Extremely preterm infants (EPI, gestational age [GA] <28 weeks) and extremely low birth weight infants (ELBWI, birth weight [BW] <1000 g) are both high-risk neonates and pose challenges in perinatal medicine. Despite mechanical advances and the efforts of neonatologists over the last few decades, EPI and ELBWI have still been subjected to neonatal complications, death, and long-term neurodevelopmental impairments.[1–4] While delivery room intubation (DRI) effectively provides breathing assistance for preterm infants, the incidence of bronchopulmonary dysplasia (BPD) concomitantly increases,[5,6] resulting in neurological impairments.[6–8] Antenatal steroids (ANS)[9,10] and enhanced delivery room resuscitation strategies are associated with a reduction in the need for DRI [11–13] and incidence of BPD, thus improving the outcomes of preterm infants.[14,15]
Few studies from China regarding delivery room resuscitation of EPI and ELBWI have been reported. Thus, this multicenter study aimed to primarily evaluate the incidence, risk factors of DRI and secondarily assess rates of survival and BPD of EPI and ELBWI in China.
The study was approved by the Ethics Committee of Peking University First Hospital.
This study was conducted within the North China Neonatal Alliance, which comprised 44 centers. Clinical data of EPI (GA <28 weeks) and ELBWI (BW <1000 g) were analyzed from tertiary and secondary hospitals in Beijing, Tianjin, Hebei, Shanxi Province, and Inner Mongolia Autonomous Region in North China between January 1, 2017 and December 31, 2018. Inclusion criteria for the study were preterm infants with a GA <28 weeks or BW <1000 g, who were admitted within 72 h of birth with complete data. Exclusion criteria were infants with lethal congenital heart diseases, such as Tetralogy of Fallot and complete transposition of the great arteries; malformed digestive systems, such as intestinal stenosis and intestinal atresia; or central nervous system disorders, and inborn metabolic diseases.
This study was conceptualized and coordinated by the Pediatric Department of Peking University First Hospital as the host unit, and was reviewed by the collaborative hospitals. All collaborators agreed to sign a cooperation agreement. Data were collected by collaborators using a questionnaire designed with EpiData Software (The EpiData Association, Odense, Denmark). Collected data were stored, analyzed at the host unit reviewing the data. Collected data comprised infants’ and mothers’ demographics, delivery room resuscitation information, major respiratory complications, respiratory assistance, and outcomes at discharge regarding infants. The EPI and ELBWI were categorized by GA, BW, outcomes at discharge and whether or not have BPD.
For consistency, the following criteria were defined and adopted: (1) small for gestational age (SGA) was defined as a newborn whose BW was <10th percentile for GA according to Fenton Growth Curves; (2) ANS describes a completed drug course of a mother that received four consecutive intramuscular injections of dexamethasone before delivery; (3) ANS exposure was defined as a mother who received less than four intramuscular injections of dexamethasone before delivery; (4) respiratory assistance was presented as one form of non-invasive ventilation (NIV) that consisted of nasal continuous positive airway pressure, bi-level positive airway pressure, non-invasive positive pressure ventilation (NIPPV), or another form of mechanical ventilation (MV) referred to as endotracheal intubation; (5) antepartum infection was described as premature rupture of the membranes ≥18 h or mothers with fever or contaminated amniotic fluid; (6) respiratory distress syndrome (RDS) was defined as a newborn who was diagnosed with progressive dyspnea with a chest radiograph showing homogeneous, diffuse fine-grained change in two lungs. Severe RDS was confirmed by a chest radiograph showing the heart margin, a diaphragmatic blurred shadow, or white lung; and (7) BPD was diagnosed if infants required oxygen at 36 weeks corrected GA.
Outcomes at discharge
There were three main outcomes at discharge: (1) discharge according to medical advice was described as infants who underwent complete care until vital signs were stable and could be discharged from the hospital according to the physicians’ recommendation; (2) discharge against medical advice was defined as infants who did not require a ventilator but whose therapy was terminated by the parents before the physicians’ recommendation to discharge, or infants who were transferred for surgery; and (3) death was referred to as infants that died despite receiving therapy or as a result of parents terminating treatment when infants were mechanically ventilated shortly after birth.
