The Survival Rate of Extremely Low Birth Weight Infants Improved in Guangdong Province, China

Background With the increase in low (ELBW) their studies of the outcomes of ELBW are from The rose with increasing BW, the ascending level of regional and The incidence of complications was neonatal respiratory distress syndrome (85.2%), bronchopulmonary dysplasia (63.7%), retinopathy of prematurity (39.3%), intraventricular hemorrhage (29.4%), necrotizing enterocolitis (12.0%), and periventricular leukomalacia (8.0%). Among the 1156 nonsurvivors, 90.0% of infants died during the neonatal period ( ≤ 28 days), and the other died after the neonatal period. A total of 768 ELBW infants died after medical care withdrawal, with economic factors and expected outcome being important causes. statistical analyses were performed using SPSS 18.0 for Windows (IBM, Armonk, NY, USA). Continuous variables were presented as the means ± standard deviation (SD) when their distributions were highly skewed or as medians (P25, P75) when their distributions were not skewed and were analyzed using t-tests or Mann-Whitney tests. Categorical variables were presented as rates and odds ratios with 95% condence intervals (CIs), which were analyzed using chi ‐ square tests. P < 0.05 was considered statistically signicant.


Introduction
Low birth weight premature infants have a particularly high risk for morbidity and mortality 1,2 . In recent decades, the outcomes of preterm infants, especially extremely preterm (gestational age [GA] < 28 weeks) and extremely low birth weight (ELBW, birth weight [BW] < 1000 grams) infants, have improved worldwide due to the use of antenatal steroids, pulmonary surfactant treatment and advances in perinatal health care, such as neonatal resuscitation, mechanical ventilation and nutritional management [3][4][5][6] . However, mortality and morbidity vary widely across countries or regions. Generally, more improvements have been gained in developed countries or regions, such as the United States 2,7 , the United Kingdom 8 , Japan 9,10 and Singapore 11 .
Available data of extremely preterm and ELBW infants are very important for family counseling and clinical practice improvement.
Many neonatal networks or collaborative study groups, such as the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) in the United States 7,12 , Canada Neonatal Network (CNN) 13 , Neonatal Research Network of Japan (NRNJ) 10,14 , Etude Epidémiologique sur les Petits Ages Gestationnels (EPIPAGE) in France 15 , and EPICure in the United Kingdom 8,16 , have worked well and continuously monitored the outcomes of these infants. However, in mainland China, a similar national or provincial network has not been established. The outcomes of extremely preterm and ELBW infants observed in a large population remain unclear. Therefore, we initiated a collaborative study group including twenty-six neonatal intensive care units (NICUs) from Guangdong Province of China to perform a multicenter survey of the short-term outcomes at discharge of extremely preterm or ELBW infants from 2008 to 2017. In a previous paper, the outcomes of extremely preterm infants were summarized and analyzed 17 . In this paper, we solely focus on the outcomes of ELBW infants.

Demographics of ELBW infants and mothers
From 2008 to 2017, 2575 ELBW infants were enrolled in this survey. The overall survival rate at discharge was 55.11% (1419 of 2575). The lowest BW in the survivors was 480 grams. In total, the median BW was 900 (800, 950) grams, and the distribution ranged from 22 (0.85%) for less than 500 grams, 52 (2.02%) for 500 -599 grams, 150 (5.83%) for 600 -699 grams, 372 ( To clarify the current treatment and outcome of ELBW infants, we speci cally grouped the ELBW infants based on whether they survived, as presented in Table 1. Both the BW and GA in the survivor group were greater than those in the nonsurvivor group (p < 0.001). In the survivor group, there were fewer infants with Apgar scores ≤ 3 at 1 min and ≤ 3 or 4∼7 at 5 min (all p < 0.001). The survivor group had a longer hospital stay and a higher rate of receiving surfactant therapy (p < 0.001), but there was no signi cant difference between those who required two or more doses of surfactant therapy. No signi cant difference in sex was found between the survivor and nonsurvivor groups. The mothers in the survivor group had a higher proportion of antenatal steroid therapy and cesarean section (both p < 0.001) but a lower incidence of cervical incompetence (p < 0.01). Interestingly, the mothers in the survivor group even had higher incidences of premature rupture of membranes (p < 0.001), fetal distress (p < 0.05) and pregnancy-induced hypertension syndrome (p < 0.001).
Between the survivor and nonsurvivor groups, there was a similar incidence in the history of pregnancy problems, as in mother's age (≥ 35 years), multiple pregnancy (twins/triplets), infection in the perinatal period, gestational diabetes mellitus, or placental disease (placental abruption/placenta previa).
Both the number and survival rates of ELBW infants increased from 2008 to 2017. The number of ELBW infants discharged from the involved NICUs increased rapidly from 91 cases in 2008 to 466 cases in 2017, as shown in Table 2. Moreover, the proportion of ELBW infants among all discharged preterm infants rose annually from 1.09% in 2008 to 2.62% in 2017 (p < 0.001), and the proportion of ELBW infants among all discharged infants increased annually from 0.27% in 2008 to 0.77% in 2017 (p < 0.001, Fig.   1). It was encouraging that the survival rate of ELBW infants improved steadily from 41.76% in 2008 to 62.02% in 2017 (p < 0.001, Table 2).

