The Effect of Postnatal Systemic Corticosteroid on Neurodevelopmental Outcome in Very Low Birth Weight Preterm Infants

Article information

Neonatal Med. 2025;32(1):10-20

Publication date (electronic) : 2025 May 31

doi : https://doi.org/10.5385/nm.2025.32.1.10

Joo Yun Yang, MD ¹

, Young Min Youn, MD ¹

, Jung In Kang, MD ¹

, Ye Jin Han, MD ¹

, Do Kyung Lee, MD ¹

, Hyun Kyung Bae, MD ¹

, So-Yeon Shim, MD, PhD^,¹^,²

¹Department of Pediatrics, Ewha Womans University Seoul Hospital, Seoul, Korea

²Division of Neonatology, Department of Pediatrics, Ewha Womans University College of Medicine, Seoul, Korea

Correspondence to: So-Yeon Shim, MD, PhD Division of Neonatology, Department of Pediatrics, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, 260 Gonghang-daero, Gangseo-gu, Seoul 07804, Korea Tel: +82-2-6986-4227 Fax: +82-2-6986-3024 E-mail: simso@ewha.ac.kr

Received 2025 March 26; Revised 2025 April 27; Accepted 2025 May 14.

Abstract

Purpose

This study aimed to investigate the effects of postnatal systemic corticosteroids on neurodevelopment in very low birth weight (VLBW) preterm infants.

Methods

This was a population-based study of the Korean Neonatal Network of VLBW infant born at 23⁺⁰ and 31⁺⁶ weeks of gestation between 2013 and 2020. VLBW preterm infants assessed using the Bayley Scales of Infant and Toddler Development, third edition (BSID-III) at 18–24 months of corrected age and 3 years of age were enrolled. The primary outcomes were BSID-III scores and neurodevelopmental delays, with scores of <85. Socioeconomic status and clinical variables were adjusted for using multivariate regression analyses.

Results

In total, 517 infants were enrolled in this study. Among the 216 (41.8%) infants who received postnatal systemic corticosteroids, the rate of cognitive delay was significantly higher at 18–24 months of corrected age than at 3 years of age. The rates of language and motor delays were significantly higher both at 18–24 months of corrected age and at 3 years of age. When multivariate logistic regression was performed, postnatal systemic corticosteroid use was significantly associated with cognitive delay at 18–24 months of corrected age, but not at 3 years of age. There was no significant association between postnatal systemic corticosteroid use and language or motor delay at 18-24 months of corrected age or at 3 years of age after multivariate logistic regression.

Conclusion

Postnatal systemic corticosteroid use in VLBW preterm infants increased the risk of cognitive delay at 18–24 months of corrected age, but not at 3 years.

Keywords: Adrenal cortex hormones; Infant, very low birth weight; Infant, premature; Developmental delay

INTRODUCTION

Bronchopulmonary dysplasia (BPD) is one of the most common complications of prematurity, and its incidence increases with decreasing gestational age (GA) and birth weight. In recent years, as survival rates for very low birth weight (VLBW) infants (<1,500 g) have increased, so has the incidence of BPD [1]. Some VLBW infants are administered systemic corticosteroids to prevent and treat BPD, and several studies have shown that corticosteroid therapy improves lung function and reduces the duration of ventilator and oxygen use in preterm infants [2-4].

However, systemic corticosteroid use is associated with adverse effects, including short-term complications such as hyperglycemia, gastrointestinal bleeding, growth retardation, and sepsis [5,6], as well as long-term neurodevelopmental delays in preterm infants [7-15]. Yeh et al. [7] reported that systemic corticosteroid use was linked to poorer motor and cognitive function at school age compared with controls. O'Shea et al. [8] found that the risk of cerebral palsy at 12 months corrected age was higher in the corticosteroid group. Due to concerns regarding potential neurodevelopment impairment, the American Academy of Pediatrics does not recommend the routine use of corticosteroids in VLBW preterm infants [16]. However, systemic corticosteroids are still used in clinical practice to prevent and treat BPD. Nevertheless, recent studies on systemic corticosteroid use are scarce, particularly those analyzing Korean data; therefore, we used data from the Korean Neonatal Network (KNN) to investigate the effects of systemic corticosteroids on neurodevelopment in VLBW preterm infants.

This study evaluated the neurodevelopmental function of preterm infants at 18–24 months of corrected age and 3 years of age to determine the impact of systemic corticosteroid use on the long-term neurodevelopmental outcomes of VLBW preterm infants born at <32 weeks of gestation for the prevention and treatment of preterm infants.