Continuous variables with a normal distribution were described as the mean ± standard deviation (SD) and compared by analysis of variance among the three groups and multiple comparisons were performed using Fisher least significant difference procedure. Continuous variables with a normal distribution in univariate analysis for BPD were described as the mean ± SD and compared between two groups using t-test. Data with skew distributions were shown as the median (interquartile range [IQR]) and compared using a Mann-Whitney U test between two groups and Kruskal-Wallis H test between three groups. Categorical variables were expressed as the counts and percentages and compared using χ2tests or Fisher exact test, in which P value was adjusted with Bonferroni method for multiple comparisons and less than 0.017 was considered as statistically significant. We used multivariable logistic regression analysis to assess the association between DRI and the perinatal risk factors and potential confounders, identified as a priori on the basis of clinical importance. A similar logistic regression was fitted to assess the association between BPD and potential factors. P value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 22.0 software (IBM, Armonk, NY, USA).
In total, 33 centers (30 tertiary hospitals and three secondary hospitals) from North China Neonatal Alliance participated in this study. Twelve, four, eight, three, and six centers were located in Beijing, Tianjin, Hebei Province, Shanxi Province, and Inner Mongolia Autonomous Region, respectively. Of the 34,179 preterm infants (GA <37 weeks) who were admitted to these institutions, between January 1, 2017 and December 31, 2018, 952 cases were EPI and ELBWI and eligibled for this study.
A cohort of 952 infants (498 [52.3%] males) were enrolled for the study, of whom 152 infants were not born in the participated centers. The median (IQR) age of the admitted infants was 0.43 (0.25, 0.90) h. Infants were categorized into three groups according to GA and BW: <28 weeks and <1000 g (n = 380); <28 weeks and ≥1000 g (n = 273), and ≥28 weeks and <1000 g (n = 299). The mean (SD) GA was 27.7 (1.8) weeks. Infants with GA of <25, 25, 26, 27, and ≥28 weeks accounted for 4.3% (41/952), 7.2% (69/952), 18.1% (172/952), 39.0% (371/952), and 31.4% (299/952), respectively. The mean (SD) BW was 938 (162) g. Infants weighing <750, 750 to 899, 900 to 999, and ≥1000 g accounted for 9.6% (91/952), 26.8% (255/952), 35.0% (333/952), and 28.7% (273/952), respectively. Among the 679 ELBWI, infants born at <28 weeks accounted for 56.0% (380/679), and among the 653 EPI, infants weighing <1000 g accounted for 58.2% (380/653) [Table 1].
Table 1 -
Characteristics of infants in three groups (n
||<28 weeks and <1000 g
||<28 weeks and ≥1000 g
||≥28 weeks and <1000 g
|GA (weeks), mean ± SD
||27.7 ± 1.8
||26.4 ± 1.1
||27.3 ± 0.5†
||29.7 ± 1.5†,‡
|BW (g), mean ± SD
||938 ± 162
||839 ± 119
||1127 ± 109†
||891 ± 90†,‡
|Male, n (%)
|SGA, n (%)
BW: Birth weight; GA: Gestational age; SD: Standard deviation; SGA: Small for gestational age. ∗Comparison among the three groups. †Compared with <28 weeks and <1000 g group, P < 0.01. ‡Compared with <28 weeks and ≥1000 g group, P < 0.01. §F value.
The overall mean (SD) maternal age was 32.2 (4.7) years. The mean (SD) maternal age of <28 weeks and <1000 g,<28 weeks and ≥1000 g, ≥28 weeks and <1000 g group was 32.6 (4.4), 31.8 (4.6), 32.3 (5.1) years, respectively (F = 2.4, P = 0.100). It was noted that the mothers of the EPI group (GA <28 weeks) received additional assisted reproductive technology (30.3% [198/653] vs. 16.4% [49/299], χ2 = 14.3, P < 0.001), and experienced a higher proportion of antepartum infection (30.0% [196/653] vs. 18.4% [55/299], χ2 = 14.3, P < 0.001) compared to the mothers of infants with ≥28 weeks and <1000 g. However, the mothers of infants with ≥28 weeks and <1000 g showed an increased incidence of hypertension (61.5% [184/299] vs. 18.2% [119/653], χ2 = 177.3, P < 0.001), higher occurrence of cesarean delivery (82.3% [246/299] vs. 26.3% [172/653], χ2 = 260.5, P < 0.001), and lower incidence of forceps delivery (1.3% [4/299] vs. 5.4% [35/653], χ2 = 6.4, P < 0.05) compared to the EPI group (GA <28 weeks). Mothers of the infants in the <28 weeks and ≥1000 g group had the lowest rate of hypertension (P < 0.05).
