Effect of bronchopulmonary dysplasia and pneumonia on the neurodevelopment of preterm infants: a cerebral blood flow study
Original Article

Effect of bronchopulmonary dysplasia and pneumonia on the neurodevelopment of preterm infants: a cerebral blood flow study

Ning Wang1, Xin Zhao1, Kaiyu Wang2, Junjie Liao1, Lingsong Meng3, Zhiwei Cheng4, Xueyan Liu1, Tan Ding1, Yiwei Fu1, Junfeng Zhao1, Lin Lu1

1Department of Radiology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China; 2MR Research China, GE Healthcare, Beijing, China; 3Department of Medical Technology, Shangqiu Medical College, Shangqiu, China; 4Department of Medical Records Management, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China

Contributions: (I) Conception and design: N Wang, K Wang, L Lu; (II) Administrative support: L Lu, X Zhao; (III) Provision of study materials or patients: N Wang, J Liao; (IV) Collection and assembly of data: N Wang, J Liao, X Liu, T Ding, Y Fu; (V) Data analysis and interpretation: N Wang, Z Cheng, L Meng, J Zhao; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Lin Lu, MM. Department of Radiology, The Third Affiliated Hospital of Zhengzhou University, No. 7, Kangfu Qianjie, Erqi District, Zhengzhou 450052, China. Email: lulin3186@126.com.

Background: Infants with bronchopulmonary dysplasia (BPD) are prone to lung infections, such as pneumonia, due to structural and functional abnormalities. Recurrent pneumonia can exacerbate lung inflammation and worsen BPD. This study aimed to investigate the value of three-dimensional arterial spin labeling (3D-ASL) in assessing cerebral hemodynamics in preterm neonates with BPD with or without neonatal pneumonia (NP).

Methods: Preterm infants with a gestational age (GA) of <32 weeks and a birth weight <1,500 g who underwent magnetic resonance imaging (MRI) examination at term-equivalent age (TEA; 37–42 weeks) were enrolled from October 2021 to May 2023 and placed into a BPD-and-NP group (BPD-NP group), a BPD-alone (BPD group), and a without-BPD-or-NP (control group). The cerebral blood flow (CBF) was measured and compared between the three groups for the following areas: the bilateral frontal, parietal, temporal, and occipital cortices and white matter; basal ganglia; thalamus; cerebellum; and hippocampus. Correlation analysis was performed between the CBF in brain regions with significant differences between groups and Children’s Developmental Center of China (CDCC) scores. The receiver operating characteristic (ROC) curve was used to assess the diagnostic performance of CBF.

Results: A total of 50 preterm infants were enrolled in the study, including 10 infants in the BPD-NP group, 20 in the BPD group, and 20 in the control group. The duration of assisted ventilation was significantly longer in the BPD-NP and BPD groups than in the control group (P=0.003 and P=0.010, respectively). Compared to controls, infants with BPD had a significantly higher CBF in the left parietal white matter (P=0.046), left occipital white matter (P=0.041), right temporal cortex (P=0.021), and right occipital white matter (P=0.037). The BPD-NP group exhibited a lower CBF than did the BPD group in the left parietal white matter (P=0.041) and right temporal white matter (P=0.019). Within the BPD-NP group, the CBF was lower in the left occipital white matter and higher in the left cerebellum compared to the corresponding areas in the right hemisphere (P=0.006 and P=0.047, respectively). In the BPD group, CBF was lower in the left basal ganglia and higher in the left hippocampus compared to the corresponding areas in the right hemisphere (P=0.012 and P=0.037, respectively). In BPD infants, left occipital WM CBF was negatively correlated with MDI (R=−0.455, P=0.044) and PDI (R=−0.485, P=0.030) scores, and right occipital WM CBF was also negatively correlated with MDI (R=−0.638, P=0.002) and PDI (R=−0.747, P<0.001) scores. ROC curve analysis indicated significant diagnostic utility of CBF for both BPD and BPD-NP. The area under the curve (AUC) values for BPD were 0.717 in the left parietal white matter, 0.732 in the right temporal cortex, 0.704 in the left occipital white matter, and 0.720 in the right occipital white matter. For BPD-NP, the AUC values were 0.790 in the left parietal white matter and 0.788 in the right temporal white matter.

Conclusions: Preterm BPD infants with or without NP exhibited different CBF patterns. Moreover, the correlation between CBF in the white matter of the occipital lobe and CDCC scores suggests that BPD may exert an effect on the neurodevelopment of preterm infants.

