DOI: https://doi.org/10.21203/rs.3.rs-2190757/v1
Objective: To evaluate the association between pulmonary hemorrhage and bronchopulmonary dysplasia (BPD) in very low birth weight infants (VLBWIs).
Methods: The study participants were all VLBW newborns admitted from January 1, 2019 to December 31, 2021. The finally included subjects were VLBWIs who survived to discharge. This study was divided into pulmonary hemorrhage group (PH group, n=33) and non-pulmonary hemorrhage group (Non-PH group, n=181).
Results: By univariate analysis it was found that premature rupture of membranes, tracheal intubation in the delivery room, duration of mechanical ventilation, course of invasive ventilation (≥3 courses), pulmonary surfactant (>1 dose), medically and surgically treated patent ductus arteriosus, grade III-IV RDS, and early onset sepsis showed significant differences between groups (p<0.05). By univariate analysis, pulmonary hemorrhagedid not increase the risks of BPD and moderate to severe BPD. However, if the interference of invasive ventilation is excluded, pulmonary hemorrhage could increase the incidence of BPD (aOR=3.295, 95%CI1.183-9.179).
Conclusion: Our data suggests that pulmonary hemorrhage is not associated with the development of BPD and moderate to severe BPD in VLBWIs.
In recent years, with the increasing pregnancy rate at advanced maternal age and the improvement of assisted reproductive technology, premature infants are becoming more common. But, due to the immature lung development, many premature babies are prone to respiratory distress syndrome (RDS), apnea, pulmonary hemorrhage and other respiratory diseases, and often need mechanical ventilation [1–3]. Among them, because of smaller gestational age and lower birth weight, very low birth weight infants (VLBWIs) are vulnerable to pulmonary hemorrhage, which can result in respiratory failure, death and other chronic consequences [4–5].
So far, there has been continuous controversy about whether pulmonary hemorrhage could induce bronchopulmonary dysplasia (BPD) [6–7]. Li j et al carried out a single center retrospective study and found that moderate to severe BPD was significantly higher in the group with massive pulmonary hemorrhage (12/51 VLBWIs in the group with pulmonary hemorrhage vs 17/548 VLBWIs in the group without pulmonary hemorrhage, p < 0.05) [7]. However, Wang TT et al believed the opposite [8/30 extremely low birth weight infants (ELBWIs) in the pulmonary hemorrhage group vs 41/130 ELBWIs in the non-pulmonary hemorrhage group, p = 0.602] [6]. Based on the above contradictory views, this retrospective study was conducted to investigate whether pulmonary hemorrhage could increase the incidence of BPD in VLBWIs.
This is a single center, retrospective cohort study.
(1) Inclusion criteria: The study participants were all VLBW newborns admitted to the neonatal intensive care unit (NICU) of Children's Hospital Affiliated to Nanjing Medical University from January 1, 2019 to December 31, 2021. The finally included subjects were VLBWIs who successfully survived to discharge.
(2) Exclusion criteria: Infants with serious congenital malformations, hereditary metabolic diseases and death during hospitalization were excluded. Newborns with incomplete information in the case report form (CRF) were also excluded.
(3) Diagnostic criteria: Pulmonary hemorrhage was defined as bright red blood secretion from the endotracheal tube that was associated with clinical deterioration, including increased ventilator support with a fraction of inspired oxygen (FiO2) increase of > 0.3 from the baseline [8] or an acute drop in hematocrit (> 10%) [9], in addition to multi-lobular infiltrates on chest radiography. RDS was defined according to the latest guideline − 2019 European Consensus Guidelines on the Management of Respiratory Distress Syndrome (ECGMRDS) [10]. Bronchopulmonary dysplasia (BPD) was defined and graded based on a requirement for oxygen at 36 weeks postmenstrual age (NHLBI/NICHD 2010) [11]. Retinopathy of prematurity (ROP) was defined and classified according to the papers published by the International Classification Committee on retinopathy of prematurity [12]. Intraventricular hemorrhage (IVH) was defined and classified according to the literature reported by Papile LA 1978 and Volpe JJ 2008 [13–14]. Diagnostic criteria of necrotizing enterocolitis (NEC): NEC was defined and classified according to Bell’s stage [15]. Sepsis was defined based on Expert consensus on the diagnosis and management of neonatal (version 2019) [16].