MATERIALS AND METHODS

1. Study participants and design

VLBW preterm infants born between January 2013 and December 2020 with a GA of 23–32 weeks and a birth weight of <1,500 g who were enrolled in the KNN and used systemic corticosteroids for the prevention and treatment of BPD and who had the Bayley Scales of Infant and Toddler Development, third edition (BSID-III) at 18–24 months of corrected age and at 3 years of age were enrolled. Patients with severe congenital anomalies, those who received only corticosteroid inhalation therapy, and those with no information on corticosteroid use were excluded. The KNN is a nationwide web-based network for VLBW infants with a birth weight of <1,500 g or a GA of <32 weeks, with 78 participating hospitals and approximately 80% of the nation’s VLBW infants enrolled. Hospitals participating in the KNN entered the web-based program according to definitions outlined in the entry guide. This study was approved by the KNN Committee.

2. Collection data items and definitions

Information on infants and mothers was extracted from the KNN database. Perinatal information included GA, sex, method of delivery, birth weight, head circumference, and 5-minute Apgar score. We examined the duration of ventilator use, length of hospital stay, and use of corticosteroids to prevent or treat BPD in premature infants in neonatal intensive care units (NICU). Regarding major neonatal complications, diagnoses of BPD, intraventricular hemorrhage (IVH) of stage 3 or higher, and cystic periventricular leukomalacia (PVL), sepsis, and necrotizing enterocolitis (NEC) of stage 2 or higher were evaluated. Maternal information was collected on multiple pregnancy status, diabetes, hypertension, histologic chorioamnionitis (CA), and prenatal steroid use. Socioeconomic factors included maternal educational level, maternal nationality, information about the child’s primary caregiver, and whether the child attended a daycare center or a playgroup.

The duration of ventilator use was recorded as 1 day if the infant received at least 10 minutes of either invasive or noninvasive ventilation. BPD was diagnosed if the infant required >21% oxygen for ≥28 days at 36 weeks’ postmenstrual age or discharge. Moderate BPD was assessed as requiring less than 30% oxygen at 36 weeks postmenstrual age or discharge [17]. The IVH stage was assessed based on the most severe IVH among all brain ultrasound examinations performed during the NICU stay, using the Papile classification system as a reference [18]. Cystic PVL was diagnosed if cystic changes were seen on imaging findings such as brain ultrasound and brain magnetic resonance imaging. Sepsis was diagnosed if the patient had a positive blood culture result and required systemic antibiotic therapy for more than 5 days. NEC stage was assessed accord ing to the modified Bell's staging system [19]. Histological CA was defined as acute inflammatory changes observed at the site of the placenta on histological examination. Maternal educational level was categorized into two groups based on whether she graduated from college or higher, and maternal nationality was also categorized into two groups based on whether she was South Korean. The assessment of the patients’ primary caregivers was separated into cases in which both parents were the primary caregivers.

3. Neurodevelopmental outcomes

Neurodevelopmental outcomes were assessed using the BSID-III administered at 18–24 months of corrected age and at 3 years of age. Scores were measured in the cognitive, language, and motor development domains of the BSID-III, and a score of <85 in each domain was considered developmentally delayed [20].

4. Statistics

SPSS version 30.0.0.0 (IBM) was used for the statistical analyses. Continuous variables were tested for normality, and normally distributed variables were presented as mean± standard deviation and analyzed using the Student’s t-test. Continuous variables that were not normally distributed were presented as medians (interquartile range) and analyzed using the Mann-Whitney U-test. The chi-squared test was used for categorical variables. Multiple logistic regression was used to identify the risk factors for developmental delay. A P-value of <0.05 was considered statistically.

RESULTS

1. Study participants

A total of 13,527 VLBW preterm infants born between January 2013 and 2020 with GA >23 and <32 weeks were enrolled in the KNN. Of these, 418 patients with severe congenital anomalies, 1,843 who died before discharge, and 560 who received corticosteroid inhalation therapy alone or had no information on corticosteroid use were excluded. A total of 10,640 children were followed up at 18–24 months of corrected age after discharge from the NICU, excluding 66 who died before then. Of these, 2,315 children (21.8%) visited the hospital at 18–24 months of corrected age and were administered the BSID-III, and 517 children (22.3%) were included in the study who were also administered the BSID-III at 3 years of age (Figure 1).

Figure 1.

Flow chart of the study population from the Korean Neonatal Network database. Abbreviations: NICU, neonatal intensive care unit; BSID-III, Bayley Scales of Infant and Toddler Development, third edition.

2. Clinical characteristics

The clinical characteristics and socioeconomic factors of infants and mothers of patients who received systemic corticosteroids to prevent BPD were compared with those of the control group. The systemic corticosteroid use group had a younger GA (P<0.001), smaller birth weight and head circumference (both P<0.001), longer duration of ventilator use, and longer length of stay than the control group (both P<0.001). There were no significant differences in sex or cesarean section rates between the two groups. The rates of moderate or greater BPD and sepsis were higher in the systemic corticosteroid use group (P<0.001 and P=0.005, respectively), while there were no statistically significant differences in the rates of stage 3 or higher IVH, cystic PVL, or stage 2 or higher NEC. The rate of histological CA was significantly higher in mothers in the systemic corticosteroid use group (P<0.001), and the rate of maternal education was significantly lower in mothers in the systemic corticosteroid use group (P=0.045). There were no significant differences in multiple pregnancy status, maternal diabetes, hypertension rates, prenatal steroid use, maternal nationality, primary caregiver, and attendance at day care or playgroups (Table 1).