Keywords: Arterial spin labeling (ASL); cerebral blood flow (CBF); bronchopulmonary dysplasia (BPD); neonatal pneumonia (NP); preterm infants

Submitted May 26, 2025. Accepted for publication Sep 09, 2025. Published online Oct 24, 2025.

doi: 10.21037/qims-2025-1216

Introduction

Bronchopulmonary dysplasia (BPD), a chronic lung disease arising due to various factors related to the development of the lungs at an immature stage, commonly occurs in preterm infants and those with low birth weight (BW). The incidence of BPD in premature infants with gestational age (GA) <32 weeks and BW <1,500 g is 29.2% and 21%, respectively (1,2). In recent years, with the development of perinatal care and improvements in the care of premature infants, the survival rate of preterm infants has continued to rise, as has the annual incidence of BPD (3). In addition to severely affecting lung function, BPD also significantly heightens the risk of neurodevelopmental disorders in these infants, which include cognitive, language, and motor deficits, as well as cerebral palsy (4-8).

Neonatal pneumonia (NP) is a lung infection occurring during the neonatal period and is caused by various pathogens. The risk factors include the aspiration of amniotic fluid, meconium, or breast milk (9). Due to structural and functional lung abnormalities, infants with BPD are particularly vulnerable to infections that can lead to pneumonia. Recurrent pneumonia episodes may exacerbate lung inflammation and further aggravate BPD.

Cerebral blood flow (CBF) is defined as the volume of blood flowing through 100 g of brain tissue per minute and can be used to quantify the maturity of the brain in newborns and predict the neurodevelopmental outcomes of preterm infants (10). Three-dimensional arterial spin labeling (3D-ASL) is a technique of perfusion imaging that uses water in the blood as an endogenous tracer. It can noninvasively and quantitatively measure the CBF in various brain regions without ionizing radiation and with good reproducibility, which is particularly suitable for the examination of preterm infants (11-15). One study used ASL to longitudinally quantify regional CBF in very preterm infants in an extrauterine environment and found that CBF increased significantly during the third trimester and was associated with intraventricular hemorrhage and patent ductus arteriosus (16). Additionally, a prospective study analyzed perfusion ASL data from 49 preterm infants and 15 term infants and found that the preterm infants exhibited significantly higher whole-brain CBF than did the term infants. Furthermore, within the preterm group, the CBF of the basal ganglia was positively correlated with neuromotor outcomes (17).

The literature on brain perfusion in preterm infants with BPD remains relatively sparse. Moreover, few studies have applied ASL technology to examine preterm infants with BPD complicated by NP. Therefore, in order to provide a more accurate basis for clinical diagnosis and treatment, this study analyzed the CBF changes in preterm infants with BPD with or without NP using 3D-ASL technology. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1216/rc).

Methods

Participants

From October 2021 to May 2023, preterm infants with a GA <32 weeks and a BW <1,500 g who underwent magnetic resonance imaging (MRI) examination at a term-equivalent age (TEA; 37–42 weeks) were included. The exclusion criteria were as follows: (I) cerebrovascular malformations, neonatal purulent meningitis, neonatal intracranial infection, or neonatal hypoxic ischemic encephalopathy; (II) severe asphyxia, genetic metabolic disorders, or chromosomal abnormalities; (III) white-matter (WM) injury confirmed by imaging; (IV) intracranial hemorrhage of grade III or higher; and (V) ASL images with severe artifacts. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (approval No. 2023Y198). Informed consent was obtained from the guardians of all participants.

Grouping

The diagnostic criteria for NP were adopted from Practice of Neonatology (18). Key assessment components were as follows: (I) medical history, including maternal antenatal infections, premature rupture of membranes, perinatal asphyxia, and mechanical ventilation for ≥48 hours; (II) clinical manifestations, including cough, dyspnea, grunting, irregular respiratory rhythm, temperature instability, and pulmonary auscultation abnormalities (wheezes or crackles); (III) chest X-ray findings, including infiltration, pneumatocele, atelectasis, consolidation, and pleural effusion; and (IV) laboratory results, including elevated inflammatory markers (e.g., C-reactive protein or procalcitonin). Infants with NP diagnosed during hospitalization (including both single and recurrent episodes) from birth until prior to the MRI scan were included, and those diagnosed on or after the MRI scan date were excluded. According to the 2018 diagnostic criteria for BPD from the National Institute of Child Health and Human Development (NICHD) (19) and whether BPD was combined with NP, participants were divided into three groups: preterm infants with both BPD-and-NP (BPD-NP group), preterm infants with BPD alone (BPD group), and preterm infants without BPD or NP (control group). Based on preliminary trial data, the sample size was estimated with PASS 2025 software (NCSS LLC, Kaysville, UT, USA; https://www.ncss.com/software/pass/). With a two-sided α of 0.05, 90% power, and a 1:2:2 allocation for the BPD-NP, BPD, and control groups, respectively, the required total sample size was estimated to be 35. To enhance feasibility, the study ultimately enrolled 50 preterm infants.

