 infants able to complete evaluation for CP at 18-24 months of corrected age, among them 300 infants classified as EUGR IG , and 488 infants classified as EUGR F .b There were 2058 infants able to complete evaluation for NDI at 18-24 months of corrected age, among them 709 infants classified as EUGR IG , and 1209 infants classified as EUGR F .c There were 2600 infants able to complete anthropometric measurement at 18-24 months of corrected age, among them 956 infants classified as EUGR IG , and 1577 infants classified as EUGR F .Abbreviations: aOR, adjusted odds ratio; CI, confidence interval; CP, cerebral palsy; EUGR F , extrauterine growth restriction defined by Fenton chart; EUGR IG , extrauterine growth restriction defined by IG-21 ST chart; IG-21 ST , intergrowth-21st; OR odds ratio; NDI, neurodevelopmental impairment.