Table 1.

Comparison of Clinical Variables in Enrolled Patients according to Administration of Postnatal Systemic Corticosteroids

3. Neurodevelopmental outcomes

Scores on the cognitive, language, and motor domains of the BSID-III, administered at 18–24 months corrected age, were all significantly lower in the systemic corticosteroid use group compared to the control group (84.6±15.1 vs. 89.4±15.7, P<0.001; 81.5±15.9 vs. 85.4±16.9, P=0.004; and 84.0±16.5 vs. 90.2±17.1, P<0.001, respectively). The rates of cognitive, language, and motor developmental delays were significantly higher in the systemic corticosteroid use group than in the control group (42.9% vs. 27.5%, P<0.001; 57.1% vs. 44.6%, P=0.007; and 43.4% vs. 28.9%, P<0.001, respectively). Scores in the cognitive, language, and motor domains of the BSID-III at age 3 years were all significantly lower in the systemic corticosteroid use group compared to the control group (85.9±16.0 vs. 89.2±16.4, P=0.011; 81.5±19.0 vs. 85.8±18.2, P=0.004; and 81.7±16.3 vs. 87.7±17.5, P<0.001, respectively). The rates of delayed language and motor development were significantly higher in the systemic corticosteroid use group (52.1% vs. 41.3%, P=0.019; and 49.3% vs. 37.9%, P=0.012, respectively). However, there was no significant difference in the rate of delayed cognitive development (37.0% vs. 29.2%, P=0.076) (Table 2).

Table 2.

Comparison of Neurodevelopmental Outcomes in Enrolled Patients at 18–24 Months Corrected Age and at 3 Years of Age according to Administration of Postnatal Systemic Corticosteroids

The clinical characteristics and socioeconomic factors of patients and controls with developmental delays on the BSIDIII, administered at 18–24 months of corrected age, were also analyzed. All groups with cognitive, language, and motor developmental delays had a younger GA (P=0.004, P=0.004, and P<0.001, respectively), lower birth weight and head circumference (all P<0.001; P=0.005, P=0.017, and P=0.002, respectively), longer duration of ventilator use, and longer length of stay (all P<0.001). The rates of moderate or greater BPD and stage 3 or higher IVH were higher in all groups with cognitive, language, and motor developmental delays (P=0.001, P<0.001, and P<0.001, respectively; P<0.001, P=0.002, and P<0.001, respectively). The rates of cystic PVL were higher in groups with cognitive and motor developmental delays (P=0.002 and P< 0.001, respectively). There was no significant difference in the rates of sepsis and stage 2 or higher NEC. The prevalence of systemic corticosteroid use was significantly higher in all groups with cognitive, language, and motor developmental delays (53.4% vs. 36.7%, P<0.001; 48.4% vs. 36.3%, P=0.007; and 52.5% vs. 36.9%, P<0.001, respectively). There were no significant differences between the clinical characteristics of the mothers in the developmentally delayed and control groups in any domain. Attendance at day care or playgroup was significantly lower in all groups with cognitive, language, and motor developmental delays (P<0.001, P=0.003, and P<0.001, respectively) (Table 3).

Table 3.

Comparison of Clinical Variables in Enrolled Patients at 18–24 Months Corrected Age according to Neurodevelopmental Delay

The clinical characteristics and socioeconomic factors of the patient and control groups with developmental delays in the BSID-III at 3 years of age were also analyzed. All groups with cognitive, language and motor developmental delays had younger GA (P=0.028, P=0.006, and P<0.001, respectively), lower birth weight and head circumference (all P<0.001; P=0.009, P=0.011, and P=0.009, respectively), longer duration of ventilator use and longer length of stay (P=0.002, P<0.001, and P<0.001; all P<0.001, respectively). The rates of moderate or greater BPD, stage 3 or higher IVH, and stage 2 or higher NEC were higher in all groups with cognitive, language, and motor developmental delays (P=0.006, P<0.001, and P<0.001; P=0.006, P<0.001, and P<0.001; P=0.004, P=0.046, and P=0.002, respectively). The rates of cystic PVL and sepsis were higher in the group with developmental motor delays (P=0.003 and P=0.024, respectively). The prevalence of systemic corticosteroid use was significantly higher in the group with language and motor developmental delays (48.1% vs. 37.5%, P=0.019 and 48.9% vs. 37.5%, P=0.012, respectively); however, there was no significant difference between the group with cognitive developmental delays and the control group (48.2% vs. 39.5%, P=0.076). The proportion of mothers with a college diploma or higher and the proportion attending day care or playgroup were significantly lower in all groups with cognitive, language, and motor developmental delays (P<0.001, P<0.001, and P=0.005; and all P<0.001) (Table 4).