Clinical data collection

Clinical information including gender, GA at birth, BW, 1-minute Apgar score, 5-minute Apgar score, corrected GA at MRI scan, days of life at MRI scan, duration of assisted ventilation, and preterm complications such as sepsis, patent ductus arteriosus (PDA), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), and intracranial hemorrhage (ICH; grades I–II).

Neurodevelopmental outcomes

Neurodevelopmental assessments of preterm infants were conducted according to the Infant-Toddler Intelligence Development Scale from the Children’s Developmental Center of China (CDCC), which includes both an intelligence scale and motor scale, with the results being expressed as the mental development index (MDI) and the psychomotor development index (PDI), respectively. The grading scheme for these indices is as follows: 130 points and above, very excellent; 120–129 points, excellent; 110–119 points, above average; 90–109 points, average; 80–89 points, below average; 70–79 points, critical state; and below 69 points, intellectual deficiency.

MRI acquisition

All infants underwent MRI examinations at TEA with a 3.0-T scanner (SIGNA Pioneer, GE HealthCare, Chicago, IL, USA). For sedation, 5 mg/kg of phenobarbital was administered intravenously 30 minutes before the examination, after which the patient was positioned supine on the examination bed, after deep sleep. The head was properly aligned, hearing was protected with cotton balls and soundproof sponges, and a 16-channel head coil was used to scan the entire brain. The 3D-ASL parameters were those outlined by the International Society for Magnetic Resonance in Medicine (ISMRM) perfusion study group and the European consortium for ASL imaging in dementia (20). The parameters for 3D-ASL were as follows: repetition time (TR) =4,781 ms, echo time (TE) =11.7 ms, slice thickness =3 mm, slices =28, postlabel delay (PLD) =2.0 s (20), and acquisition time =3 minutes and 18 seconds. The axial 3D CUBE double-inversion recovery gray-matter (Ax CUBE DIR GM) sequence was also acquired for structural information under the following parameters: TR =5,002 ms, TE =83.2 ms, slice thickness =2 mm, slices =84, and acquisition time =4 min and 54 s.

Image processing

Images were postprocessed with the Advantage Workstation 4.7 (GE HealthCare). Initially, the acquired images were transferred to the workstation for generation of ASL perfusion-weighted color-coded maps. Subsequently, the color-coded maps were fused with the Ax CUBE DIR GM images. Finally, regions of interest (ROIs) were manually delineated on the fused images, including the cortical and WM regions of the frontal, parietal, temporal, and occipital lobes, as well as the basal ganglia, thalamus, cerebellum, and hippocampus. The level and position of ROIs were consistent across different participants, while for the same participants, ROIs were placed symmetrically on both sides of the brain, with ROI sizes of 20±5 mm2, as shown in Figure 1. The average of three measurements was taken as the final value.

Figure 1 Schematic diagram of ROI delineation. 1, 2: frontal cortex; 3, 4: parietal WM; 5, 6: parietal cortex; 7, 8: basal ganglia; 9, 10: thalamus; 11, 12: frontal WM; 13, 14: occipital WM; 15, 16: occipital cortex; 17, 18: temporal cortex; 19, 20: temporal WM; 21, 22: hippocampus; 23, 24: cerebellum. ROI, region of interest; WM, white matter.

Statistical analysis

Data analysis was performed with SPSS 26 (IBM Corp., Armonk, NY, USA; https://www.ibm.com/products/spss-statistics), and figures were generated with GraphPad Prism 10.1.2 (Dotmatics, Boston, NY, USA; https://www.graphpad.com). For quantitative data, normality and homogeneity of variance tests were conducted. Normally distributed data are presented as the mean ± standard deviation (SD), while nonnormally distributed data are presented as the median (Q1, Q3). When the three groups had normally distributed data with equal population variances, group comparisons were performed via one-way analysis of variance (ANOVA); otherwise, the Kruskal-Wallis rank-sum test was applied. If significant differences are found between the three groups, pairwise comparisons were conducted. The P values were adjusted via the Bonferroni method. Paired t-tests or Wilcoxon signed-rank tests were used to compare the CBF between the left and right sides of different ROIs within groups. Categorical data are presented as the number and percentage, and group comparisons were performed with the Chi-squared test or Fisher exact test. For brain regions demonstrating significant intergroup differences in CBF, Pearson correlation analysis for CBF and CDCC scores was performed. Receiver operating characteristic (ROC) curve analysis was applied to evaluate the diagnostic efficacy of CBF in brain regions that differed across the study groups, and the area under the curve (AUC) was calculated to quantify diagnostic accuracy. Statistical significance was set at P<0.05.

