Risk factors for severe bronchopulmonary dysplasia in a Chinese cohort of very preterm infants

Jing Huang; Wei Shen; Fan Wu; Jian Mao; Ling Liu; Yanmei Chang; Rong Zhang; Xiuzhen Ye; Yinping Qiu; Li Ma; Rui Cheng; Hui Wu; Dongmei Chen; Ling Chen; Ping Xu; Hua Mei; Sannan Wang; Falin Xu; Rong Ju; Zhi Zheng; Xinzhu Lin; Xiaomei Tong

doi:10.15537/smj.2024.45.4.20230741

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Figure 1
- A flow chart of the infant selection process. NICUs: neonatal intensive care units, BW: birth weight, NICHD: the National Institute of Child Health and Human Development, BPD: bronchopulmonary dysplas
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Figure 2
- Histogram of bronchopulmonary dysplasia incidence according to severity by: A) weeks of gestational age at birth and B) birth weight. BPD: bronchopulmonary dysplasia

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Table 1

- Definitions and diagnostic criteria.

Condition(s)	Definition and diagnostic criteria
SGA	BW <P10 (10th percentile) of the average BW of infants having identical GA and gender.¹³
hsPDA	The diameter of PDA was >1.5 mm, left aortic/atrial diameter was ≥1.3, and bidirectional bi-phase (or left-to-right) shunt was present. In addition, presence of at least one of the following clinical manifestations: tachypnea, cardiac murmur, tachycardia, pulse pressure elevation (>25 mmHg), flushing or cardiac dilation, hypotension, and water pulse or cardiac enlargement.¹⁴
NEC	Bell’s staging criteria¹⁵
EOS & LOS	The expert consensus on neonatal sepsis diagnosis and management (version 2019)¹⁶
Interventional ROP	Surgery (laser or cryocoagulation) or application of bevacizumab
FI	Emesis or abdominal distention, gastric residual volume >50% of prior feeding volume, and an enteral feeding reduction, delay, or withdrawal¹⁷
MBDP	The expert consensus on clinical management of metabolic bone disease of prematurity¹⁸
NRDS, IVH grade III-IV, PVL, and ROP	The 5th edition of practical neonatology¹⁹
EUGR	P10 of weight below the growth graph at 36 weeks of modified GA or at discharge in accordance with the Fenton 2013 growth curves²⁰
Days to full enteral feeding	The time obtained for oral milk feeding to attain a 150 mL/kg/day value²¹
GV following BW regain (g/kg/day)	[1000 × ln (Wn/W1)]/[Dn - D1], where Wn and W1 denote the BWs at discharge and birth, whereas Dn and D1 stand for the overall length of stay and days to regain BW²²

SGA: small for gestational age, BW: birth weight, GA: gestational age, hsPDA: hemodynamically significant patent ductus arteriosus, PDA: patent ductus arteriosus, NEC: neonatal necrotizing enterocolitis, EOS: early onset sepsis, LOS: late-onset sepsis, ROP: retinopathy of prematurity, FI: feeding intolerance, MBDP: metabolic bone disease of prematurity, NRDS: neonatal respiratory distress syndrome, IVH: intraventricular hemorrhage, PVL: periventricular leukomalacia, ROP: retinopathy of prematurity, EUGR: extrauterine growth retardation, GV: growth velocity

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Table 2

- Comparison of baseline characteristics.