Delivery room resuscitation for EPI and ELBWI
The overall rate of DRI among infants was 55.9% (532/952). A 5-min Apgar score <5 was observed for 3.9% (36/952) of the total infants. Infants with a BW ≥1000 g or GA ≥28 weeks did not require positive pressure ventilation, with rates of 27.8% (76/273) and 31.4% (101/299), respectively. The infants with a GA <28 weeks and BW <1000 g had a higher rate of DRI (69.5% [264/380]), chest compression (18.2% [69/380]), and epinephrine use (10.8% [41/380]) compared with infants with a BW ≥1000 g or GA ≥28 weeks (P < 0.001). Overall, 27.0% of infants received pulmonary surfactants (PS) therapy during delivery room resuscitation of which infants with GA <28 weeks accounted for the rate of PS therapy (82.5% [212/257]) [Table 2].
Table 2 -
Delivery room resuscitation of infants in three groups (n
||<28 weeks and <1000 g
||<28 weeks and ≥1000 g
||≥28 weeks and <1000 g
|No positive pressure ventilation, n (%)
|Intubation, n (%)
|Chest compressions, n (%)
|Epinephrine, n (%)
|PS in DR, n (%)
|5-min Apgar score <5, n (%)
BW: Birth weight; DR: Delivery room; GA: Gestational age; PS: Pulmonary surfactant. ∗Comparison among the three groups. †Compared with <28 weeks and <1000 g group, P < 0.01. ‡Compared with <28 weeks and ≥1000 g group, P < 0.01.
We assessed the risk factors for DRI by multivariable logistic regression analysis. Independent variables for the analysis included GA <28 weeks (reference: ≥28 weeks), BW <1000 g (reference: ≥1000 g), male (reference: female), SGA at birth (reference: non-SGA), ANS (reference: no), antepartum infection (reference: no), multiple births (reference: single birth), delivery mode (natural, cesarean, and forceps deliveries [reference: natural]), and hypertension (reference: no). Overall, GA <28 weeks, BW <1000 g, antepartum infection, and forceps delivery were risk factors for DRI (P < 0.05) [Table 3].
Table 3 -
Multivariable logistic regression analysis of risk factors
|GA <28 weeks
|BW <1000 g
BW: Birth weight; CI: Confidence interval; DRI: Delivery room intubation; GA: Gestational age; OR: Odds ratio. ∗Natural delivery as referrence, delivery mode included natural, cesarean, and forceps deliveries.
Overall, 65.9% (672/952), 25.3% (241/952), and 8.8% (84/952) of all EPI and ELBWI were discharged according to medical advice, died during hospitalization, and discharged against medical advice (whose outcomes remained unknown), respectively. The mean duration of hospitalization of infants discharged according to medical advice was 69.6 (18.0) days; for the dead infants, death occurred at a median age of 3.0 (1.7, 10.0) days after birth; for the infants discharged against medical advice, they were discharged at a median age of 12.0 (3.3, 31.8) days (P < 0.05). Overall, the infants between the three groups had a similar mean GA of 27.9 (1.7), 27.2 (1.9), and 27.9 (1.9) weeks, respectively; and a similar mean BW of 959 (153), 883 (174), and 941 (164) g, respectively (P > 0.05).
Perinatal factors and respiratory complications for infants with different outcomes
Non-survivors had a higher rate of DRI, MV, ≥2 doses of PS therapy, severe RDS, and pulmonary hemorrhage; however, they also had a lower rate of ANS exposure (all P < 0.05). These infants also had a lower incidence of ≥1 complete course of ANS (P > 0.05) [Figure 1].
