Neonatal Intensive Care Quality Level-Dependent Variations in the Survival Rate of Infants with a Birth Weight of 500 g or Less in Korea: A Nationwide Cohort Study

Objective: Recent evidence suggests that the survival of peri-viable infants with birth weight (BW) ≤500 g could be improved with better care practices in the neonatal intensive care unit (NICU). This study aimed to investigate the care quality level of NICU-dependent variations in the survival rate of infants with BW ≤500 g. Methods: To determine the quality of NICU care-dependent variations in the survival rate, 226 eligible infants of BW ≤500 g and ≥22 weeks gestation registered in the Korean Neonatal Network between 2013 and 2017 were grouped according to the survival rates of infants at 23–24 weeks gestation, reflecting the care quality level of each NICU as group I (≥50%, n = 107) and group II (<50%, n = 119). Results: The survival rate of group I infants (40.2%, 43/107) was significantly higher than that of group II infants (14.3%, 17/119). Significantly reduced deaths from birth to the age of 7 days due to cardiorespiratory causes were the primary contributors to improved survival. In multivariable Cox hazard model analyses, besides the gestational age and BW, antenatal steroid use, cesarean section, pH, and base excess at admission were associated with improved infant survival. Conclusions: The survival rate of pre-viable infants with BW ≤500 g could be improved by providing better NICU quality care practices, including better cardiorespiratory management starting from delivery room resuscitation.

© 2022 The Author(s). Published by S. Karger AG, Basel

Introduction

Recent advances in perinatal and neonatal intensive care have resulted in improved survival of extremely preterm infants [1-3]. However, the limited viability of infants born too immaturely to survive remains a persistent challenge for perinatal care providers. While gestational age (GA) and birth weight (BW), alone or in combination, are most widely used for predicting the survival of peri-viable infants [4], GA alone might be subject to a degree of error, especially when early ultrasonography is not available [5]. BW might exert an independent effect on survival [6, 7] and thus, may be an additional objective tool for predicting the outcomes of peri-viable infants. However, the survival rates of peri-viable infants with BW ≤500 g were quite variable between and within countries, ranging from 22% to 68% [8-10], and improved survival rates from 40% to 68% over the 10-year study period were reported in a Japanese national study [9]. These findings suggest that the limit of viability is not static and could be influenced by several perinatal factors, such as the provision of proactive management [8, 11] and care quality in individual neonatal intensive care units (NICUs) [3, 12].

As single-center experiences might be subject to bias due to small sample sizes and/or variations in clinical practices, evaluating data from a population-based nationwide neonatal network would be ideal to identify the main contributors of survival in infants of BW ≤500 g. The Korean Neonatal Network (KNN) is an ongoing nationwide, multicenter, prospective, and web-based cohort registry system for very low BW infants (VLBWIs) [10, 13-17]. In our previous studies, we observed that the survival rates of peri-viable infants born at 23–24 gestational weeks (GW) reflected the quality of perinatal and neonatal intensive care of each NICU, and improved survival of infants at 23–24 GW was associated with significantly fewer morbidities in more mature infants at 25–26 GW [14, 16, 18, 19]. In the present study, we hypothesized that care quality level of each NICU might influence the survival of the peri-viable infants with infants with BW ≤500 g and investigated the effects of clinical factors on survival of these infants.

MethodsPatients

The patient data were obtained from the web-based KNN database registry, which prospectively registered the clinical information of VLBWIs, covering >80% of VLBWIs born in Korea. Trained staff collected the infants’ demographic and clinical information electronically using a standard operating procedure. We determined the quality level of each NICU-dependent variation in the survival rates of infants with BW ≤500 g by dividing the hospitals within KNN into those with survival rates of infants at 23–24 GW ≥50% (group I) and those with survival rates <50% (group II) [14, 16, 18, 19]. We also investigated the effects of clinical variables on the survival of these infants.