Groups	Mild BPD (n=590)	Moderate BPD (n=250)	sBPD (n=82)	H/c²	P-values
GA (weeks)	29.1 (28.1-30)	28.7 (27.3-29.7)^*	27.7 (26.6-29.3)^*	34.601	<0.001
BW (g)	1187 (1023-1320)	1085 (924-1250)^*	1025 (875-1160)^*	49.159	<0.001
Antenatal corticosteroids	489 (82.9)	190 (76.0)	54 (65.9)^*	15.389	<0.001
Male gender	321 (54.4)	143 (57.2)	54 (65.9)	3.976	0.137
Cesarean delivery	351 (59.5)	133 (53.2)	42 (51.2)	4.085	0.130
Multiple births	197 (33.4)	105 (42.0)	31 (37.8)	5.753	0.056
SGA	80 (13.6)	39 (15.6)	13 (15.9)	0.769	0.681
Five-minute Apgar score of ≤7	94 (15.9)	37 (14.8)	38 (15.0)^†	47.327	<0.001
Gestational hypertension	122 (20.7)	49 (19.6)	15 (18.3)	0.324	0.850
Gestational diabetes	106 (18.0)	48 (19.2)	10 (12.2)	2.108	0.349

Values are presented as numbers and precentages (%) or median and interquartile range (IQR).

BPD: bronchopulmonary dysplasia, sBPD: severe bronchopulmonary dysplasia, GA: gestational age, BW: birth weight, SGA: small for gestational age

↵^* A p-value of <0.05.
↵^† A p-value of <0.017.

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Table 3

- Comparison of complications and main treatments.

Groups	Mild BPD (n=590)	Moderate BPD (n=250)	sBPD (n=82)	H/c²	P-values
NRDS	484 (82.0)	203 (81.2)	74 (90.2)	3.793	0.150
hsPDA	136 (23.1)	87 (34.8)^†	44 (53.7)^†§	38.473	<0.001
NEC (≥ stage 2)	47 (8.0)	23 (9.2)	7 (8.5)	0.353	0.838
Surgical NEC	11 (1.9)	8 (3.2)	3 (3.7)	1.970	0.373
EOS	108 (18.3)	54 (21.6)	19 (23.2)	1.923	0.382
LOS	84 (14.2)	56 (22.4)^†	29 (35.4)^†	25.265	<0.001
NI	202 (34.2)	104 (41.6)	49 (59.8)^†§	21.189	<0.001
IVH grade III~IV	13 (2.2)	7 (2.8)	5 (6.1)	4.149	0.126
PVL	21 (3.6)	11 (4.4)	5 (6.1)	1.337	0.512
ROP	275 (46.6)	102 (40.8)	54 (65.9)^†§	15.581	<0.001
Interventional ROP	24 (4.1)	19 (7.6)	16 (19.5)^†§	29.496	<0.001
FI	231 (39.2)	107 (42.8)	42 (51.2)	4.683	0.096
MBDP	19 (3.2)	13 (5.2)	4 (4.9)	2.061	0.357
EUGR	266 (45.1)	126 (50.4)	53 (64.6)^†	11.645	0.003
Postnatal steroids	175 (29.7)	69 (27.6)	43 (52.4)^†§	19.415	<0.001
Anemia	570 (96.6)	248 (99.2)	81 (98.8)	5.444	0.066
RBCTs (≥3)	134(22.7)	136(54.4)^†	62(75.6)^†§	137.777	<0.001
Cumulative days of antibiotics	14 (8-22)	16 (10-28)^*	20.5 (11.7-36)*	20.191	<0.001
Invasive mechanical ventilation (days)	1 (0-5)	4 (1-9.2)^*	15.5 (3-40)*^‡	108.521	<0.001
Invasive mechanical ventilation (≥7 days)	104(17.6)	86(34.4)^†	52(63.4)^†§	89.747	<0.001
Non-invasive mechanical ventilation (days)	26 (17-34)	31 (22-43)*	36.5 (20.8-49.5)^*	54.193	<0.001
oxygen time (days)	13 (6.2-22)	19 (11-28)*	14.5 (6.7-24.2)	32.802	<0.001
Total hospital stay(days)	55 (46-66)	66 (56-81)*	83 (67-101)^*‡	174.401	<0.001

Values are presented as numbers and precentages (%) or median and interquartile range (IQR).