(4) Exposure and grouping: The exposure factor was whether the infant had pulmonary hemorrhage during hospitalization. This study was consequently divided into pulmonary hemorrhage group (PH group) and non-pulmonary hemorrhage group (Non-PH group).
(5) Outcomes: The main outcome was the incidences of all BPD and moderate to severe BPD. The secondary outcomes were pneumothorax, IVH (≥ grade III), NEC (≥ grade II), ROP and length of hospital stay.
(1) Clinical data: CRF data of all subjects were collected by two neonatologists and checked by a third person. Clinical data including maternal hypertension, maternal diabetes, amniotic fluid turbidity, prenatal glucocorticoid, birthweight, gestational age, gender, fetal distress, mode of delivery, Apgar score, history of resuscitation, invasive and non-invasive mechanical ventilation, use of caffeine and pulmonary surfactant (PS), RDS, medically and surgically treated PDA, sepsis, NEC (≥ stage II), IVH (≥ grade III), BPD during hospitalization.
(2) Postnatal resuscitation: Postnatal resuscitation of all VLBWIs was performed in accordance with the Chinese neonatal resuscitation guidelines [17]. After birth, newborns were given warm and positive pressure ventilation with mask, and subsequent respiratory support was provided by T-piece. The need for further endotracheal intubation is determined by the neonatologist in the delivery room [17]. After resuscitation, the patient was transferred to NICU for further assessment by the doctor on duty. Invasive or non-invasive ventilation was adopted, and surfactant was first supplemented according to the severity of RDS.
(3) Therapy for respiratory diseases: During the hospitalization, the attending physician decided on the application of invasive ventilation [synchronized intermittent mandatory ventilation (SIMV), synchronized intermittent positive pressure ventilation (SIPPV), high frequency oscillatory ventilation (HFOV)], extubation and non-invasive ventilation [nasal continuous positive airway pressure (nCPAP), nasal intermittent positive pressure ventilation (NIPPV), high flow nasal cannula (HFNC) and non-invasive high frequency oscillatory ventilation (nHFOV)]. The indications for endotracheal intubation in NICU were evaluated by two standards [18]. (1) Absolute indications: invasive ventilation is required for any of the following conditions: ① Repeated apnea; ② Partial pressure of carbon dioxide (PaCO2) > 60mmHg with persistent acidosis; ③ Partial pressure of oxygen (PaO2) < 50 ~ 60mmHg, inhaled oxygen concentration > 60%~70%. (2) Relative indications, in which invasive ventilation can be considered for any of the following situations: ① Intermittent apnea, which is ineffective for treatment; ② Severe dyspnea; ③ Blood gas analysis deteriorated sharply, PaCO2 increased and PaO2 decreased. The use of caffeine and repeated surfactants was also based on the 2019 ECGMRDS guidelines [10].
Statistical analysis was performed using SPSS 13.0 software. For univariate analysis, quantitative data which obey normal distribution were showed as mean and standard deviation. Comparisons between the two groups were performed using t or t’ test. For skew distribution data, the median and interquartile range are used. Mann-Whitney test was used for comparison. In terms of qualitative data, Pearson Chi-square test was performed. For multivariate analysis, binary logistic regression analysis was used. We assessed the potential confounding variables in our statistical modeling if the p value of univariate analysis was less than 0.05. Adjusted odds ratio (aOR) with 95% confidence interval (CI) were then collected. p < 0.05 was considered statistically significant.
