Pulmonary hypertension in infants with bronchopulmonary dysplasia: risk factors, mortality and duration of hospitalisation

Objectives: Pulmonary hypertension (PH) is a complication of bronchopulmonary dysplasia (BPD) and associated with increased mortality and morbidity. Our aim was to identify, in infantswith BPD, the effect of PHonhealth-care utilisation and health related cost of care. Methods: An electronic data recording systemwas used to identify infants ≤32weeks of gestationwho developedBPD. PH was classified as early (≤28 days after birth) or late (>28 days after birth). Results: In the studyperiod, 182 infants developedBPD; 22 (12.1%) developed late PH. Development of late PH was associated with a lower gestational age [24.6 (23.9–26.9) weeks, p=0.001] and a greater need for positive pressure ventilation on day 28 after birth (100%) compared to infants without late PH (51.9%) (odds ratio (OR) 19.5, 95% CI: 2.6–148), p<0.001. Late PH was associated with increased mortality (36.4%) compared those who did not develop late PH (1.9%) after adjusting for gestational age and ventilation duration (OR: 26.9, 95% CI: 3.8–189.4), p<0.001. In infants who survived to discharge, late PH development was associated with a prolonged duration of stay [147 (118–189) days] compared to the infants that did not develop late PH [109 (85–149) days] (p=0.03 after adjusting for gestational age). Infants who had late PH had a higher cost of stay compared to infants with BPDwho did not develop late PH (median £113,494 vs. £78,677, p=0.016 after adjusting for gestational age). Conclusions: Development of late PH was associated with increased mortality, a prolonged duration of stay and higher healthcare cost.


Introduction
The survival rates of extremely premature infants have improved significantly in the last few decades, but are associated with long term morbidities [1][2][3]. Bronchopulmonary dysplasia (BPD) is the most common adverse outcome and can result in complications which may extend into adulthood [4]. One of the significant contributory factors for morbidity and mortality in infants with BPD is the development of pulmonary hypertension (PH) [5].
The incidence of pulmonary hypertension in infants with BPD ranges from 17 to 37% [6][7][8]. The pathogenesis of pulmonary vascular disease associated with BPD is multifactorial and can be attributed to the interaction of maternal, genetic and postnatal factors. Inhibition of angiogenesis has been associated with decreased alveolarization and pulmonary vascular growth in an animal model [9]. The arrest of vascular growth and the reduction in the alveolarcapillary surface result in impaired gas exchange. Thus, the lungs are exposed to prolonged ventilation and high oxygen levels along with hemodynamic and inflammatory stressors. This causes pulmonary arterial remodelling leading to fibrosis of the vessel walls [10]. The risk factors associated with the development of pulmonary hypertension include intrauterine growth restriction, preeclampsia, maternal substance abuse, lower gestational age and birthweight, patent ductus arteriosus (PDA) requiring treatment and sepsis [8,[11][12][13][14].
The gold standard to diagnose pulmonary hypertension is cardiac catheterization, but this is often difficult to perform in BPD infants who may have significant vascular and haemodynamic complications [15]. Two-dimensional echocardiography, however, is a valuable tool for screening and diagnosis of PH in such patients [10]. Various studies have investigated the risk factors, outcomes [5-8, 11, 14, 16-21] and evolution of pulmonary hypertension in BPD infants [7,8,14,[19][20][21]. The identified risk factors include early pulmonary hypertension, postnatal steroid administration, tracheostomy and tracheitis [5,16,17]. Outcomes associated with PH in BPD infants include increased mortality and morbidity including a prolonged duration of invasive ventilation, increased occurrence of severe IVH and prolonged hospitalization [5,7,8,14,[19][20][21]. Our aim was to identify, in infants with BPD, the effect of PH on health-care utilisation and the health related cost of care.

Study subjects
An observational study was conducted of infants admitted to the neonatal unit at a London hospital, United Kingdom (UK) between January 2017 and December 2020. Badgernet, an electronic patient record database, was used to identify study subjects. The criteria for inclusion were (i) infants born at or prior to 32 weeks' gestation (ii) birthweight less than 1,500 g and (iii) development of BPD (oxygen requirement for at least 28 days from birth) [22]. Infants who died before 36 weeks of gestation, but required oxygen for at least 28 days were included in the study [23].
Infants had an echocardiogram when there was a clinical suspicion of pulmonary hypertension as evidenced by different preductal and post-ductal saturations, a persistently high oxygen requirement above 60% and/or requiring increased mean airway pressures to maintain oxygenation. Some infants had an echocardiogram for assessment of whether they had a patent ductus arteriosus (PDA). Infants whose echocardiogram reports were not available, who were admitted for short surgical procedures such as inguinal hernia and laser photocoagulation and those with major respiratory and cardiac anomalies were excluded from the study.

Ethical approval
The study was registered with the local Clinical Governance and Audit Department and did not require informed parental consent.

