Epoprostenol Does Not Affect Mortality in Neonates with Congenital Diaphragmatic Hernia

Abstract

Purpose Epoprostenol (also called prostaglandin, PGI) is used for pulmonary hypertension in newborns with congenital diaphragmatic hernia (CDH) in some centers. The effects of PGI on survival in newborns with CDH were examined.

Methods A retrospective analysis of the Congenital Diaphragmatic Hernia Study Group registry between 2007and 2011 was performed. Patient-level logistic regression was applied in a subset of 29 hospitals with a history of PGI use to relate the probability of death to the use of PGI within 7 days of surgery after controlling for ethnicity, prenatal diagnosis, prenatal steroids, CDH defect, chromosomal abnormalities, liver location, complex cardiac anomalies, 5-minute Apgar score, and operative day of life. This analysis was repeated after excluding 50% of the patients with the lowest probabilities (< 0.042 mean propensity score) of receiving treatment. To reduce confounding by indication, a separate mixed effects logistic regression analysis was performed in 58 hospitals to relate the hospital-level mortality to the proportion of patients administered PGI after controlling for hospital-level covariates.

Results Epoprostenol was administered within 7 days of surgery for 80 (7.3%) of these subjects. Epoprostenol use was associated with higher mortality (odds ratio [OR] 4.39, 95% confidence interval [CI] 2.04–9.48) in the patient-level analyses without covariate adjustment. The direct association of epoprostenol use with mortality was partially reduced after covariate adjustment (adjusted OR 2.24, 95% CI 0.95–5.29, p = 0.07), and further attenuated after both covariate adjustment and restriction of the analysis to patients with propensity scores > 0.042 (adjusted OR 1.71, 95% CI 0.68–4.29, p = 0.26). A total of 182 of the 1,639 patients included in the center-level dataset died after 7 days of operation. There was no statistically significant association of mortality with the proportion of patients administered epoprostenol in hospital-level analysis (adjusted OR 0.63, 95% CI 0.34–1.17 per 25% increase, p = 0.15).

Conclusion The discrepancy of results between the hospital and patient-level analyses suggests that the association of mortality and PGI in the patient-level analyses resulted from bias by indication. Hospital-level results provided no evidence of a benefit of PGI use on survival, but may have failed to detect a true benefit due to limited statistical power. Further use of PGI in this population should only be recommended after rigorous evaluation, such as a randomized controlled trial.

Keywords

congenital diaphragmatic hernia - pulmonary hypertension - respiratory failure - epoprostenol - extracorporeal membrane oxygenation

• References

• 1 Wynn J, Krishnan U, Aspelund G , et al. Outcomes of congenital diaphragmatic hernia in the modern era of management. J Pediatr 2013; 163 (1) 114-119 , e1
• 2 Kinsella JP, Ivy DD, Abman SH. Pulmonary vasodilator therapy in congenital diaphragmatic hernia: acute, late, and chronic pulmonary hypertension. Semin Perinatol 2005; 29 (2) 123-128
• 3 Mohseni-Bod H, Bohn D. Pulmonary hypertension in congenital diaphragmatic hernia. Semin Pediatr Surg 2007; 16 (2) 126-133
• 4 Dillon PW, Cilley RE, Mauger D, Zachary C, Meier A. The relationship of pulmonary artery pressure and survival in congenital diaphragmatic hernia. J Pediatr Surg 2004; 39 (3) 307-312 , discussion 307–312
• 5 Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004; 351 (14) 1425-1436
• 6 Smyth EM, FitzGerald GA. The eicosanoids: prostaglandins, thromboxanes, leukotrienes, & related compounds. In: Katzung BG, Masters SB, Trevors AJ, , eds. Basic and Clinical Pharmacology. 12th ed. New Delhi: Tata McGraw-Hill; 2012: 313-329
• 7 Bos AP, Tibboel D, Koot VC, Hazebroek FW, Molenaar JC. Persistent pulmonary hypertension in high-risk congenital diaphragmatic hernia patients: incidence and vasodilator therapy. J Pediatr Surg 1993; 28 (11) 1463-1465
• 8 De Luca D, Zecca E, Vento G, De Carolis MP, Romagnoli C. Transient effect of epoprostenol and sildenafil combined with iNO for pulmonary hypertension in congenital diaphragmatic hernia. Paediatr Anaesth 2006; 16 (5) 597-598
• 9 van Walraven C, Davis D, Forster AJ, Wells GA. Time-dependent bias was common in survival analyses published in leading clinical journals. J Clin Epidemiol 2004; 57 (7) 672-682
• 10 Ashworth JR, Lander AD. Congenital diaphragmatic hernia: the impact of this congenital anomaly on paediatric morbidity and mortality. Fetal Matern Med Rev 2003; 14 (2) 145-154
• 11 Signorello LB, McLaughlin JK, Lipworth L, Friis S, Sørensen HT, Blot WJ. Confounding by indication in epidemiologic studies of commonly used analgesics. Am J Ther 2002; 9 (3) 199-205