From January 1, 2019 to December 31, 2021, 275 VLBWIs were hospitalized in our NICU, including 42 cases with pulmonary hemorrhage and 233 cases with non-pulmonary hemorrhage. After screening by inclusion and exclusion criteria, 214 VLBWIs were finally included in the study, including 33 survival cases in the pulmonary hemorrhage group and 181 survival cases in the non-pulmonary hemorrhage group (Fig. 1). The comparison between the groups showed that there were significant differences in premature rupture of membranes (PROM) and tracheal intubation in the delivery room (p < 0.05). Table 1.
|
PH group (n = 33) |
Non-PH group (n = 181) |
χ2/t |
p value |
|
|---|---|---|---|---|
|
Maternal data |
||||
|
Maternal age (Mean ± SD, years) |
32.27 ± 6.30 |
30.57 ± 4.47 |
1.486 |
0.145 |
|
Full course of prenatal glucocorticoid # [n(%)] |
7(21.2) |
69(38.1) |
3.485 |
0.062 |
|
Fetal distress [n(%)] |
6(18.2) |
12(6.6) |
3.452 |
0.063 |
|
Amniotic fluid turbidity [n(%)] |
3(9.1) |
19(10.5) |
0.000 |
1.000 |
|
Cesarean section [n(%)] |
21(63.6) |
90(49.7) |
2.164 |
0.141 |
|
Maternal diabetes† [n(%)] |
5(15.2) |
26(14.4) |
0.000 |
1.000 |
|
Maternal hypertension* [n(%)] |
6(18.2) |
25(13.8) |
0.150 |
0.699 |
|
PROM > 18 hours [n(%)] |
13(39.4) |
16(8.8) |
19.711 |
0.0009 |
|
Neonatal data |
||||
|
Tracheal intubation in the delivery room [n(%)] |
24(72.7) |
69(38.1) |
13.603 |
0.0002 |
|
Apgar score at 1minute (Mean ± SD) |
6.94 ± 1.83 |
6.49 ± 2.19 |
1.220 |
0.228 |
|
Apgar score at 5minute (Mean ± SD) |
8.03 ± 1.26 |
7.90 ± 1.58 |
0.455 |
0.650 |
|
Birthweight (Mean ± SD, grams) |
1165.15 ± 168.77 |
1185.30 ± 278.97 |
-0.401 |
0.689 |
|
Male [n(%)] |
19(57.6) |
103(56.9) |
0.005 |
0.943 |
|
Gestational age (Mean ± SD, weeks) |
29.29 ± 1.90 |
28.93 ± 1.79 |
1.028 |
0.305 |
|
Small for gestational age [n(%)] |
5(15.2) |
16(8.8) |
0.644 |
0.422 |
| #Prenatal glucocorticoid use refers to the full course of treatment / (those who have not applied and have not completed the full course of treatment). †Maternal diabetes includes diabetes in pregnancy and gestational diabetes. *Maternal hypertension refers to hypertensive disorders in pregnancy. | ||||
There were significant differences between the two groups in the main diagnosis, including medically and surgically treated PDA as well as grade III-IV RDS (p < 0.05). There were significant differences between the two groups in the use of surfactant, the duration and course of invasive ventilation (p < 0.05). Table 2.