Table 4.

Comparison of Clinical Variables in Enrolled Patients at 3 Years of Age according to Neurodevelopmental Delay

The effect of systemic corticosteroid use on developmental delay was analyzed using multiple logistic regression, controlling for the effects of other independent variables based on the results of the analysis between the developmental delay and control groups in each domain. The controlled variables were GA, birth weight, head circumference, duration of ventilator use, length of stay, major neonatal complications, and socioeconomic factors that were significant in a single analysis. The risk of cognitive developmental delay with systemic corticosteroid use was significantly increased at 18–24 months corrected age (odds ratio [OR], 2.00; 95% confidence interval [CI], 1.02 to 3.94; P=0.004), but with no significant effect at 3 years of age (OR, 1.54; 95% CI, 0.77 to 3.07; P=0.222). In contrast, systemic use of corticosteroids had no significant effect on the risk of delayed language and motor development at 18–24 months corrected age and at 3 years of age (OR, 1.29; 95% CI, 0.71 to 2.34; P=0.413) (OR, 1.57; 95% CI, 0.80 to 3.06; P=0.187) (OR, 0.97; 95% CI, 0.52 to 1.82; P=0.927) (OR, 1.18; 95% CI, 0.62 to 2.23; P=0.620, respectively) (Table 5).

Table 5.

Adjusted Odds Ratios of Postnatal Systemic Corticosteroid Administration for Neurodevelopmental Delay at 18–24 Months Corrected Age and at 3 Years of Age

DISCUSSION

This study evaluated the impact of systemic corticosteroid use for the prevention and treatment of BPD in VLBW preTable term infants born at <32 weeks of GA on the long-term neurodevelopmental outcomes of patients at two time points: 18–24 months of corrected age and 3 years of age. Children who used systemic corticosteroids had significantly lower scores on each domain of the BSID-III at 18–24 months corrected age and 3 years of age than controls and significantly higher rates of developmental delay in each domain. These findings are similar to those of other studies that evaluated systemic corticosteroid use and neurodevelopmental outcomes in preterm infants [7-15]. Needelman et al. [15] sought to determine whether systemic administration of dexamethasone adversely affected the neurodevelopmental outcomes of preterm infants born at 28 week’ GA or less. In this study, dexamethasone use was significantly associated with mild developmental delay on the mental and motor scales of the BSID-II administered at 6–8 months of corrected age. In addition, dexamethasone use was significantly associated with developmental delay, even after adjusting for other variables that may affect neurological development in preterm infants [15].

In this study, delays in language and motor development were significantly associated with systemic corticosteroid use, as measured by the BSID-III, at 18–24 months of corrected age and at 3 years of age. In contrast, delayed cognitive development was significantly associated with systemic corticosteroid use only at 18–24 months corrected age. In contrast to previous studies, this study reanalyzed the data after adjusting for other clinical factors that influence neurodevelopmental delays and found that systemic corticosteroid use did not increase the risk of language and motor delays at 18–24 months of corrected age or 3 years of age. However, this study demonstrated that even after adjusting for clinical factors, the occurrence of cognitive developmental delay at 18–24 months of corrected age was associated with systemic corticosteroid use. However, this association with cognitive developmental delay was not present when assessed at 3 years of age, which does not necessarily mean that development improved as preterm infants grew but may be related to the fact that the rate of cognitive developmental delay among VLBW preterm infants remained similar as the infants grew older [21-23]. Linsell et al. [21] assessed the cognitive development of preterm infants born at less than 26 weeks’ GA at 30 months corrected age, 6, 11, and 19 years of age and found that cognitive delays identified in infancy persisted into adulthood without improvement. Breeman et al. [22] studied VLBW infants born at less than 32 weeks’ GA and weighing less than 1,500 g and found that cognitive delays persisted from 20 months corrected age to 26 years of age. This suggests that changes in the brain parenchyma caused by premature birth constrain neurodevelopment [22]. Other studies have shown that brain lesions formed in the neonatal period persist into adulthood and are significantly related to intelligence [23].

In addition to systemic corticosteroid use, many other factors influence the long-term neurodevelopmental outcomes of VLBW preterm infants [24-30]. GA is a strong clinical marker associated with neurodevelopmental outcomes in VLBW infants [24,25]. In this study, we determined the impact of systemic corticosteroid use on neurodevelopmental outcomes after adjusting for GA.

