Hypertensive disorders of pregnancy and retinopathy of prematurity in extremely preterm infants: A causal mediation analysis

OBJECTIVES: Consensus has not been reached regarding the association between hypertensive disorders of pregnancy (HDP) and retinopathy of prematurity (ROP) in preterm infants. We aimed to clarify the effect of HDP on the risk of ROP based on causal mediation analysis using a population-based database from the Neonatal Research Network of Japan. STUDY DESIGN: A retrospective study was performed using clinical data of 11,798 infants born at less than 28 weeks of gestation between 2003 and 2017 (HDP group: n = 1,615, non-HDP group: n = 10,183). MAIN OUTCOME MEASURES: Causal mediation analysis was performed to decomposes the total effect into the mediated (indirect) and non-mediated (direct) effects of HDP on treated ROP and severe ROP after adjusting for covariates while evaluating fetal growth restriction (birthweight Z-score) as a mediator. RESULTS: The incidences of treated ROP and severe ROP in the HDP and non-HDP groups were 32.4% vs. 36.0% and 4.1% vs. 6.3%, respectively. The total, direct, and indirect effects of HDP on treated ROP, expressed as risk ratio with 95% confidence interval (CI), were 1.043, (95% CI 0.955-1.124), 0.913 (0.832-0.996), and 1.142 (1.102-1.183), respectively. The total, direct, and indirect effects of HDP on severe ROP were 0.845 (95% CI 0.645-1.086), 0.684 (0.511-0.892), and 1.234 (1.105-1.387), respectively. CONCLUSION: Maternal HDP has a direct protective effect against ROP in extremely preterm infants, whereas fetal growth restriction acts as a pathway that indirectly increases the risk of ROP. The overall effect of HDP on ROP appears to be neutral as these opposing effects offset each other.