Data Collection

We compared maternal and neonatal variables, including GA, BW, Apgar scores at 1 and 5 min, sex, delivery mode, small for GA (SGA; BW below the 10th percentile), antenatal steroid use, premature rupture of membranes (PROM), chorioamnionitis, body temperature at admission to the NICU, pH, and base excess at <1 h of life between the survivors and non-survivors. GA was determined from the obstetric history based on the last menstrual period. Antenatal steroid use was defined as the administration of any corticosteroid to the mother at any time before delivery to accelerate fetal lung maturity. PROM was defined as the rupture of membranes >24 h before labor onset, and chorioamnionitis was confirmed by placental pathology.

We compared the proportionate cause-specific mortality rates in terms of the timing of death between groups I and II. The cause of death, confirmed by the principal investigator of each NICU, was categorized according to the Korean Standard Classification of Diseases-7 based on the International Classification of Diseases (10th revision, Clinical Modification). The following mutually exclusive categories were considered: cardiorespiratory causes, including respiratory distress syndrome, pulmonary hypertension, pulmonary hemorrhage, air leak syndrome, and bronchopulmonary dysplasia (BPD) defined as the use of supplemental oxygen at 36 GW [20]; neurological causes, including asphyxia, severe intraventricular hemorrhage (IVH) [21], and its sequelae; infectious causes, including sepsis; gastrointestinal causes, including necrotizing enterocolitis (NEC) [22]; and others, including multisystem failures of unknown etiology. The prevalence of major morbidities in survivors, including BPD, IVH (≥grade 3), cystic periventricular leukomalacia, NEC (>stage 2), sepsis defined as positive blood culture in symptomatic infants plus >5 days of antibiotic treatment [15], and retinopathy of prematurity defined as any retinopathy of prematurity requiring surgery to prevent visual loss [16], was compared between groups I and II. The KNN developed a unique data quality management system composed of automatic and manual query generation and regular external site-visit monitoring [13].

Statistical Analysis

Continuous variables were presented as mean ± standard deviation and compared using the Student’s t test or Mann-Whitney U test. Categorical variables were presented as percentages and frequencies and were compared using the χ2 or Fisher’s exact test. A comparison between the cumulative survival rates according to hospital group was performed using a Kaplan-Meier analysis. A multivariable Cox proportional hazards model was used to estimate the odds ratio (OR) with 95% confidence intervals (CI) to identify clinical factors associated mortality and to determine the differences in the timing and cause-specific death between group I and II. Multivariate analysis included only the clinical variables with p < 0.05 by univariate analysis to control for the effects of confounding variables. Listwise deletion technique was used to handle the missing data. SPSS version 25.0 (SPSS Inc., IBM Corp., Armonk, NY) was used for all statistical analyses; a p value < 0.05 was considered statistically significant.

ResultsStudy Population

Of the 281 infants with BW ≤500 g born between January 2013 and December 2017, 22 infants of <22 GW, 7 out-born infants, 12 infants with unidentified outcomes due to transfer to another hospital, 9 infants with life-threatening congenital anomalies, and 6 infants without records of survival status were excluded, and 226 infants were ultimately enrolled in the study (Fig. 1). Subsequently, to determine the care quality level of each NICU-dependent variation in the survival rates of infants with BW ≤500 g, we divided the infants born in NICUs with survival rates of infants at 23–24 GW ≥50% as group I (107 patients from 17 NICUs) and those born in NICUs with survival rates <50% as group II (119 patients from 29 NICUs).

Fig. 1.

Flowchart of the study design for patient enrollment.

/WebMaterial/ShowPic/1479975Survival Rates of the Group I and II Infants with BW ≤500 g

Figure 2 illustrates the survival curves of group I and II infants with BW ≤500 g, plotted using the Kaplan-Meier method. The 40.2% (43/107) cumulative survival rate of group I was significantly higher than 14.3% (17/119) of group II (p < 0.01).

Fig. 2.

Survival rates of the infants according to the hospital groups by Kaplan-Meier method.

