Safety of Enalapril in Infants Admitted to the Neonatal Intensive Care Unit
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Enalapril is used to treat hypertension and congestive heart failure in infants. However, enalapril is not labeled for neonates, and safety data in infants are sparse. To evaluate the safety of enalapril in young infants, we conducted a retrospective cohort study of infants who were exposed to enalapril in the first 120 days of life and were cared for in 348 neonatal intensive care units from 1997 to 2012. We determined the proportion of exposed infants who developed adverse events, including death, hypotension requiring pressors, hyperkalemia, and elevated serum creatinine. Using multivariable logistic regression, we examined risk factors for adverse events, including postnatal age at first exposure, exposure duration, gestational age group, small for gestational age status, race, sex, 5-min Apgar score, and inborn status. Of a cohort of 887,910 infants, 662 infants (0.07%) were exposed to enalapril. Among exposed infants, 142 infants (21%) suffered an adverse event. The most common adverse event was hyperkalemia (13%), followed by elevated serum creatinine (5%), hypotension (4%), and death (0.5%). Significant risk factors for adverse events included postnatal age <30 days at first exposure and longer exposure duration. This study is the largest to date examining the safety of enalapril in young term and preterm infants without significant structural cardiac disease.
KeywordsEnalapril Drug safety Infant pharmacology Pharmacoepidemiology
The Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee
Daniel K. Benjamin Jr., MD, PhD, Katherine Y. Berezny, BSMT, MPH, Michael Cohen-Wolkowiez, MD, PhD, Duke Clinical Research Institute, Durham, NC; Gregory L. Kearns, PharmD, PhD, Arkansas Children’s Hospital, Little Rock, AR; Matthew M. Laughon, MD, MPH, University of North Carolina, Chapel Hill, NC; Ian M. Paul, MD, MSc, Penn State College of Medicine, Hershey, PA; Michael J. Smith, MD, MSCE, University of Louisville, Louisville, KY; John van den Anker, MD, PhD, George Washington University School of Medicine and Health, Washington, DC; Kelly Wade, MD, Children’s Hospital of Philadelphia, Philadelphia, PA.
The Eunice Kennedy Shriver National Institute of Child Health and Human Development
David Siegel, MD, Perdita Taylor-Zapata, MD, Anne Zajicek, PharmD, Zhaoxia Ren, MD, PhD, Ekaterini Tsilou, MD, Alice Pagan, BBA.
The EMMES Corporation (Data Coordinating Center)
Ravinder Anand, PhD, Traci Clemons, PhD, Gina Simone, BS.
Dr. Ku receives research support from the National Institute of Child Health and Human Development (5T32GM086330-03, 5T32HD043029-13, and 4K12HD043494-14). Dr. Zimmerman receives research support from the Duke Clinical and Translational Science Awards (KL2TR001115-03). Dr. Hornik receives research support for research from the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) (UL1TR001117). Dr. Smith receives salary support for research from the NIH and the National Center for Advancing Translational Sciences of the NIH (UL1TR001117), the National Institute of Child Health and Human Development (HHSN275201000003I and 1R01-HD081044-01) and the Food and Drug Administration (1R18-FD005292-01); he also receives research support from Cempra Pharmaceuticals (subaward to HHS0100201300009C) and industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Dr. Benjamin and Dr. Clark have nothing to disclose.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
For this type of study, formal consent is not required. Approval for this study was obtained from the Duke University Institutional Review Board.
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