|
PH group (n = 33) |
Non-PH group (n = 181) |
χ2/Z |
p value |
|
|---|---|---|---|---|
|
Main diagnosis |
||||
|
Grade III-IV RDS [n(%)] |
22(66.7) |
31(17.1) |
36.763 |
0.0001 |
|
Medically and surgically treated PDA [n(%)] |
19(57.6) |
38(21.0) |
19.114 |
0.0001 |
|
Early onset sepsis [n(%)] |
17(51.5) |
25(13.8) |
25.152 |
0.0005 |
|
Therapy for respiratory diseases |
||||
|
Use of surfactant [n(%)] |
28(84.8) |
140(77.3) |
0.930 |
0.335 |
|
More than one dose of surfactant [n(%)] |
24(72.7) |
32(17.7) |
43.776 |
0.0004 |
|
Duration of caffeine application (Median + quartile, days) |
||||
|
Duration of invasive ventilation (Median + quartile, days) |
264(143, 528.5) |
99(62.5, 192) |
-4.496 |
0.0007 |
|
Duration of non-invasive ventilation (Median + quartile, days) |
319(174.5, 688) |
469.5(168, 744) |
-0.257 |
0.789 |
|
Course of invasive ventilation(≥ 3 courses) [n(%)] |
6(18.2) |
7(3.9) |
7.672 |
0.006 |
|
Course of non-invasive ventilation(≥ 3 courses) [n(%)] |
6(18.2) |
15(8.3) |
2.071 |
0.150 |
There were significant differences in BPD, moderate to severe BPD, IVH (≥ grade III) and length of hospital stay between groups (p < 0.05). Table 3.
|
PH group (n = 33) |
Non-PH group (n = 181) |
χ2/Z |
p value |
|
|---|---|---|---|---|
|
BPD [n(%)] |
26(78.8) |
98(54.1) |
6.956 |
0.008 |
|
Moderate to severe BPD [n(%)] |
16(61.5) |
38(38.8) |
4.331 |
0.037 |
|
Length of hospital stay (Median + quartile, days) |
67.81 ± 21.99 |
56.48 ± 18.30 |
3.126 |
0.002 |
|
Pneumothorax [n(%)] |
0(0.0) |
0(0.0) |
/ |
/ |
|
NEC (≥ grade II) [n(%)] |
3(9.1) |
11(6.1) |
0.068 |
0.794 |
|
ROP [n(%)] |
8(24.2) |
23(12.7) |
2.139 |
0.144 |
|
IVH (≥ grade III) [n(%)] |
4(12.1) |
3(1.7) |
6.635 |
0.010 |
Variables with p < 0.05 in Table 1 and Table 2 (PROM, tracheal intubation in the delivery room, use of surfactant more than once, grade III-IV RDS, medically and surgically treated PDA, early onset sepsis, and duration and course of invasive ventilation) were included in the multivariable analysis as confounding factors. Considering the relationship between BPD and mechanical ventilation, two models were adopted. Model 1 included PROM, tracheal intubation in the delivery room, duration of mechanical ventilation, course of invasive ventilation (≥ 3 courses), more than one dose of PS, medically and surgically treated PDA, grade III-IV RDS, and early onset sepsis. Model 2 just included PROM, tracheal intubation in the delivery room, more than one dose of PS, medically and surgically treated PDA, grade III-IV RDS, and early onset sepsis. It was found that pulmonary hemorrhage did not increase the risks of BPD and moderate to severe BPD. However, if the interference of invasive ventilation is excluded, pulmonary hemorrhage could increase the incidence of BPD (aOR = 3.295, 95%CI1.183-9.179). Table 4.
|
aOR |
95%CI |
p value |
|
|---|---|---|---|
|
All BPD* |
2.647 |
0.879–7.968 |
0.083 |
|
All BPD# |
3.295 |
1.183–9.179 |
0.023 |
|
Moderate to severe BPD* |
2.096 |
0.672–6.540 |
0.203 |
|
Moderate to severe BPD# |
2.619 |
0.885–7.752 |
0.082 |
| *Model 1; #Model 2. | |||
Due to the smaller gestational age, lower birth weight and immature lung development, very preterm infants are vulnerable to pulmonary hemorrhage. According to reports from different centers, the incidence in VLBWI vary from 0.5–11.0%, while the mortality is as high as 50–82% [19–21]. Our data showed that the incidence was 15.3% (42/275), and the mortality rate was 21.4% (9/42) in VLBWIs. Although the survival rate seems improved, longer mechanical ventilation is often needed after pulmonary hemorrhage.