/WebMaterial/ShowPic/1479973Clinical Characteristics

Table 1 presents the demographic and clinical findings of the enrolled infants of BW ≤500 g. While GA and pH at admission of groups I, II, and total infant groups, antenatal steroid use, base excess, and body temperature at admission of group I and total infants, and Apgar score at 1 and 5 min and cesarean section of group II and total infants were significantly higher in the survivors than in the non-survivors, PROM of group I and total infants, and multiple pregnancy of the total infants were significantly lower in the survivors than in the non-survivors.

Table 1.

Demographic and perinatal characteristics in infants with BW ≤500 g

/WebMaterial/ShowPic/1479983Clinical Factors Associated with Survival

Table 2 shows the multivariable Cox regression analysis associated with survival in each group and the total number of infants with BW ≤500 g. While group II was significantly associated with a lower survival than group I, higher BW of the group I, II, and total infants, a higher GA of the group II and total infants, higher cesarean section rate and base excess at admission of the group II, and higher antenatal steroid use and pH at admission of the group I infants were associated with significantly higher survival rates of the infants. In Cox hazard regression analysis, the adjusted odds ratio (95% CI) for survival rates in group I of the 23–24 GW subgroup (2.94 [1.53–5.64] [p < 0.01]), and of BW 301–400 g (3.94 [1.40–11.09] [p = 0.01]) and 401–500 g (1.93 [1.11–3.34] [p = 0.02]) subgroups were significantly higher than group II (online suppl. Table 1, 2; for all online suppl. material, see www.karger.com/doi/10.1159/000527613). For group comparison, significantly higher GA (p = 0.02) and antenatal steroid use (p = 0.04) were observed in the total group I than group II (online suppl. Table 3).

Table 2.

Cox proportional hazards regression models of clinical factors associated with survival in infants with BW ≤500 g

/WebMaterial/ShowPic/1479981Proportionate Cause-Specific Mortality in Terms of the Timing of Death

Table 3 shows the proportionate cause-specific mortality in terms of the timing of death. In a Cox hazard regression analysis, the total and birth-to-postnatal day (P) 7 mortality rates due to cardiorespiratory causes in group II were significantly higher than those in group I.

Table 3.

Proportionate cause-specific mortality rate in terms of timing of death in the infants with BW ≤500 g

/WebMaterial/ShowPic/1479979Morbidities of the Survivors

Table 4 shows the major morbidities in the survivors of groups I and II. There were no significant differences in morbidities, such as BPD, IVH, and sepsis, between the surviving infants in groups I and II.

Table 4.

Major morbidities of the surviving infants with BW ≤500 g

/WebMaterial/ShowPic/1479977Discussion

While the wide differences in the survival rate of these peri-viable infants were primarily due to inter-center variations in proactive perinatal and neonatal treatment [8, 11], our KNN data still showed wide NICU care quality level-dependent variations in the survival rate of infants with BW ≤500 g, ranging from 40.2% in group I to 14.3% in group II, despite the routine implementation of the same proactive management policies. In concordance with our data, after the Swedish National Board of Health and Welfare recommended the centralization of care for all extremely preterm births at six university hospitals with an emphasis on in utero maternal transfer, the survival rate of infants at 22 weeks gestation in the nation tripled from 10% to 30% [23]. Overall, these findings suggest that the survival rate of infants at the limit of viability is not static, and it could be improved with the provision of better perinatal and neonatal intensive care in addition to proactive management policies [3, 12, 17, 18].

