270 - Persistent Pulmonary Hypertension among infants undergoing Therapeutic Hypothermia for Hypoxic Ischemic Encephalopathy - A systematic review and meta-analysis

Publication Number: 4266.270

RASHIDA JAVED, University Hospitals Birmingham NHS Trust, LEICESTER, England, United Kingdom; Tim J. Van Hasselt, University of Leicester, Leicester, England, United Kingdom; Narasimha Rao, King Abdullah Specialist Children's Hospital, Jeddah, Makkah, Saudi Arabia; Harsha Gowda, University Hospitals Birmingham NHS Trust, Birmingham, England, United Kingdom

Background: Perinatal asphyxia is a risk factor for developing persistent pulmonary hypertension (PPHN). In animal studies, hypothermia has been linked to increased pulmonary vascular resistance. A one-degree drop in temperature can raise pulmonary vascular resistance by 1-2%. In neonates with perinatal asphyxia, it is suggested that the increased oxygen requirement during therapeutic hypothermia (TH) is likely due to PPHN and may have serious clinical consequences.

Objective: The aim of this study was to perform a systematic review and meta-analysis to examine the association between persistent pulmonary hypertension and receipt of therapeutic hypothermia, compared to those who did not receive TH, among infants with moderate or severe hypoxic-ischaemic encephalopathy (HIE).

Design/Methods: Systematic review and meta-analysis based on Ovid, Medline, Embase and Cochrane central searches 01/01/2000 to 31/03/2025. We performed search of articles using terms related to neonates, hypoxic ischaemic encephalopathy, therapeutic hypothermia, persistent pulmonary hypertension in newborns, and neonatal intensive care units.

Results: Among 185 articles identified using search strategy, 19 articles were assessed for eligibility. Eight RCTs met the inclusion criteria, and seven were included in meta-analysis. Figure 1 (PRISMA flow diagram).
We conducted a meta-analysis using a random effects model for the outcome of PPHN, comparing TH with normothermia or usual care, involving a pooled population of 1006 infants across seven studies.The overall relative risk was 1.13 (95% confidence interval 0.81 to 1.57), with no statistically significant evidence of an association between TH and PPHN. Figure 2 (Forest plot).
Moderate heterogeneity was observed across studies (I2 28.5%), although the 95% confidence intervals of all studies crossed one. Figure 3 (Funnel plot). Examining the funnel plot of RCTs, there was a broadly symmetrical distribution of studies, with no studies outside the pseudo 95% confidence intervals, suggesting a lack of evidence for publication bias.
We noted risk of bias in the blinding of participants across included RCTs. We assessed nine observational studies and performed a narrative review. We noted that a considerable number of infants developed PPHN across TH and normothermia groups.

Conclusion(s): We did not find evidence of an association between TH and PPHN in infants with moderate to severe HIE, although a considerable number of infants developed PPHN across both groups. We suggest that clinicians should be aware of the risk of PPHN among infants undergoing TH to allow prompt investigation and management.

PRISMA flow diagram


Forest plot of RCTs
Forest plot of RCTs of therapeutic hypothermia (TH) vs normothermia (NT) for the outcome of persistent pulmonary hypertension of the newborn (PPHN), by included gestation and high-income country (HIC) versus low/middle income country (LMIC). Heterogeneity is presented using as the measure of I2

Funnel plot of RCTs
Funnel plot of RCTs of therapeutic hypothermia vs normothermia for the outcome of persistent pulmonary hypertension of the newborn (PPHN)