Survival rates of ELBW infants improved with increasing BW
With the increase in BW, the number of ELBW infants increased sharply from 22 in the group with BW < 500 grams to 1294 in the group with BW 900 -999 grams, as demonstrated in Table 3. Only one infant survived with BW < 500 grams. However, the survival rate rose dramatically from 30.77% in the group with BW 500 -599 grams to 65.53% in the group with BW 900 -999 grams (p < 0.001). Of course, the survival rate of infants weighing 500 -749 grams was lower than that of infants weighing 750 -999 grams (35.15% (129 of 367) vs. 58.97% (1289 of 2186), OR = 0.377, 95% CI: 0.300 -0.475, p < 0.001).  ). However, the overall survival rates increased with the ascending level of regional economic development (p < 0.05). This is shown in Table 4. Variations in survival rates between general hospitals and specialist hospitals Among the twenty-six NICUs involved, seven were in specialist hospitals (maternal and children's hospitals), and the others were in general hospitals. The median BW and mean GA of ELBW infants discharged from specialist hospitals (880 (790, 950) grams and 27.59 ± 2.03 weeks, respectively) were both smaller than those of infants discharged from general hospitals (900 (800, 950) grams and 28.22 ± 2.05 weeks, respectively, both p < 0.001). However, the overall survival rate of ELBW infants discharged from specialist hospitals was higher than that of infants discharged from general hospitals (OR = 1.416, 95% CI: 1.208 -1.660, p < 0.001) ( Table  4).  (Fig. 2).  Table 6. The chi-square test showed that there was a signi cant difference in the distribution of survival days between the two groups (p < 0.001).

Disussion
The outcome of ELBW infants has become a hot topic in recent decades worldwide. In this study, we con rmed that the number of ELBW infants increased rapidly from 2008 to 2017 in Guangdong Province, China. At the same time, the survival rate improved steadily year by year. These data from China provide helpful information to complement the understanding of ELBW infants from developing countries.
Similar to reports from other countries, our study has suggested an increase in ELBW infants. From the 1990s or 2000s, the number of ELBW infants began to increase in many developed countries [24][25][26] . In our study, we also see a signi cant increase in ELBW infants over the ten years, from 1.09 per 1000 discharged infants in 2008 to 2.62 per 1000 discharged infants in 2017. A 2.4-fold increase is noted. Although this is not a national population-based survey, it can partly re ect the situation of ELBW infants in China.
The improvement in the outcome of ELBW infants depends on the development of the economy and the advancement of medicine. During the past decades, the mortality rate of ELBW infants has decreased in many developed countries or regions. In Japan, the neonatal mortality rate and the mortality rate of ELBW infants during NICU stays were 13.0% and 17.0% in 2005 9 . In the United States, the standardized mortality rates for infants weighing 501-750 grams and 751-1000 grams in 2009 were 36.6% and 11.7%, respectively 27 . In Korea, the survival rate of ELBW infants increased dramatically from 14.0% in 1985-1989 to 69.6% in 2010-2014 28 .
However, in China, it was reported that just half of ELBW infants survived in 2011 29 . In our survey, the overall survival rate of ELBW infants at discharge was 55.11%, while it was 46.41% in 2011. An encouragingly improving tendency was found, from 41.76% in 2008 to 62.02% in 2017. This re ects the great progress gained.
The achievement of economic development can promote advancements in medicine. We found that the survival rate of ELBW infants in different regions was positively correlated with the level of economic development. Hong Kong, a developed modern city neighboring Guangdong Province but not involved in this study, reports a higher survival rate 30 . In China, specialist hospitals, such as children's hospitals or maternal and children's hospitals, have more and better facilities in neonatal care than general hospitals.
As a result, a higher survival rate was noted in the specialist hospitals in our study. A similar phenomenon was found in another multicenter study from China 30 .
Perinatal management is essential for the outcomes of ELBW infants. Many studies have shown that antenatal corticosteroids effectively decrease the mortality of preterm infants and even reduce various complications, such as NRDS, NEC, IVH and ROP 31,32 .
Although there is still some controversy regarding the side effects 33 , there is a consensus that the advantages of prenatal corticosteroids outweigh the disadvantages 4,34 . Unfortunately, only 49.2% of infants' mothers received antenatal corticosteroids in this study, but this gure was 80%-90% in developed countries 12,35,36 . Therefore, this situation should be changed as soon as possible.
Interestingly, many studies have shown that the premature rupture of membranes (PROM) and pregnancy-induced hypertension (PIH) syndrome are high-risk factors for premature delivery and infant death 37,38 , but our study showed that the incidence of PROM and PIH syndrome in the survivor group was higher than that in the nonsurvivor group. Moreover, cesarean section was more common in the survivor group. A possible explanation is that PROM or PIH syndrome could have been an early warning that attracted the attention of pregnant women and led them go to the hospital for help in a timely manner. When they were admitted to the hospital, more active medical care, such as antenatal corticosteroids, cesarean section, neonatal resuscitation and pulmonary surfactant, was given. Nevertheless, the other potential reasons still need to be further studied and analyzed.
ELBW infants are unstable and tend to suffer various complications due to their prematurity. Without active life support, many infants die during the neonatal period, especially in the rst 7 days of age, and some die due to critical illnesses despite receiving active treatments. In our study, 90.0% of nonsurviving infants died during the neonatal period, while nearly 68.3% died in the rst 7 days, and the majority died after medical care withdrawal (Table 6). Although active treatment withdrawal in these infants is a controversial issue, it truly exists in developing countries because of the high hospital costs in addition to the high risk for later complications 39 . We can reasonably believe that the outcomes of ELBW infants will continue to improve with the continued economic development and advancement of medicine in China.
To the best of our knowledge, this study covers the largest population sample and the longest time span addressed by such studies on ELBW infants in China to date. It can provide helpful information for family consultation, clinical practice and further research.
However, there are some limitations in this study. First, it is not a population-based or nationwide study. Second, the long-term outcomes of ELBW infants are not addressed, and further studies are needed.