NEC: neonatal necrotizing enterocolitis, EOS: early onset sepsis, LOS: late-onset sepsis, NI: nosocomial infection, IVH: intraventricular hemorrhage, PVL: periventricular leukomalacia, ROP: retinopathy of prematurity, FI: feeding intolerance, MBDP: metabolic bone disease of prematurity, EUGR: extrauterine growth restriction, RBCTs: red blood cell transfusions

↵^* P<0.05
↵^† p<0.017 cf. the mild BPD group.
↵^‡ P<0.05
↵^§ p<0.017 cf. the moderate BPD group. NRDS: neonatal respiratory distress syndrome, hsPDA: hemodynamically significant patent ductus arteriosus

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Table 4

- Comparison of growth and nutrition.

Groups	Mild BPD (n=590)	Moderate BPD (n=250)	sBPD (n=82)	H	P-values
Time to start enteral feeding (hours)	23 (11.8-36)	24 (10-48)	46.5 (24-144)^‡§	34.757	<0.001
Days to full enteral feeding(days)	29 (21-38)	33 (25-44)^‡	36.5 (26.7-52.5)^‡	37.693	<0.001
Duration of parenteral nutrition(days)	24 (16-33)	27 (20.7-39)^‡	35.5 (24.7-46.7)^‡§	54.894	<0.001
Cumulative fasting(days)	1 (1-5)	2 (1-6.9)^‡	3 (2-10)^‡§	43.03	<0.001
Accumulative amino acids (g/Kg)^†	17.0(14.7-19.1)	17.1 (14.2-19.0)	17.0(15.0-19.0)	0.491	0.782
Accumulative fat emulsions(g/Kg)^†	13.0 (10.5-15.0)	13.6 (11.0-15.6)	14.0 (11.5-15.9)	4.808	0.09
Accumulative calories (kcal/Kg)^†	500 (431-564)	490 (413-560)	472 (400-540)^‡	9.387	0.009
Total calories up to110kcal/kg (days)	9 (7-16)	11(7-17)	14.5 (8-26)^‡§	25.417	<0.001
Oral calories up to110kcal/kg.d (days)	26 (19-34)	30 (22-40)^‡	33 (26-45)^‡	43.341	<0.001
Days to regain BW (days)	9 (7-12)	9 (6-11)	10 (7-12)	2.092	0.351
GV (g/Kg.d)	15.8 (13.8-18.2)	15.2 (13.1-19.7)	14.4(12-16.8)^‡	10.813	0.004
Greatest weight loss (%)	6.0 (3.2-9.4)	6.4 (3.2-10.0)	6.9 (3.2-9.7)	0.759	0.684

Values are presented as median and interquartile ranges (IQR).

GV: growth velocity, BPD: bronchopulmonary dysplasia, sBPD: severe bronchopulmonary dysplasia, BW: Birth weight, GV: growth velocity

↵^† During the first week;
↵^‡ p-value of <0.05 cf. the mild BPD group;
↵^§ p-value of <0.05 cf. the moderate BPD group.

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Table 5

- Correlative factors for the severity level of bronchopulmonary dysplasia.

Variables	B	SE	Wald χ²	P-values	OR (95%CI)
BW	-9.00E-04	4.00E-04	-2.19	0.0288	0.999 (0.998-0.999)
No antenatal corticosteroids	0.83	0.18	4.61	<0.001	2.316 (1.620-3.310)
Invasive mechanical ventilation (<7 daya)	-1.78	0.18	-10.12	<0.001	0.169 (0.120-0.238)
RBCTs (<3)	-1.44	0.17	-8.55	<0.001	0.237 (0.171-0.330)
No hsPDA	-0.65	0.17	-3.85	0.001	0.524 (0.377-0.729)
No NI	-0.65	0.16	-4.10	<0.001	0.520 (0.380-0.711)
Time to start enteral feeding	0.0057	0.0015	3.87	<0.001	1.006 (1.003-1.009)
Total calories up to 110 kcal/kg.d	0.0189	0.0085	2.21	0.0268	1.019 (1.002-1.036)