Identifying the clinical factors associated with improved survival of pre-viable infants is essential for developing new and effective clinical strategies to overcome the limitations of viability [17, 18]. In our previous single-center and nationwide studies, a higher Apgar score at 5 min, body temperature at admission to the NICU, and antenatal steroid use were associated with improved survival of viable infants [14, 15, 17, 18]. In the present study, besides GA and BW, antenatal steroid use and pH at admission in group I and cesarean section and base excess at admission in group II were significantly associated with an improved survival of the infants at the limit of viability. However, our data of significantly higher cesarean section observed only in group II but not in group I suggest that the seeming association between cesarean section and improved survival of the peri-viable infants might just reflect a selection bias [24]. Taken together, these findings suggest that improvements in the perinatal and neonatal intensive care processes that encompass antenatal steroid use, better delivery room management, including resuscitation performed by an experienced skillful neonatologist, and close attention to admission body temperatures are required to improve the survival of infants at the limit of viability [9, 17, 18, 25].

Identifying the timing and causes of death is essential for understanding the factors that contribute to mortality in peri-viable infants. In the present study, significantly improved survival from birth to P7 due to a significant reduction in deaths related to cardiorespiratory causes, including RDS, pulmonary hemorrhage, and air leak syndrome, was the primary contributor to improved survival in group I than in group II infants. Patel et al. [2] reported that the significantly improved survival of infants at 23 weeks gestation was mainly attributable to reduced deaths up to P7 due to pulmonary causes. In our previous studies [17, 18, 25], improved the ultimate survival of infants at 23–24 weeks gestation was primarily attributable to significantly reduced mortality from birth to P7 due to pulmonary causes. Collectively, these findings suggest that a better early admission care to the NICU, including gentle meticulous respiratory care, might be primarily responsible for the improved survival of infants at the limit of viability.

There might be a concern that an improved survival of infants at the limit of viability will be accompanied by an increase in morbidities in the survivors. However, in the present study and other studies [9], the incidence of major morbidities among survivors remained unchanged. In our previous studies [14, 18, 19], an improved survival of the infants at 23–24 weeks gestation was accompanied by significantly higher survival and lower morbidities in the more mature infants at 25–26 weeks gestation. In concordance with our data, Stoll et al. [3] reported that improved the survival of infants at 23–24 weeks gestation during the last two decades was accompanied by a significantly improved survival with fewer morbidities in the more mature infants at 25–28 weeks gestation. Overall, these findings suggest that the provision of better perinatal and neonatal care practices to improve survival of the infants at the limit of viability might simultaneously contribute to improving survival with less morbidity in more mature infants.

The present study has several limitations. This was a retrospective analysis of prospectively collected nationwide cohort data covering all the tertiary NICUs in Korea, and the temporal changes in the survival rate of infants at ≤500 g could not be analyzed due to short data collection time span. The relatively small sample size of the subgroups, especially in the survivors of group II, might be another limitation of this study. However, the statistically significant improved survival observed in group I infants compared with this small sample size subgroup might redeem this limitation. Although the principal investigator of each NICU confirmed the primary cause of death, occasionally, it was difficult to determine the primary cause of death in a complex situation when multiple causes were observed to interact. To address the possible misclassification in listing the causes of death, we characterized broader categories, including cardiorespiratory death, in addition to specific causes of death, including RDS and BPD. In conclusion, our nationwide data showed that the survival rate of peri-viable infants with a BW ≤500 g was not static, and could be improved by providing better NICU quality care practices, including better cardiorespiratory management starting from delivery room resuscitation.

Statement of Ethics

The KNN registry was approved by the Samsung Medical Center Institutional Review Board (2013-03-002) and the Institutional Review Boards of all 70 hospitals participating in the KNN. Written consent was obtained from the parents of the infants during enrollment in the KNN.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This research was supported by a fund (2022-ER0603-00#) by Research of the Korea National Institute of Health.

Author Contributions

Misun Yang conceptualized and designed the study, carried out the initial analyses, and drafted the initial manuscript. Yun Sil Chang conceptualized and designed the study and reviewed and revised the manuscript. So Yoon Ahn and Se In Sung collected data and reviewed and revised the manuscript. Yun Sil Chang and Won Soon Park coordinated and supervised data collection and critically reviewed the manuscript. All authors approved the final manuscript as submitted.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.

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