In the single analysis, GA, birth weight and head circumference, duration of ventilator use, length of hospital stay, moderate or greater BPD, stage 3 or higher IVH, cystic PVL, sepsis, stage 2 or higher NEC, maternal level of education, maternal nationality, primary caregiver of the patient, and whether the infant attended day care or play group were associated with the risk of neurodevelopmental delay. Multiple logistic regression analysis showed that GA and stage 3 or higher IVH were significantly associated with the risk of cognitive delay at 18–24 months of corrected GA, whereas GA, maternal education level, stage 2 or higher NEC, and length of hospital stay were significantly associated with cognitive delay at 3 years of age. After adjusting for these factors, systemic corticosteroid use had a significant effect on cognitive developmental delay at 18–24 months of corrected age. The results showed that the risk of delayed language and motor development did not significantly increase with systemic corticosteroid use, but the risk of delayed cognitive development at 18–24 months of corrected age was significantly increased. IVH and cystic PVL are also important factors affecting neurodevelopmental outcomes in preterm infants [26]. In this study, we found that the incidence of cystic PVL was significantly higher in the group with motor developmental delay at 18–24 months of corrected age and at 3 years of age. Among the socioeconomic factors that influence neurodevelopmental outcomes, maternal education is an important factor [27]. In this study, maternal level of education was not significantly associated with delayed cognitive development at 18–24 months of corrected age, but was associated with delayed cognitive development at 3 years of age.

There are studies that suggest differences in outcomes based on the type of corticosteroid used systemically to prevent and treat BPD [14,31,32]. Zayat et al. [14] found an increased risk of cognitive developmental abnormalities in the dexamethasone and betamethasone groups in preterm infants <30 weeks’ GA, but no significant association in the hydrocortisone group. In a study by Baud et al. [32] evaluating development at 2 years of age in preterm infants with GA greater than 24 weeks and less than 28 weeks who received hydrocortisone at 0.5 mg/kg twice daily for 7 days and then 0.5 mg/kg once daily for 3 days, there was no significant association between low-dose hydrocortisone and neurodevelopmental delay. Other studies have also identified differences in outcomes based on the duration and total dose of systemic corticosteroid use [11,12,15,33,34]. In a study of VLBW preterm infants less than 28 weeks and less than 1,000 g birth weight, Douglas et al. [12] found that the risk of cerebral palsy increased significantly with increasing cumulative dose of systemic corticosteroid use, and scores in the areas of cognitive and motor development were significantly lower. This study did not analyze those factors because the KNN input does not include data related to the duration and total dose of systemic corticosteroid use, nor does it reflect the type of systemic corticosteroid used. Future studies that refine the type of corticosteroids used systemically, the duration of administration, and the total dose may contribute to a useful protocol for the systemic administration of corticosteroids for the prevention and treatment of BPD in VLBW preterm infants.

A limitation of this study is that of the 1,745 participants who took the BSID-III at 18–24 months of corrected age, only 517 (22.3%) took the BSID-III at 3 years of age. This is likely related to the lower overall follow-up rates in the KNN at 18–24 months of corrected age and at 3 years of age (46.2% and 29.2%, respectively). However, a prematurity continuation management project is being implemented to increase the followup rate of premature babies, and continuous efforts are being made, such as placing coordinators in each hospital; therefore, we expect more accurate analysis results in the future.

The KNN does not have entry criteria or indications for initiating systemic corticosteroid therapy; therefore, they could not be analyzed. There were also differences in the morbidity and follow-up rates between the systemic and nonsystemic corticosteroid use groups in this study. The systemic corticosteroid arm had lower morbidity (9.9% vs. 15.9%, P< 0.001) and a higher proportion of children who had taken the BSID-III at both 18–24 months of corrected age and 3 years of age (31.6% vs. 19.8%, P<0.001), thus potentially biasing the results of the analysis owing to the lack of information on indications for systemic corticosteroid use and differences in morbidity and follow-up rates. There is also the potential for statistical errors when analyses of cognitive, language, and motor development at 18–24 months of corrected age and 3 years of age were tested simultaneously. However, this study was based on a nationwide cohort and analyzed a larger sample size than other studies, which adds significance to its findings. Further studies aimed at reducing these biases and errors will likely yield more meaningful results.

The strength of this study is that it was based on a nationwide multicenter cohort that enrolled approximately 80% of the nation's VLBW babies. A study using the Effective Perinatal Intensive Care in Europe (EPICE) cohort of preterm infants born between 2011 and 2012 in 11 European countries at GA 22–32 weeks also found that systemic corticosteroid use significantly increased the risk of delayed motor development at 24 months of corrected age [14]. This study is important because it includes more recent data than studies using the European cohort. This study also differs from previous studies in that it assessed the impact of systemic corticosteroids on neurodevelopmental outcomes in VLBW preterm infants at two time points, 18–14 months corrected age and 3 years of age, rather than only at one time point, to determine whether the impact of corticosteroids changed as the infants grew.

Systemic corticosteroid use for the prevention and treatment of BPD in VLBW preterm infants has been associated with an increased risk of long-term neurodevelopmental delays. However, after adjusting for potential confounding factors affecting neurodevelopmental delays in preterm infants, systemic corticosteroid use did not significantly increase the risk of language and cognitive delays at 18–24 months of corrected age, or neurodevelopmental delays at 3 years of age. However, there was a significantly increased risk of cognitive developmental delay at 18–24 months corrected age. Cautious use of systemic corticosteroids for the prevention and treatment of BPD in VLBW preterm infants is recommended.