Infants discharged according to medical advice
Of the 627 infants that were discharged according to medical advice, 29.3% (181/627) were diagnosed with BPD. Univariate analysis revealed that preterm infants with BPD had a smaller GA and BW; higher rates of DRI, RDS, severe RDS, administration of ≥2 doses of PS therapy, and pulmonary hemorrhage; lower rate of ANS; and were more likely to be male, use MV, and have prolonged MV (all P < 0.05). Compared to the infants with non-BPD, infants with BPD had a lower rate of antepartum infection (21.5% [39/181] vs. 30.0% [134/446]) and a longer duration of hospitalization (77.1 ± 18.9 days vs. 66.6 ± 16.7 days, P < 0.001) [Table 4].
Table 4 -
Univariate analysis of risks for bronchopulmonary dysplasia among 627 infants discharged according to medical advice.
|GA (weeks), mean (SD)
||27.6 ± 1.4
||28.0 ± 1.8
|BW (g), mean (SD)
||932 ± 155
||970 ± 152
|Male, n (%)
|SGA, n (%)
|Antepartum infection, n (%)
|ANS, n (%)
|Inborn birth, n (%)
|DRI, n (%)
|RDS, n (%)
|Severe RDS, n (%)
|RDS receiving ≥2 doses of PS, n (%)
|Pulmonary hemorrhage, n (%)
|MV, n (%)
|MV duration (days), median (IQR)
||8.0 (2.9, 18.0)
||0.0 (0.0, 4.6)
|MV duration ≥7 days, n (%)
|DOH (days), mean (SD)
||77.1 ± 18.9
||66.6 ± 16.7
ANS: Antenatal steroid; BPD: Bronchopulmonary dysplasia; BW: Birth weight; DOH: Duration of hospitalization; DRI: Delivery room intubation; GA: Gestational age; IQR: Interquartile range; MV: Mechanical ventilation; PS: Pulmonary surfactant; RDS: Respiratory distress syndrome; SD: Standard deviation; SGA: Small for gestational age. ∗t value.
To assess the risk factors for BPD, independent variables included GA (weeks), BW (g), male (reference: female), SGA at birth (reference: non-SGA), hypertension (reference: non-hypertension), ANS (reference: no), antepartum infection (reference: no), DRI (reference: no), administration of PS in the delivery room (reference: no), RDS (reference: no), receiving ≥2 doses of PS therapy (reference: ≤1 doses of PS therapy), pulmonary hemorrhage (reference: no), and MV duration of ≥7 days (reference: <7 days). Multivariable logistic regression analysis confirmed that risk factors for BPD were male, DRI, RDS, requiring ≥2 doses of PS therapy, and MV duration of ≥7 days (P < 0.05). However, larger BW, ANS exposure, and administration of PS in the delivery room were preventive factors for BPD (P < 0.05). GA, SGA, hypertension, antepartum infection, and pulmonary hemorrhage were not associated with BPD (P > 0.05) [Table 5].
Table 5 -
Multivariable logistic regression analysis of risk factors
|Administration of PS in delivery room
|RDS receiving ≥2 doses of PS
|MV duration ≥7 days
ANS: Antenatal steroid; CI: Confidence interval; BPD: Bronchopulmonary dysplasia; BW: Birth weight; DRI: Delivery room intubation; MV: Mechanical ventilation; OR: Odds ratio; PS: Pulmonary surfactant; RDS: Respiratory distress syndrome.
This cohort of EPI and ELBWI admitted to neonatal intensive care units (NICUs) in North China were used to evaluate the outcomes of treating high-risk preterm infants. The survival rate of preterm infants was 65.9% at discharge, while the mortality rate was 25.3%. The remaining 8.8% were discharged against medical advice, and thus the outcomes are unknown. Of the total 952 infants, 61.3% and 55.9% were exposed to ANS and underwent DRI, respectively. Infants with BPD comprised 29.3% of the preterm infants discharged according to medical advice.