Assessment of pulmonary hypertension
The echocardiograms of the infants were reviewed by one author, a neonatologist trained in echocardiography and further reviewed by a paediatric cardiologist. The presence of PH was defined based on quantitative or qualitative assessments. Quantitative assessment included the presence of tricuspid regurgitant jet velocity (TRJV)>3 m/s (right ventricular systolic pressure (RVSP)>36 mm Hg). In the absence of tricuspid regurgitation, qualitative assessment was used to detect PH using the following parameters: (i) flattened or left deviated intraventricular septum in ventricular systole (ii) right to left shunting across a patent foramen ovale, atrial septal defect, ventricular septal defect or patent ductus arteriosus, if present (iii) right ventricular hypertrophy or dysfunction [15].

Definitions and risk factors
BPD was defined as per the Jobe and Bancalari criteria [22]. Early PH was defined as PH diagnosed within 28 days after birth, while late PH diagnosed after 28 days [16]. Severe intraventricular haemorrhage was defined as Grade 3 or 4 as described by Papile [24].
The last echocardiogram during the admission was used to identify the presence of PH at discharge or death. Risk factors for late PH assessed included maternal preeclampsia, substance abuse, small for gestational age (SGA) (defined as birthweight less than 10th percentile or less than −1.28 standard deviation for gestational age [25]), positive pressure ventilation (PPV) at 28 days after birth, medically or surgically treated patent ductus arteriosus (PDA), sepsis (positive blood culture requiring intravenous antibiotics) and presence of early PH.

Outcomes
We assessed the mortality in the cohort and the total duration of stay in the survivors. Additionally, the total cost of stay was calculated based on national average costs of neonatal unit stay. We also compared the length and cost of stay in infants whom PH resolved prior to discharge against the ones in whom PH did not resolve prior to death or discharge. The average daily cost ranges from £437 to £1,218 was graded based on the intensity of care coded as intensive care, high dependency and special care (Table 1) [26]. The duration of care at each level of care was extracted from Badgernet and used to estimate the total cost of stay in the neonatal unit.

Statistical analysis
On testing for normality using Shapiro-Wilk test, the data was found to be non-normally distributed. Therefore, the Mann-Whitney U test was used for comparing the continuous variables and Chi-square test for dichotomous variables. Multiple logistic or linear regression was used to adjust for confounding variables. All the risk factors were adjusted

Results
A total of 428 premature infants were admitted to the neonatal unit during the study period, 211 (49.3%) subsequently developed BPD; 189 infants were included in the analysis and 29 infants were excluded ( Figure 1). The included infants had a median (interquartile range) gestational age of 25.9 (24.9-27.7) weeks and birthweight of 769 (667-930) grams (Table 2). Twenty-one (11.5%) infants had early PH of which six (28.5%) subsequently developed late PH. Twenty-two (12%) infants had late PH. Amongst the 22 infants with late PH, pulmonary hypertension resolved in 10 infants, four had pulmonary hypertension at discharge from neonatal care and eight died with pulmonary hypertension (Figure 2).
The characteristics of infants who developed early PH, late PH, both early and late and no PH have been detailed in Table 3 Table 4].
Eleven infants (6%) died in the study population. Eight had pulmonary hypertension at death, of those eight, six had developed PH within 28 days after birth (Figure 2). The presence of late PH was independently associated with

Discussion
We have demonstrated late PH was associated with a higher mortality and a longer duration of stay compared to infants with BPD without PH. Furthermore, we found that the total cost of stay for infants with late PH and BPD was higher compared to those who did not develop late PH.   Our study showed that while the incidence of overall mortality was 6% in the study population, the presence of late PH was associated with a 36% increase in mortality. Studies have described the association of PH and mortality with an incidence ranging from 10 to 38% [7,8,14,17,18,27]. Notably, among the eight infants who died with pulmonary hypertension, six of them had developed PH within 28 days (Figure 2). Two studies have shown that early PH increases the risk for severe BPD and development of late PH in infants with BPD, but did not describe the impact of this on mortality [16,17]. This highlights the need for early as well as regular screening for pulmonary hypertension via echocardiographic assessment in infants with BPD.
One study reported the healthcare utilization of infants with PH associated with BPD presenting after two months of age into a BPD clinic and found that the infants were hospitalised for a longer duration and had more respiratory morbidity than infants with BPD but no PH [28]. Our study reported on the total cost of stay based on national average in infants with BPD and PH and to our knowledge this is the first study which specifically looked into the effect of pulmonary hypertension in infants with bronchopulmonary dysplasia on health care costs.
Our study has strengths and some limitations. In our study population we used echocardiography to identify pulmonary hypertension; echocardiography is considered to be an effective and reliable screening tool for detection of pulmonary hypertension in infants with BPD [29]. A limitation, however, was that the infants had echocardiograms at various time intervals according to clinical need rather than at specific intervals, but this makes our results generalisable to clinical practice.
In conclusion, infants with late PH had a longer duration of hospitalization and increased mortality compared to the infants without late PH. The presence of late PH in infants with BPD resulted in increased healthcare costs.