Notes

Ethical statement

The KNN registry received approval from the Institutional Review Board (IRB) at each participating hospital (approval No. SEUMC 2021-02-035). Informed consent was obtained from the parents during enrollment by the neonatal intensive care units participating in the KNN. All methods were carried out in accordance with the IRB-approved protocol and in compliance with relevant guidelines and regulations.

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Author contributions

Conception or design: J.Y.Y., S.Y.S.

Acquisition, analysis, or interpretation of data: All authors.

Drafting the work or revising: J.Y.Y., S.Y.S.

Final approval of the manuscript: All authors read and approved the final manuscript.

Funding

This research was supported by the National Institute of Health (NIH) research project (2025-ER0601-00#).

Acknowledgments

None

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Variable	Postnatal systemic corticosteroid		P-value
Variable	No (n=298)	Yes (n=219)	P-value
Infant characteristics and neonatal morbidities
Gestational age (wk)	28.6 (27.1–30.0)	26.1 (24.9–27.6)	<0.001^*
Male sex	150 (50.3)	112 (51.1)	0.927^†
Cesarean section	247 (82.9)	176 (80.4)	0.536^†
Birth weight (g)	1,068.5±264.3	855.5±226.8	<0.001^‡
Head circumference at birth (cm)	25.6±2.2	23.9±2.3	<0.001^‡
Apgar scores 5 min	7.1±1.7	6.4±1.8	<0.001^‡
Duration on ventilation (d)	33.5 (12.0–54.0)	77.0 (55.5–102.0)	<0.001^*
Length of stay (d)	75.0 (57.0–96.0)	116.0 (97.0–143.5)	<0.001^*
Moderate BPD	100 (34.0)	178 (82.4)	<0.001^†
IVH, grade ≥3	27 (9.1)	27 (12.3)	0.291^†
PVL	27 (9.1)	29 (13.2)	0.171^†
Sepsis	49 (16.4)	59 (26.9)	0.005^†
NEC, stage ≥2	21 (7.0)	27 (12.3)	0.06^†
Maternal characteristics and socioeconomic status
Multiple birth	96 (32.2)	62 (28.3)	0.392^†
Maternal diabetes	36 (12.1)	18 (8.2)	0.203^†
Maternal hypertension	73 (24.5)	42 (19.2)	0.184^†
Chorioamnionitis	93 (33.7)	103 (51.5)	<0.001^†
Antenatal steroid	275 (92.3)	191 (88.4)	0.184^†
Maternal educational < college	46 (23.4)	23 (14.4)	0.045^†
Mother from foreign country	4 (1.3)	5 (2.3)	0.640^†
Parents as primary caretaker	277 (96.9)	207 (97.2)	1.000^†
Day care center attendance	130 (46.3)	83 (42.1)	0.423^†

Variable	Postnatal systemic corticosteroid		P-value
Variable	No (n=298)	Yes (n=219)	P-value
Neurodevelopment at 18–24 months corrected age
Cognitive score	89.4±15.7	84.6±15.1	<0.001^*
Language score	85.4±16.9	81.5±15.9	0.004^*
Motor score	90.2±17.1	84.0±16.5	<0.001^*
Cognitive delay (%)	82 (27.5)	94 (42.9)	<0.001^†
Language delay (%)	133 (44.6)	125 (57.1)	0.007^†
Motor delay (%)	86 (28.9)	95 (43.4)	<0.001^†
Neurodevelopment at 3 years of age
Cognitive score	89.2±16.4	85.9±16.0	0.011^*
Language score	85.8±18.2	81.3±19.0	0.004^*
Motor score	87.7±17.5	81.7±16.3	<0.001^*
Cognitive delay (%)	87 (29.2)	81 (37.0)	0.076^†
Language delay (%)	123 (41.3)	114 (52.1)	0.019^†
Motor delay (%)	113 (37.9)	108 (49.3)	0.012^†