Respiratory support is the essence of delivery room resuscitation. In our study, 55.9% of infants were intubated, which is less than that reported by studies in 2015 from the United States and Italy, respectively. Studies concerning risk factors for DRI are limited. A multicenter study of premature infants (born at 29th–32nd weeks GA), reported that older GA, ANS exposure, and premature rupture of the membranes (>18 h) could reduce the degree of delivery room resuscitation, and maternal chorioamnionitis could decrease the risk of oxygenation or continuous positive airway pressure and intubation requirement, but SGA infants had an increased risk of DRI. A previous study showed that intrauterine infection could accelerate fetal lung maturation, which would reduce the risk of intubation. However, in the current study, prenatal infection was a risk factor for DRI, which does not correspond with previous research, as the infants in this study were more immature, and our definition of infection was non-histological chorioamnionitis. Additionally, in the current study, the number of SGA infants was high and rate of ANS exposure was lower. Therefore, these factors may aid in reducing the need for DRI and improve comprehensive management. Previous studies have shown that DRI is related to the premature death rate and rate of BPD.[5,21] Recent reports have indicated that increasing the peak inspiratory pressure, positive-end expiratory pressure of NIV, and application of nasal intermittent positive pressure ventilation reduced the need for intubation in the delivery room, rate of intubation within 24 h after birth, and MV duration for preterm infants with a GA <29 weeks. As there was a higher rate of DRI required for EPI and ELBWI, this study showed that suitable breathing support devices are imperative in the delivery room, and that practices of resuscitation should be improved with the focus during resuscitation being on long-term lung protection.
The survival rate of preterm infants was 65.9% in this study, which is lower than previous reports worldwide,[17,22,23] but higher than those reported by other studies in China.[24–26] In total, 8.8% of preterm infants were discharged against medical advice, with a median age of 14 days after birth. Thus, the outcomes of these infants were not determined. The median age of infants that died in this study was three days old. Among the infants that had died, high rates of DRI, serious RDS, administration of ≥2 doses of PS therapy, MV, and pulmonary hemorrhage were observed, indicating that early mortality was associated with vigorous resuscitation, the early onset of severe respiratory diseases, and comprehensive management of EPI and ELBWI. Similar results were reported in a multicenter study in Finland in 2019, where the median age of mortality of EPI was within two days after birth and the causes of mortality were younger GA, RDS, and severe intracranial hemorrhage.
BPD remains one of the most common and important complications in preterm infants, which is associated with long-term outcomes.[15,28] In this study, the incidence of BPD was lower than that of similar preterm infants examined in previous studies.[17,22,23,25,29] This discrepancy may be because partial preterm infants were discharged against medical advice. BPD not only pre-disposes preterm infants to respiratory diseases, but also results in adverse effects on long-term cardiovascular health, neurodevelopment,[28,30] mortality, and disability, as well as other comorbidities due to the chronic hypoxia resultant from BPD and prematurity. Therefore, optimizing management strategies for infants susceptible to BPD and decreasing the overall incidence of BPD will be crucial in improving short and long-term prognoses. Immature lungs and RDS increase the occurrence rate of BPD. In the current study, while multivariate analysis established that RDS with ≥2 doses of PS therapy was a risk factor for BPD, larger BW, ANS exposure, and a single administration of PS therapy in the delivery room were associated with a reduction of BPD. These results are similar to those of Rutkowska et al and Lapcharoensap et al. In addition, no association between GA and BPD was observed in the current study, possibly because of the fewer preterm infants with a smaller and limited range of GA. Perinatal care exerts a critical effect on the outcomes of EPI and ELBWI. In addition to prolonging the gestational period and maintaining healthy intrauterine growth, ensuring ANS exposure to prevent gestational complications and RDS is essential in reducing the rate of BPD. Moreover, in addition to perinatal care, integrated management strategies for preterm infants susceptible to BPD in NICUs are crucial. Although respiratory assistance and PS therapy were provided for preterm infants with RDS, this study demonstrated that the occurrence of BPD was related to DRI and MV duration (≥7 days). Furthermore, administration of PS in the delivery room was a preventive factor for BPD. European Consensus Guidelines on the Management of RDS recommend that a GA <26 weeks is an indication of prophylactic PS treatment, while PS usage is an indicator for DRI. Therefore, it is hypothesized that the higher incidence of DRI and active administration of PS in the delivery room have a positive effect on decreasing the risk factors for BPD. In addition, improving the implementation of NIV, and thus a reduction in intubation, were beneficial in reducing the occurrence of BPD. To prevent prematurity, systematic usage of NIPPV, avoidance of hyperoxia exposure, PS use, caffeine, and vitamin A were associated with a reduction in the occurrence rate of BPD. Raghuram et al showed that PS therapy can aid in reducing the rate of BPD.