Results

Participant characteristics

Fifty preterm infants were included in this study, of whom 10 were placed in the BPD-NP group, 20 in the BPD group, and 20 in the control group (Figure 2). The duration of assisted ventilation of the BPD-NP and BPD groups was significantly longer than that in the control group (P=0.003 and P=0.010, respectively). No significant differences were observed in gender, GA at birth, BW, 1-minute Apgar score, 5-minute Apgar score, corrected GA at MRI scan, days of life at MRI scan, and preterm complications (P>0.05) (Table 1).

Figure 2 Flowchart of preterm infant enrollment. ASL, arterial spin labeling; BPD, bronchopulmonary dysplasia; BW, birth weight; GA, gestational age; MRI, magnetic resonance imaging; NP, neonatal pneumonia; TEA, term-equivalent age.

Table 1

Comparison of demographic data and complications between three groups of preterm infants

Variables BPD-NP (n=10) BPD (n=20) Control (n=20) χ2/F/H P value
Demographic
   Male sex 5 [50] 12 [60] 10 [50] 0.483 0.785
   GA at birth (weeks) 29.21±1.91 28.64±1.44 29.73±1.70 2.210 0.121
   BW (g) 978.00±141.96 956.80±137.32 1,047.00±151.88 2.065 0.138
   1-minute Apgar score 8.00 (5.75, 8.25) 7.00 (6.00, 8.00) 7.65±1.63 1.351 0.509
   5-minute Apgar score 8.40±0.84 8.00 (7.25, 9.00) 9.00 (8.00, 9.00) 2.092 0.351
   Corrected GA at MRI scan (weeks) 38.80±0.59 38.00 (37.43, 39.32) 37.86 (37.57, 38.39) 5.017 0.081
   Days of life at MRI scan (d) 68.10±13.10 68.90±11.20 60.05±14.56 2.625 0.083
   Assisted ventilation (d) 61.10±14.37† 58.50 (38.75, 69.50)‡ 30.75±22.15 13.748 0.001*
Complications
   Sepsis 2 [20] 8 [40] 6 [30] 1.287 0.526
   PDA 8 [80] 13 [65] 12 [60] 1.203 0.548
   ROP 5 [50] 4 [20] 3 [15] －§ 0.117
   NEC 2 [20] 2 [10] 6 [30] －§ 0.312
   ICH (grades I–II) 2 [20] 3 [15] 3 [15] －§ 1.000

Continuous data with a normal distribution are presented as the mean ± standard deviation, while those with a nonnormal distribution are presented as the median (Q1, Q3). Categorical data are presented as n [%]. †, BPD-NP vs. control, P<0.05; ‡, BPD vs. control, P<0.05; *, P<0.05. §, Fisher exact test. BPD, bronchopulmonary dysplasia; BPD-NP, bronchopulmonary dysplasia and neonatal pneumonia; BW, birth weight; GA, gestational age; ICH, intracranial hemorrhage; MRI, magnetic resonance imaging; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus; ROP, retinopathy of prematurity.

Intergroup comparison of CBF

Compared with that in the control group, the CBF in the BPD-NP group was not significantly different (P>0.05), while that in BPD group was significantly higher in the left parietal WM (P=0.046), left occipital WM (P=0.041), right temporal cortex (P=0.021), and right occipital WM (P=0.037). Compared with the BPD group, the BPD-NP group had a significantly lower CBF in the left parietal WM (P=0.041) and right temporal WM (P=0.019). No statistically significant differences in CBF were observed in the other brain regions (P>0.05) (Table 2 and Figure 3).