Variable	Cognitive delay		P-value	Language delay		P-value	Motor delay		P-value
Variable	No (n=341)	Yes (n=176)	P-value	No (n=259)	Yes (n=258)	P-value	No (n=336)	Yes (n=181)	P-value
Infant characteristics and neonatal morbidities
Gestational age (wk)	28.0 (26.0–29.4)	27.0 (25.6–28.6)	0.004^*	28.0 (26.1–29.6)	27.3 (25.6–28.9)	0.004^*	28.0 (26.3–29.6)	26.7 (25.1–28.4)	<0.001^*
Male sex	168 (49.3)	94 (53.4)	0.424^†	125 (48.3)	137 (53.1)	0.311^†	170 (50.6)	92 (50.8)	1.000^†
Cesarean section	277 (81.2)	146 (83.0)	0.718^†	212 (81.9)	211 (81.8)	1.000^†	277 (82.4)	146 (80.7)	0.704^†
Birth weight (g)	1,014.6±261.9	907.9±273.0	<0.001^‡	1,021.3±260.8	935.1±273.1	<0.001^‡	1,019.3±263.5	902.0±266.7	<0.001^‡
HC at birth (cm)	25.2±2.3	24.5±2.5	0.005^‡	25.2±2.3	24.7±2.4	0.017^‡	25.2±2.3	24.5±2.4	0.002^‡
Apgar scores 5 min	6.8±1.8	6.9±1.8	0.290^‡	6.8±1.7	6.8±1.8	0.759^‡	6.8±1.8	6.8±1.8	0.512^‡
Duration on ventilation (d)	45.0 (25.0–74.0)	59.0 (34.0–87.0)	<0.001^*	45.0 (23.0–71.0)	57.0 (32.0–87.0)	<0.001^*	44.0 (24.0–71.0)	646.0 (37.0–94.0)	<0.001^*
Length of stay (d)	86.0 (61.0–116.0)	103.0 (76.0–136.5)	<0.001^*	87.0 (60.0–115.0)	99.0 (73.0–132.0)	<0.001^*	83.5 (37.0–94.0)	108.0 (78.0–142.0)	<0.001^*
Moderate BPD	166 (49.3)	112 (64.7)	0.001^†	117 (45.9)	161 (63.1)	<0.001^†	156 (46.8)	122 (68.9)	<0.001^†
IVH, grade ≥3	23 (6.7)	31 (17.6)	<0.001^†	16 (6.2)	38 (14.7)	0.002^†	17 (5.1)	37 (20.4)	<0.001^†
PVL	26 (7.6)	30 (17.0)	0.002^†	21 (8.1)	35 (13.6)	0.064^†	20 (6.0)	36 (19.9)	<0.001^†
Sepsis	68 (19.9)	40 (22.7)	0.532^†	48 (18.5)	60 (23.3)	0.225^†	64 (19.0)	44 (24.3)	0.197^†
NEC, stage ≥2	27 (7.9)	21 (12.0)	0.177^†	23 (8.9)	25 (9.7)	0.857^†	27 (8.1)	21 (11.6)	0.245^†
Postnatal systemic corticosteroid	125 (36.7)	94 (53.4)	<0.001^†	94 (36.3)	125 (48.4)	0.007^†	124 (36.9)	95 (52.5)	<0.001^†
Maternal characteristics and socioeconomic status
Multiple birth	105 (30.8)	53 (30.1)	0.954^†	76 (29.3)	82 (31.8)	0.612^†	104 (31.0)	54 (29.8)	0.870^†
Maternal diabetes	34 (10.0)	20 (11.4)	0.735^†	27 (10.4)	27 (10.5)	1.000^†	33 (9.8)	21 (11.6)	0.631^†
Maternal hypertension	67 (19.6)	48 (27.3)	0.062^†	53 (20.5)	62 (24.0)	0.385^†	77 (22.9)	38 (21.0)	0.696^†
Chorioamnionitis	136 (43.5)	60 (36.8)	0.194^†	100 (42.6)	94 (39.8)	0.610^†	121 (40.1)	75 (43.1)	0.581^†
Antenatal steroid	305 (90.2)	161 (91.5)	0.765^†	230 (89.5)	236 (91.8)	0.448^†	301 (90.1)	165 (91.7)	0.677^†
Maternal education < college	45 (18.0)	24 (22.4)	0.409^†	30 (15.7)	39 (23.5)	0.085^†	49 (19.8)	20 (18.3)	0.896^†
Mother from foreign country	4 (1.2)	5 (2.8)	0.308^†	1 (0.4)	8 (3.1)	0.043^†	5 (1.5)	4 (2.2)	0.806^†
Parents as primary caretaker	316 (96.9)	168 (97.1)	1.000^†	241 (97.2)	243 (96.8)	1.000^†	314 (97.5)	170 (96.0)	0.518^†
Day care center attendance	161 (51.3)	52 (31.7)	<0.001^†	122 (51.7)	91 (37.6)	0.003^†	158 (50.5)	55 (33.3)	<0.001^†