Considering the lung injury caused by pulmonary hemorrhage and subsequent long-term invasive ventilation, it seems that pulmonary hemorrhage can increase the incidence of BPD. A retrospective study found that moderate to severe BPD was significantly higher in the group with massive pulmonary hemorrhage (647 VLBWIs, p < 0.05) [7]. In contrast, another study showed that no differences in moderate to severe BPD between pulmonary hemorrhage group and non-pulmonary hemorrhage group (7/17 and 40/107 ELBWIs respectively, p > 0.05) [6]. Tomaszewska M et al further performed a retrospective case-control study and found infants with oxygen dependence at 28 days in pulmonary hemorrhage group is not significantly more than infants in non-pulmonary hemorrhage group (24/29 and 17/29 VLBWIs respectively, p > 0.05) [8]. However, almost all the reports studying on the association between BPD and pulmonary hemorrhage are univariate analysis which limits the reliability of the results.
Previous study has definitely shown that severe RDS and hemodynamically significant PDA (hsPDA) are triggers of pulmonary hemorrhage [22]. And the mechanism of pulmonary hemorrhage is mainly related to pulmonary congestion, pulmonary edema and pulmonary small vessel embolism [23]. Moreover, newborns with severe RDS and hsPDA often need longer invasive ventilation, which may increase the possibility of BPD. Our univariate analysis showed that in the comparison of survival VLBWIs, pulmonary hemorrhage increased the risks of BPD (pulmonary hemorrhage group 26/33 vs non-pulmonary hemorrhage group 98/181, p = 0.008) and moderate to severe BPD (pulmonary hemorrhage group 16/33 vs non-pulmonary hemorrhage group 38/181, p = 0.037). In fact, the correlation between invasive ventilation and BPD has already been widely reported [24]. Pulmonary hemorrhage also could prolong and increase the duration and frequency of invasive ventilation (Table 3). However, through further multivariate analysis, pulmonary hemorrhage did not increase the risks of BPD (aOR = 2.647, 95%CI0.879-7.968) and moderate to severe BPD (aOR = 2.096, 95%CI0.672-6.540). But, if the interference of invasive ventilation is excluded, pulmonary hemorrhage could increase the incidence of BPD (aOR = 3.295, 95%CI1.183-9.179), but did not increase the chance of moderate to severe BPD (aOR = 2.619, 95%CI 0.885–7.752).
Limitations
We should note that the sample size of this study is not large enough. In addition, some data including coagulation function, cardiac hemodynamics are not available because of respective study design. Consequently, better designed multicenter study is still necessary.
In conclusion, by univariate analysis we found that PROM, tracheal intubation in the delivery room, duration of mechanical ventilation, course of invasive ventilation (≥ 3 courses), PS (> 1 dose), medically and surgically treated PDA, grade III-IV RDS, and early onset sepsis showed significant differences between pulmonary hemorrhage group and non-pulmonary hemorrhage group. By univariate analysis, pulmonary hemorrhage did not increase the risks of BPD and moderate to severe BPD.
Ethics
This study was approved by the ethics committee of Children's Hospital of Nanjing Medical University (Number: NJCH202004037-1). The study was exempt from informed consent by the institutional review board committee due to its retrospective nature. All data were fully anonymized before further statistical analysis. All the procedures were followed in accordance with the Declaration of Helsinki.
Acknowledgements
The authors would like to thank the parents of the patients for their understanding.
Funding
This study has no fund support.
Conflict of Interest Disclosures
None reported.
Authors' contributions
Jing-jing Pan wrote this paper and analyzed the data. Mei-ling Tong and Wang Jing help to analyze the data. Xiao-yu Zhou and Rui Cheng revised this paper. Yang Yang designed this study.
Consent for publication
All authors listed have read the complete manuscript and have approved submission of the paper.
Availability of data and materials
The dataset used during this study are available from the corresponding author on reasonable request.