Table 2

Comparison of CBF (mL/100 g/min) between and within the three groups of preterm infants

ROI Left/right BPD-NP (n=10) BPD (n=20) Control (n=20) F/H P value
Frontal cortex Left 19.98±3.55 20.53±3.73 17.83 (17.02, 22.87) 1.182 0.554
Right 19.77±3.15 20.91±3.25 19.14±4.06 1.237 0.300
P value 0.678 0.431 0.627
Parietal cortex Left 19.77±3.18 21.52±4.47 20.07 (14.79, 21.57) 2.201 0.333
Right 20.13±3.53 21.98±4.44 21.12 (14.72, 22.83) 2.300 0.317
P value 0.521 0.385 0.118
Temporal cortex Left 18.40±3.84 19.22±3.13 16.16 (13.92, 19.66) 4.025 0.134
Right 17.63±2.41 19.88±4.22‡ 16.39 (12.91, 19.11) 7.301 0.026*
P value 0.200 0.614 0.352
Occipital cortex Left 20.84±3.65 22.43±4.27 20.04 (16.34, 23.81) 2.924 0.232
Right 20.67±3.58 22.61±4.03 19.75 (15.58, 24.56) 2.431 0.297
P value 0.743 0.731 0.825
Basal ganglia Left 31.18±7.37 32.47±7.59 27.64 (24.19, 34.25) 1.463 0.481
Right 31.23±4.70 33.96±7.43 31.84 (24.68, 34.70) 2.115 0.347
P value 0.962 0.012* 0.510
Thalamus Left 35.58±7.77 38.90±10.74 37.08 (28.27, 41.42) 0.787 0.675
Right 35.49±6.16 39.34±10.34 37.06 (29.44, 39.07) 2.068 0.356
P value 0.169 0.408 0.533
Frontal WM Left 9.90±1.40 10.60±1.91 9.37 (7.83, 10.79) 2.999 0.223
Right 9.46±1.00 10.63±2.06 9.37 (7.97, 10.38) 4.877 0.087
P value 0.274 0.614 0.399
Parietal WM Left 7.10±0.74 8.35±1.39‡ 7.10 (6.37, 8.39) 8.482 0.014*
Right 7.28±0.78 7.93±1.37 7.12 (6.55, 8.34) 2.123 0.346
P value 0.486 0.376 0.695
Temporal WM Left 9.43±1.94 11.68±2.56 9.83 (8.66, 11.23) 5.200 0.074
Right 8.69±1.95 11.20±2.54 10.03 (8.74, 11.50) 7.488 0.024*
P value 0.091 0.256 0.576
Occipital WM Left 7.61±1.25 9.17±1.86‡ 7.37 (6.33, 8.71) 7.534 0.023*
Right 8.09±1.27 9.38±2.19‡ 7.43 (6.43, 9.05) 6.337 0.042*
P value 0.006* 0.527 0.305
Cerebellum Left 22.63±3.13 21.67 (18.97, 29.79) 21.97 (14.98, 23.82) 1.123 0.570
Right 21.92±4.02 24.00±6.98 21.13 (14.27, 25.44) 2.150 0.341
P value 0.047* 0.575 0.145
Hippocampus Left 28.49±7.44 30.10±5.69 26.87 (21.27, 30.39) 3.899 0.142
Right 27.22±5.87 29.59±6.16 24.96 (21.75, 30.88) 3.155 0.207
P value 0.059 0.037* 0.398

Continuous data with a normal distribution are presented as the mean ± standard deviation, while those with a nonnormal distribution are presented as the median (Q1, Q3). ‡, BPD vs. control, P<0.05; , BPD-NP vs. BPD, P<0.05; *, P<0.05. BPD, bronchopulmonary dysplasia; BPD-NP, bronchopulmonary dysplasia and neonatal pneumonia; CBF, cerebral blood flow; ROI, region of interest; WM, white matter.

Figure 3 Comparison of CBF between the three groups. *, P<0.05. BPD, bronchopulmonary dysplasia; BPD-NP, bronchopulmonary dysplasia and neonatal pneumonia; CBF, cerebral blood flow; WM, white matter.

Intragroup comparison of CBF

In the BPD-NP group, the CBF was lower in the left occipital WM and higher in the left cerebellum as compared to the corresponding areas of the right hemisphere (P=0.006 and P=0.047, respectively). In the BPD group, the CBF of the left basal ganglia was lower than that of the right side (P=0.012), and the CBF of the left hippocampus was higher than that of the right side (P=0.037). No statistically significant differences in CBF were observed between the left and right hemispheres in the other brain regions (P>0.05) (Table 2 and Figure 4).

Figure 4 Comparison of CBF between the left and right sides. (A) Comparison of CBF between the left and right sides in the BPD-NP group. (B) Comparison of CBF between the left and right sides in the BPD group. (C) Comparison of CBF between the left and right sides in the control group. *, P<0.05. BPD, bronchopulmonary dysplasia; BPD-NP, bronchopulmonary dysplasia and neonatal pneumonia; CBF, cerebral blood flow; WM, white matter.