Variable	Cognitive delay		P-value	Language delay		P-value	Motor delay		P-value
Variable	No (n=349)	Yes (n=162)	P-value	No (n=280)	Yes (n=237)	P-value	No (n=296)	Yes (n=221)	P-value
Infant characteristics and neonatal morbidities
Gestational age (wk)	27.9 (26.0–29.4)	27.3 (25.6–28.7)	0.028^*	28.0 (26.1–29.4)	27.3 (25.4–28.9)	0.006^*	28.0 (26.3–29.6)	27.1 (25.1–28.9)	<0.001^*
Male sex	167 (47.9)	95 (56.5)	0.079^†	132 (47.1)	130 (54.9)	0.097^†	143 (48.3)	119 (53.8)	0.247^†
Cesarean section	289 (82.8)	134 (79.8)	0.472^†	235 (83.9)	188 (79.3)	0.216^†	245 (82.8)	178 (80.5)	0.593^†
Birth weight (g)	1,004.6±260.3	923.6±282.8	<0.001^†	1,015.2±261.4	934.6±274.6	<0.001^†	1,015.4±257.3	928.5±279.6	<0.001^†
HC at birth (cm)	25.1±2.3	24.6±2.5	0.009^†	25.2±2.3	24.7±2.5	0.011^†	25.2±2.3	24.6±2.5	0.009^†
Apgar scores 5 min	6.8±1.8	6.9±1.8	0.685^†	6.9±1.7	6.7±1.8	0.060^†	6.9±1.7	6.8±1.8	0.539^†
Duration on ventilation (d)	48.0 (26.0–72.0)	58.0 (33.0–92.0)	0.002^*	45.5 (23.0–70.5)	59.0 (34.0–89.0)	<0.001^*	47.5 (24.5–71.0)	57.0 (33.0–92.0)	<0.001^*
Length of stay (d)	87.0 (62.0–115.0)	102.0 (72.0–138.5)	<0.001^*	87.0 (61.0–114.0)	98.0 (73.0–134.0)	<0.001^*	86.0 (62.5–115.0)	99.0 (72.0–138.0)	<0.001^*
Moderate BPD	173 (50.1)	105 (63.6)	0.006^†	123 (44.4)	155 (66.5)	<0.001^†	136 (46.4)	142 (65.4)	<0.001^†
IVH, grade ≥3	27 (7.7)	27 (16.1)	0.006^†	16 (5.7)	38 (16.0)	<0.001^†	16 (5.4)	38 (17.2)	<0.001^†
PVL	34 (9.7)	22 (13.1)	0.318^†	23 (8.2)	33 (13.9)	0.052^†	21 (7.1)	35 (15.8)	0.003^†
Sepsis	73 (20.9)	35 (20.8)	1.000^†	55 (19.6)	53 (22.4)	0.516^†	51 (17.2)	57 (25.8)	0.024^†
NEC, stage ≥2	23 (6.6)	25 (15.0)	0.004^†	19 (6.8)	29 (12.3)	0.046^†	17 (5.7)	31 (14.1)	0.002^†
Postnatal systemic corticosteroid	138 (39.5)	81 (48.2)	0.076^†	105 (37.5)	114 (48.1)	0.019^†	111 (37.5)	108 (48.9)	0.012^†
Maternal characteristics and socioeconomic status
Multiple birth	116 (33.2)	42 (25.0)	0.071^†	94 (33.6)	64 (27.0)	0.129^†	98 (33.1)	60 (27.1)	0.174^†
Maternal diabetes	36 (10.3)	18 (10.7)	1.000^†	28 (10.0)	26 (11.0)	0.830^†	28 (9.5)	26 (11.8)	0.482^†
Maternal hypertension	71 (20.3)	44 (26.2)	0.166^†	56 (20.0)	59 (24.9)	0.220^†	62 (20.9)	53 (24.0)	0.475^†
Chorioamnionitis	134 (42.4)	62 (38.8)	0.505^†	109 (43.1)	87 (39.0)	0.420^†	112 (41.6)	84 (40.6)	0.890^†
Antenatal steroid	313 (90.2)	153 (91.6)	0.723^†	29 (89.2)	217 (92.3)	0.294^†	261 (88.8)	205 (93.2)	0.122^†
Maternal education < college	33 (13.3)	36 (33.3)	<0.001^†	24 (12..4)	45 (27.4)	<0.001^†	31 (14.4)	38 (27.0)	0.005^†
Mother from foreign country	3 (0.9)	6 (3.6)	0.064^†	2 (0.7)	7 (3.0)	0.109^†	5 (1.7)	4 (1.8)	1.000^†
Parents as primary caretaker	329 (97.3)	155 (96.3)	0.711^†	267 (98.9)	217 (94.8)	0.015^†	276 (97.2)	208 (96.7)	0.984^†
Day care center attendance	166 (51.6)	47 (30.1)	<0.001^†	137 (52.9)	76 (34.7)	<0.001^†	151 (55.1)	62 (30.4)	<0.001^†

Variable	Adjusted P-value	Adjusted OR (95% CI)
18–24 months corrected age
Cognitive delay	0.044	2.00 (1.02–3.94)
Language delay	0.413	1.29 (0.71–2.34)
Motor delay	0.187	1.57 (0.80–3.06)
3 years of age
Cognitive delay	0.222	1.54 (0.77–3.07)
Language delay	0.927	0.97 (0.52–1.82)
Motor delay	0.620	1.18 (0.62–2.23)