China is a vast country, with wide discrepancies in economy and medical care. Treatments for EPI and ELBWI in North China were assessed between 2017 and 2018. When compared with a multicenter study regarding EPI in the Guangdong Province in China between 2008 and 2017. In our study, the use of complete courses of ANS and survival were higher, BPD morbidity and infant mortality were lower, and delivery room resuscitation data were more detailed. These discrepancies are importantly associated with different therapeutic practices and the different levels of hospitals of each study. Different studies from the Chinese mainland have shown that the number of critical preterm infants is increasing in different regions and that treatment practices are improving; however, a gap in treatment practices remains compared to other developed countries.
A major strength of the study was that enrolled infants included both EPI and ELBWI. Unlike previous studies, the data were collected and rigorously assessed in detail, especially delivery room resuscitation data that previous studies from China lacked. Thirty-three NICUs participated in this study, including 30 tertiary hospitals and three secondary hospitals, which are widely distributed in the northern areas of China. Characteristics and outcomes of EPI and ELBWI, grouped by GA and BW, are highlighted in the current study.
A limitation of the current study is that the mortality and incidences of BPD of the infants who were discharged against medical advice could not be determined.
Overall, these findings are conducive towards the improvement of treatment strategies and the outcomes of EPI and ELBWI. Multiple interventions are required for prenatal management, delivery room resuscitation, and treatment practices in NICUs to ensure positive outcomes for EPI and ELBWI.
The authors would like to thank the participants and their parents, and the following clinicians who assisted in data recruitment. Wan-Xian Zhang, Department of Neonatology, Tianjin Central Hospital of Gynecology Obstetrics. Hui Zhang, Ya-Nan Jiang, Department of Pediatrics, Peking University Third Hospital. Jian-Fang Gai, Neonatal intensive care unit, Children's Hospital of Shanxi. Xiao-Li Hao, Department of Neonatology, The Second Hospital of Hebei Medical University. Xiao-Xue Zhang, Department of Neonatology, Handan Central Hospital. Yan-Guo Zhao, Department of Neonatology, Xingtai People's Hospital. Bo Tian, Department of Neonatology, Tangshan Maternal and Child Health Hospital. Ying Zhang, Department of Pediatrics, Tianjin Medical University General Hospital. Hai-Yan Jiang, Ping Zhang, Department of Pediatrics, Baogang Third Hospital of HongCi Group. Chun-Yan Guo, Department of Neonatology, Affiliated Hospital of Chengde Medical University. Sha-Sha Fan, Department of Pediatrics, Department of Pediatrics, The First Hospital of Tsinghua University. Qiao-Yan Du, Department of Neonatology, The Affiliated Hospital of Inner Mongolia Medical University. Mei-Yan Guo, Department of Neonatology, Inner Mongolia Maternal and Child Health Hospital. Xiao-Hong Fu, Department of Neonatology, Affiliated Hospital of Chifeng University. Ya-Mei Huangshan, Department of Pediatrics, Peking University People's Hospital. Min Sun, Department of Neonatology, Hebei Children's Hospital. Jin-Yan Zhang, Department of Neonatology, Tianjin First Central Hospital. Ling Xiao, Department of neonatology, Children's Hospital. Capital Institute of Pediatrics. Xiao-Xiang Li, Department of Pediatrics, Beijing Luhe Hospital. Capital Medical University. Ya-Jing Li, Department of Pediatrics, Beijing Friendship Hospital. Capital Medical University. Liang Zhang, Department of Pediatrics, Chifeng Municipal Hospital. Ya-Li Yang, Department of Neonatology, Zhangjiakou Maternal and Child Health Hospital. Hai-Yan Bao, Department of Neonatology, Xing An Meng Hospital of Inner Mongolia. Hai-Xia Cheng, Department of Neonatology, Taiyuan Maternal and Child Health Hospital. Hong-Hong Qin, Department of Gynecology and Pediatrics, PLA Rocket Force Characteristic Medical Center. Jiao Zhang, Neonatal intensive care unit, Beijing United Family Hospital. Xiao-Xian Yan, Department of Neonatology, Fen-Yang Hospital of Shanxi. Mei Sun, Department of Neonatology, Baoding Maternal and Child Health Hospital.
Conflicts of interest
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