Correlation between the CBF in brain regions with significant intergroup differences and CDCC scores

The median corrected age was 3 (interquartile range, 3–5) months at the time of scoring. In BPD infants, left occipital WM CBF was negatively correlated with MDI (R=−0.455, P=0.044) and PDI (R=−0.485, P=0.030) scores, and right occipital WM CBF was also negatively correlated with MDI (R=−0.638, P=0.002) and PDI (R=−0.747, P<0.001) scores (Figure 5).

Figure 5 The correlation of CBF in the occipital WM of preterm BPD infants with MDI (A,B) and PDI (C,D) scores. CBF, cerebral blood flow; MDI, mental development index; PDI, psychomotor development index; WM, white matter.

ROC curve analysis

The diagnostic efficacy of CBF for BPD

ROC curve analyses indicated that CBF had significant efficacy in diagnosing BPD in the left parietal WM [AUC =0.717; 95% confidence interval (CI): 0.551–0.884], right temporal cortex (AUC =0.732; 95% CI: 0.576–0.889), left occipital WM (AUC =0.704; 95% CI: 0.534–0.874), and right occipital WM (AUC =0.720; 95% CI: 0.560–0.880) (Table 3).

Table 3

Diagnostic efficacy of CBF in different brain regions in the BPD and control groups

CBF AUC (95% CI) Sensitivity Specificity
Left parietal WM 0.717 (0.551–0.884) 0.850 0.600
Right temporal cortex 0.732 (0.576–0.889) 0.700 0.700
Left occipital WM 0.704 (0.534–0.874) 0.700 0.800
Right occipital WM 0.720 (0.560–0.880) 0.750 0.600

AUC, area under the curve; BPD, bronchopulmonary dysplasia; CBF, cerebral blood flow; CI, confidence interval; WM, white matter.

Efficacy of CBF in diagnosing BPD combined with NP

ROC curve analyses indicated that CBF had significant efficacy in diagnosing BPD combined with NP in the left parietal WM (AUC =0.790; 95% CI: 0.625–0.955) and the right temporal WM (AUC =0.788; 95% CI: 0.623–0.952) (Table 4).

Table 4

Diagnostic efficacy of CBF in different brain regions in the BPD-NP and BPD groups

CBF AUC (95% CI) Sensitivity Specificity
Left parietal WM 0.790 (0.625–0.955) 0.750 0.900
Right temporal WM 0.788 (0.623–0.952) 0.700 0.800

AUC, area under the curve; BPD, bronchopulmonary dysplasia; BPD-NP, bronchopulmonary dysplasia and neonatal pneumonia; CBF, cerebral blood flow; CI, confidence interval; WM, white matter.

Discussion

In this study, we used 3D-ASL to examine changes in CBF in preterm infants with BPD with or without NP. The results revealed that infants with BPD had a higher CBF, which negatively correlated with CDCC scores.

Perfusion imaging includes a variety of techniques, such as xenon-enhanced computed tomography (CT), CT perfusion imaging, positron emission tomography (PET), single-photon emission CT (SPECT), dynamic susceptibility contrast MRI (DSC MRI), and ASL. Among these techniques, ASL can quantitatively measure CBF by labelling arterial blood flowing into the imaging area with radiofrequency pulses and tracking the process of this labelled blood flowing into the brain tissue. The strengths of ASL include a lack of contrast agent injection and no radiation hazard, making it particularly valuable for clinical applications. Previous studies have demonstrated the high accuracy of ASL in assessing CBF (21-23). Dolui et al. used ASL to measure CBF in 85 participants and compared the results with those from PET, confirming the accuracy of ASL (24). Goetti et al. also demonstrated the good consistency between ASL and DSC MRI in CBF measurement (25). ASL also exhibits excellent reproducibility (26,27). For instance, Jain et al. conducted two ASL scans on the same cohort within 2–4 weeks and found that the CBF values measured by ASL had high stability and reproducibility (28). Research on the application of ASL in neonates has been gradually intensifying (29-33). As technology progresses, the application prospects of ASL in the field of neonatology will continue to grow.

