Mini-symposium: Secondary Pulmonary HypertensionRisk Factors for Development of Pulmonary Hypertension in Infants with Bronchopulmonary Dysplasia: Systematic Review and Meta-Analysis
Introduction
Improved rates of survival for premature infants over the last 40 years has allowed babies born with gestational ages as low as 23 weeks to survive. This improvement in survival puts an increased number of infants at risk for the development of bronchopulmonary dysplasia (BPD), also known as chronic lung disease of prematurity. With the advances in neonatal care (surfactant use and improvements in mechanical ventilatory support), the pattern of BPD has evolved from the initial classic description by Northway et al [1]. The so-called post-surfactant era “new BPD” characterized by decreased alveolarization and compromised vasculogenesis differs from the older fibroproliferative form of BPD seen in the pre-surfactant era. Evidence shows that 18% of VLBW infants have some degree of PHT during hospitalization and this incidence increases to 25-40% in those with established BPD [2]. Occurrence of co-existing PHT secondary to BPD has a definite impact on overall morbidity and mortality in these infants. Retrospective studies of infants with BPD- associated PHT have reported mortality rates ranging from 14 to 38% [3], [4]. Several studies have examined a wide variety of risk factors for development of pulmonary hypertension in infants with BPD. Improved assessment of these risk factors might help to identify those at greatest risk for developing PHT and thereby allow us to direct adequate resources to ensure appropriate intervention and follow up. Echocardiographic screening can help to detect early cases before NICU discharge and can also guide development of an appropriate management plan based on the severity of PHT.
This systematic review analyzes the published literature to identify all the previously reported risk factors for the development of pulmonary hypertension in infants with BPD. We then performed a meta-analysis to further analyze the effect size of the risk factors, and have proposed a strategy for screening for PHT by echocardiography in infants with BPD based on these results.
Section snippets
Methods for literature search
We performed a systematic review of the literature using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [5]. After identifying the research question, a literature search was conducted on 5 databases: PubMed, Scopus, CINAHL (EBSCOHost), Web of Science and Cochrane Library, using pre-defined search terms: “pulmonary hypertension”, “bronchopulmonary dysplasia”, “chronic lung disease of prematurity”, “risk factors”, “echocardiography” and “systematic review.”
Description of the Systematic Review
The initial literature search using pre-defined search terms yielded 302 manuscripts with another 10 manuscripts identified from cross references or other sources (Figure 1). After removal of duplicates, two of the authors screened 201 manuscripts and excluded those that were review articles, pertaining to adult populations or were based on animal studies. The 27 manuscripts that included premature infants were further reviewed and a total of 17 manuscripts were further excluded as they
Discussion
This is the first systematic review and meta-analysis that has evaluated the risk factors for the development of BPD associated PHT. Based on the results of this analysis, we have identified 9 risk factors that have been consistently shown to be associated with development of PHT in infants with BPD from the pooled data of these studies. In order of decreasing risk for development of PHT in infants with BPD, these risk factors are: prolonged duration of mechanical ventilation, length of stay in
Conclusions
A systematic review of the literature identified nine different risk factors for development of BPD associated PHT and the meta-analysis helped to identify the most significant risk factors and their relative contribution to the risk of developing PHT in infants with BPD. Based on these results, a screening strategy for premature infants with BPD can be formulated. Screening for PHT may be considered in infants with more than one risk factor. Prospective studies are needed to validate this
Educational aims
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Bronchopulmonary dysplasia related pulmonary hypertension is a common problem.
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Identified risk factors for BPD related PHT can be categorized: perinatal, growth related, NICU stay related and demographic factors.
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Longer duration of non-CPAP ventilation, longer stay in NICU and oligohydramnios carried highest log odd ratios risk for PHT development.
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Although four different screening strategies were identified in literature, we propose a risk-factor based screening strategy for BPD induced PHT.
Directions for future research
Pulmonary Hypertension in infants with Bronchopulmonary Dysplasia
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Early identification of risk factors that predict the development of PH in BPD.
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Development of a risk-based screening system for all infants with BPD.
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Developing better echocardiographic measures for screening of PH in BPD infants.
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Prospective studies to assess the effectiveness of risk-based screening for PH in BPD infants.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
PROSPERO Registration
This systematic review and meta-analysis was registered with International Prospective Register of Systematic Reviews (maintained by University of York Center for Reviews and Dissemination, at http://www.crd.york.ac.uk/PROSPERO/) (Protocol #CRD42015016374)
Acknowledgments
All the authors contributed equally in this study.
References (15)
- et al.
Pulmonary hypertension in bronchopulmonary dysplasia
Semin Perinatol
(2013) - et al.
Bronchopulmonary dysplasia-associated pulmonary arterial hypertension of very preterm infants
Arch de Pediatr
(2013) Late pulmonary sequelae of bronchopulmonary dysplasia
N Engl J Med
(1990)- et al.
Echocardiographic detection of pulmonary hypertension in extremely low birth weight infants with bronchopulmonary dysplasia requiring prolonged positive pressure ventilation
J Perinatol
(2011) - et al.
Pulmonary hypertension in preterm infants with bronchopulmonary dysplasia
Korean Circ J
(2010) - et al.
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
Ann Intern Med
(2009) - et al.
Risk factors for pulmonary artery hypertension in preterm infants with moderate or severe bronchopulmonary dysplasia
Neonatology
(2012)
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2022, Seminars in Fetal and Neonatal MedicineCitation Excerpt :However, since cPHi can also result from exposure to high PBF (e.g., patent ductus arteriosus, PDA) or genetic loss-of-function mutations (e.g., T-Box Transcription Factor 4, TBX4), some categorize neonatal cPHi based on the endotype of the pulmonary vasculature and the hemodynamics phenotype, or assign BPD-PH to more than one PH group according to the World Symposium of PH (2018) [2]. Unique aberrations with in utero and postnatal pulmonary vasculature development exist that increase the risk of cPHi in certain preterm infants [16] (Table 1). Fetal growth restriction (FGR), preeclampsia, maternal diabetes, and oligohydramnios can disrupt the normal immune landscape of the placenta and adversely impact pulmonary vascular development by reducing vascular branching, altering patterns of vascular distribution, and signalling pathways with abnormal smooth muscle proliferation.