Conclusion
In conclusion, this survey presents an overall outcome of ELBW infants in China. Both the number and the survival rate of ELBW infants increased annually from 2008 to 2017.

Participating centers
All methods were carried out in accordance with relevant guidelines and regulations. The study protocol was approved by the Institutional Review Board of the Third A liated Hospital of Guangzhou Medical University and by the Ethics Committees of the Third A liated Hospital of Guangzhou Medical University. Written consent was obtained from the parents at the time of admission.
The membership of the collaborative study group was the same as previously described 17 . In brief, twenty-six NICUs were united as a collaborative study group before clinical data collection. These NICUs were located in three regions with different economic development levels in Guangdong Province and were representative of medical units offering neonatal intensive care in their respective areas as we described before 17 . The Third A liated Hospital of Guangzhou Medical University was responsible for coordinating this study. The same diagnostic criteria were applied to all enrolled NICUs.

Subjects and data collection
All ELBW infants discharged from the collaborative NICUs were studied. The study protocol was fully discussed by all members, and a standardized questionnaire for data collection, including maternal and neonatal demographics, treatments, major complications and outcomes, was designed. The study was initiated at the end of 2012 and is still ongoing. Therefore, the data from January 1, 2008, to December 31, 2012, were collected retrospectively, and data from January 1, 2013, to December 31, 2017, were collected prospectively. The relevant records of all enrolled infants and their mothers were reviewed, and a questionnaire was completed. All sheets were sent to the Third A liated Hospital of Guangzhou Medical University, and the data from each questionnaire were input into the database. To minimize bias among centers and investigators, comprehensive and systematic training was provided to the staff involved in the survey. The data collected by the researchers at each collaborative NICU were supervised and checked by the director of the NICU, who was responsible for quality assurance. The records were also checked for accuracy and completeness by collaborative centers.

De nitions and classi cations
In this survey, surviving infants were de ned as neonates who survived to the time of discharge. GA was calculated from the date of the last menstrual period or was determined by fetal ultrasound assessment. Neonatal respiratory distress syndrome (NRDS) was diagnosed in preterm infants with the onset of respiratory distress shortly after birth and a compatible chest radiograph appearance 18 . Bronchopulmonary dysplasia (BPD) was de ned as continuous oxygen dependency at 28 days of age 19 . The criteria utilized in our survey for the diagnosis of necrotizing enterocolitis (NEC) and for grading the severity of disease were based on Bell's stage 20 . Retinopathy of prematurity (ROP) and the graded standard were de ned by the international classi cation of ROP 21 . Intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) were diagnosed by cranial ultrasonography or magnetic resonance imaging (MRI). The Papile grading system was used to grade IVH 22 , and PVL was de ned as degeneration of white matter adjacent to the cerebral ventricles following cerebral hypoxia or brain ischemia 23 .

Statistical analysis
All statistical analyses were performed using SPSS 18.0 for Windows (IBM, Armonk, NY, USA). Continuous variables were presented as the means ± standard deviation (SD) when their distributions were highly skewed or as medians (P25, P75) when their distributions were not skewed and were analyzed using t-tests or Mann-Whitney tests. Categorical variables were presented as rates and odds ratios with 95% con dence intervals (CIs), which were analyzed using chi-square tests. P < 0.05 was considered statistically signi cant.

Declarations
Authors' contributions F.W. conceptualized and designed the study, carried out the initial analyses, drafted the initial manuscript, and completed its nal The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Ethics declarations Figure 1 The proportion of ELBW infants in all discharged preterm infants or in all discharged infants from 2008 to 2017. R×2 Chi-square test (linear-by-linear association) showed that the proportions of ELBW infants in all discharged preterm infants or in all discharged infants increased annually (both P 0.001).