Infants with BPD often experience recurrent hypoxia, hypercapnia, and respiratory acidosis, which predisposes these infants to hypoxic brain injury and elevates the risk of neurodevelopmental abnormalities (34,35). Sriram et al. conducted a longitudinal study on preterm infants with a GA <30 weeks and found that those with moderate/severe BPD had lower Bayley III scores in both language and motor domains at 2 years of corrected age (36). Furthermore, children with BPD are at higher risk of impairment to cognitive, language, and executive function. One prospective study evaluated 90 preterm infants using ASL technology and found that BPD can increase the cortical CBF perfusion in preterm infants (37). In our study, the cortical CBF in infants with BPD was increased, which is consistent with previous research. Studies have confirmed that BPD is an independent risk factor for WM injury in preterm infants, with infants with BPD exhibiting reduced WM volume and decreased fractional anisotropy (FA) in multiple WM regions (38). The FA value provides information about the microstructure of tissues by reflecting the anisotropy of water molecular diffusion. In our study, the CBF was increased in the WM of infants with BPD, suggesting microstructural alterations within the WM. In an experimental study that exposed neonatal mice to hypoxic conditions, chronic hypoxia induced increased cerebral capillary density and impaired myelination (39). Despite receiving standardized respiratory support, infants with BPD remain in a state of persistent inadequate oxygenation. In our study, the CBF in certain brain regions of infants with BPD was increased, potentially due to chronic hypoxia-induced cerebral angiogenesis.

Due to structural and functional abnormalities in the lungs, infants with BPD often require prolonged mechanical ventilation and oxygen therapy to support respiratory function (40). Our results suggest that preterm infants with BPD require significantly longer duration of assisted ventilation than do preterm infants without BPD. However, prolonged positive pressure ventilation and high-concentration oxygen may induce alveolar injury and fibrosis, increasing the risk of pulmonary infection (41,42). Severe pulmonary infection can cause systemic microvascular spasm, leading to inadequate tissue perfusion and reduced CBF. We observed that preterm infants with BPD-NP had lower CBF in certain brain regions as compared to those with BPD alone, verifying the influence of NP in decreasing CBF in these brain regions. However, the decreased CBF in the BPD-NP group does not imply that NP mitigates the deleterious effects of BPD on CBF. On the contrary, it may reflect the inadequate perfusion caused by systemic inflammation, hypoxemia, or vasospasm, representing a second hit superimposed on pre-existing BPD pathology. Moreover, there was no significant difference in CBF between the BPD-NP group and the control group, suggesting that NP may offset the compensatory hyperperfusion of BPD, yet this does not exclude occult microstructural damage. The BPD-NP group’s prolonged ventilatory requirement suggests this concern is warranted and may portend poorer neurodevelopmental outcomes. Future studies should include an expanded sample size, assess long-term neurodevelopmental outcomes of BPD-NP infants, integrate structural imaging with serum inflammatory markers to differentiate direct NP-induced brain injury from failure of BPD compensatory mechanisms, and analyze the relationship between perfusion changes and pneumonia severity through longitudinal CBF mapping.

Our study found no significant difference in CBF between the left and right cerebral hemispheres in the control preterm infants, consistent with previous research (43). This suggests that in the absence of severe illness, CBF is symmetrically distributed in the brain tissue on both sides. Additionally, our statistical analysis indicated that both infants with BPD and those with BPD combined with NP exhibited significant interhemispheric differences in CBF in certain brain regions. These findings suggest that the lateralization of brain development may occur in preterm infants under pathological conditions of this nature. Premature infants exhibit immature and unstable axonal connectivity within cortical-subcortical circuits. The hypoxic and inflammatory microenvironment may disrupt typical developmental trajectories through neuron-glia interactions, predisposing these infants to neurodevelopmental disorders (44-46). To systematically clarify the underlying mechanisms, future studies should use diffusion tensor imaging (DTI) to confirm the asymmetry in FA in key lateralized regions, integrate functional neuroimaging techniques to assess activity and connectivity patterns in relevant brain areas, and incorporate standardized laterality assessments with neurodevelopmental scales to determine the associations between altered lateralization and neurobehavioral outcomes.

Correlation analysis indicated negative correlations between the CBF of occipital WM and both MDI and PDI scores in preterm infants with BPD. These results suggest that increased CBF may have a potential association with neurodevelopmental impairment among infants with BPD. Research indicates that chronic hypoxic conditions may disrupt normal myelination processes, triggering pathological alterations such as aberrant angiogenesis and compensatory vasodilation (47). Therefore, increased CBF may reflect the activity of compensatory hemodynamic responses subsequent to either microstructural injury or impaired neurovascular coupling. Previous DTI studies (38,48,49) and our observed negative correlations between CBF of occipital WM and neurodevelopmental scores suggest the presence of a pathologic compensatory response in infants with BPD. Specifically, the reduced FA among infants with BPD may indicate impaired microstructural integrity, which aligns with a higher CBF being a potential biomarker of WM injury. To definitively characterize this relationship, future studies should integrate multiple modalities, such as high-resolution MRI, electroencephalography, and longitudinal neurodevelopmental assessments, to ascertain whether CBF alterations reflect adaptive neurovascular responses or maladaptive pathologic processes.

The occipital lobe, a cerebral region critical to visual information processing and sensorimotor integration, is particularly vulnerable in preterm infants and subject to neuropathological alterations due to its relatively late maturation (50). For instance, Wang et al. demonstrated that BPD induces significant FA reduction in the occipital WM of preterm infants, with concurrent marked elevation in apparent diffusion coefficient (ADC) values (49). Due to these and similar findings, CBF in the occipital WM is expected to become an important indicator for evaluating and predicting the intellectual and motor development of children with BPD. In our study, we further found that the CBF in brain regions with significant intergroup differences had AUC values ranging from 0.704 to 0.790, suggesting that the CBF in different brain regions has diagnostic value in differentiating between the conditions represented by the three groups.

One of the primary objectives of this study was to determine whether BPD, with or without NP, alters cerebral hemodynamics and neurodevelopmental outcomes in preterm infants. Our findings demonstrated that 3D-ASL MRI can noninvasively detect cerebral hemodynamic alterations in preterm infants with BPD, particularly those with comorbid NP. This suggests that BPD-associated lung disease may disrupt cerebral perfusion, potentially contributing to impaired neurodevelopment. The observed reduced CBF in the BPD-NP group (compared to that in the BPD-alone group) implies that recurrent pulmonary infection can exacerbate cerebral hypoperfusion, and thus a closer monitoring of neurological outcomes in these high-risk infants may be warranted. The correlation between occipital WM CBF and CDCC scores suggests there is a link between impaired cerebral perfusion and neurodevelopmental delay, supporting the use of CBF metrics as early biomarkers for identifying infants who may benefit from targeted interventions (e.g., neuroprotective strategies or enhanced follow-up).

One of the strengths of this study was the measurement of preterm infants’ CBF uniformly at the TEA, at which point, the cerebral development of preterm infants more closely resembles the maturational pattern observed in healthy term-born infants. In this way, we avoided the confounding effects of immaturity caused by preterm birth and could more accurately assess the disease’s impact on neurodevelopment. Furthermore, in addition to assessing CBF in the gray matter, we also measured CBF in the WM, cerebellum, and hippocampus. This could generate a more comprehensive understanding of the disease-related effects on cerebral perfusion and provide support for further investigation into the mechanisms of neurodevelopmental disorders. However, this study also involved certain limitations that should be acknowledged. First, the relatively small sample size may limit the power of the statistical analysis. Second, the lack of stratification based on the severity of BPD prevented an in-depth examination of how disease severity specifically influences CBF characteristics. Future studies should include expanded sample sizes, stratify infants with BPD according to disease severity, and further compare CBF metrics and neurodevelopmental outcomes across these subgroups to quantitatively characterize the relationships between disease severity, cerebral perfusion, and neurodevelopment.

Conclusions

The findings of this study support the ability of 3D-ASL to evaluate cerebral hemodynamics in preterm infants diagnosed with BPD, particularly in the context of NP. Infants with BPD, especially those with pneumonia, exhibited altered CBF patterns as compared to both healthy controls and those with BPD alone. Moreover, the CBF in the occipital WM of preterm infants with BPD was significantly correlated with CDCC scores, indicating that BPD exerts effects on neurodevelopment.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1216/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1216/dss

Funding: This work was supported by the Science and Technology Innovation Project of Science and Technology Department of Henan Province (No. 242102311044, to L.L.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1216/coif). K.W. is an employee of GE Healthcare. L.L. reports that this work was supported by the Science and Technology Innovation Project of Science and Technology Department of Henan Province (No. 242102311044). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (No. 2023Y198). Informed consent was obtained from the guardians of all participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Wang N, Zhao X, Wang K, Liao J, Meng L, Cheng Z, Liu X, Ding T, Fu Y, Zhao J, Lu L. Effect of bronchopulmonary dysplasia and pneumonia on the neurodevelopment of preterm infants: a cerebral blood flow study. Quant Imaging Med Surg 2025;15(11):10905-10919. doi: 10.21037/qims-2025-1216

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