Newborns and infants with complex congenital heart disease (CHD) who are deemed unsuitable for definitive intracardiac repair at this age may undergo surgical placement of a prosthetic vascular conduit, termed a “shunt,” to augment pulmonary blood flow and systemic oxygen delivery. 

“Various types of surgical shunts are employed to reroute blood from the systemic circulation or the right ventricle to the pulmonary arteries, including systemic-to-pulmonary artery shunts and right ventricle-to-pulmonary artery shunts,” explains Amy Kiskaddon, Pharm.D., M.B.A., an assistant professor of pediatrics in the Johns Hopkins University School of Medicine based at Johns Hopkins All Children’s Hospital in St. Petersburg, Florida. 

As a pediatric cardiac clinical pharmacy specialist, Kiskaddon is cognizant that neonates and infants with CHD who have received cardiac shunts may develop “shunt thrombosis” — characterized by thrombus formation within the conduit, leading to occlusion of blood flow. Such events are associated with increased morbidity and mortality after congenital heart surgery. According to reported estimates, shunt thrombosis-related mortality rates range from 21% to 40%. 

To mitigate the risk of shunt thrombosis, antithrombotic medications are commonly administered; however, evidence supporting specific prophylactic strategies remains limited. Variability exists in the selection of antithrombotic agents and dosing regimens for this patient population. 

In addition to her academic and clinical responsibilities, Kiskaddon also serves as chair of the Cardiac Disease Thrombosis and Hemostasis Working Party of the Pediatric and Neonatal Thrombosis and Hemostasis Subcommittee of the International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee. The ISTH is an international medical and scientific society dedicated to advancing the understanding, prevention, diagnosis, and management of thrombotic and hemostatic (i.e., bleeding) disorders. 

She notes, “My curiosity has always been focused on the existing literature concerning thrombosis and the thromboprophylaxis strategies employed, particularly within this vulnerable patient group. I am continually striving to improve clinical outcomes for these patients.”

Motivated by these interests, Kiskaddon and her colleagues in the ISTH working group embarked on extensive research to evaluate antithrombotic medication protocols aimed at preventing shunt thrombosis, as well as to assess thrombosis and bleeding complications in neonatal and infant populations that have cardiac shunts. 

Research Methods

The comprehensive literature review concentrated on peer-reviewed investigations of shunt thrombosis and failure, encompassing studies published between 1978 and 2023. These studies characterized variables such as shunt types, antithrombotic pharmacologic agents, dosing regimens, and clinical outcomes, including hemorrhagic events and shunt occlusion in neonatal and infant populations. The formulation and execution of the search strategies were conducted by a trained medical librarian experienced in systematic review methodologies, utilizing multiple electronic bibliographic databases — including MEDLINE and the NIH Quality Assessment Tool for Observational and Cross-Sectional Studies — to identify relevant literature. The initial study design, screening of the articles, and data extraction were carried out by Kiskaddon, first author on the study, and senior author Nhue L. Do, M.D., M.B.A., a pediatric cardiovascular surgeon at Advocate Children’s Heart Institute in Chicago. 

“In consultation with librarian Pam Williams, the search strategy was developed to capture all studies reporting on shunt thrombosis among neonates and infants with cardiac shunts, aiming to estimate the rate of thrombosis while categorizing shunt types, antithrombotic agents, and dosing strategies, and associated outcomes such as bleeding, thrombosis and shunt-related mortality,” Kiskaddon explains.

The search yielded a total of 1,540 publications pertaining to shunt thrombosis, of which 39 studies involving 4,735 patients met the inclusion criteria for further analysis.

Research Findings

The completed investigation, entitled “Antithrombotic strategies and outcomes in neonates and infants with cardiac shunts: a systematic review and meta-analysis,” was recently published in Research and Practice in Thrombosis and Hemostasis, a peer-reviewed, open-access journal published by the ISTH. 

Analysis across 39 selected studies indicates a shunt thrombosis rate of 8% among neonates and infants with cardiac shunts, and a mortality rate of 26%. Despite heterogeneity in antithrombotic regimens, aspirin emerged as the most commonly employed long-term pharmacoprophylaxis, administered either alone or in combination with other agents. 

According to Kiskaddon, “This research was initiated to investigate the types and dosing regimens of antithrombotic medications reported in studies of neonates and infants with prosthetic cardiac shunts. Our findings underscore a substantial mortality risk linked to shunt thrombosis, highlighting the necessity for prospective, multicenter studies specifically designed to evaluate various antithrombotic strategies, prognostic factors related to thrombosis and bleeding, and the utilization of standardized and validated outcome measures.”

Conclusion

“Shunt thrombosis remains a recognized serious complication in neonates and infants with CHD who require a systemic-to-pulmonary artery shunt,” says co-author Neil A. Goldenberg, M.D., Ph.D., professor of pediatrics and associate dean for research at Johns Hopkins All Children's Hospital. 

“Accordingly, there is an urgent need for collaborative efforts to conduct large multicenter prospective studies to evaluate optimum antithrombotic strategies for both the prevention and treatment of shunt thrombosis in neonates and infants with cardiac shunts. Dr. Kiskaddon’s positions in international collaborative groups through the ISTH and other societies and organizations, as well as her role as a Pharm.D.-clinical scientist specializing in antithrombotic agents and children with cardiac disease (particularly those who are critically ill or undergoing cardiac surgery) uniquely position her to make a substantial positive impact on the field, and for children with cardiac disease.”

Additional co-authors and contributors to the study are the members of the Cardiac Thrombosis and Hemostasis Working Party of the ISTH SSC Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis; Marisol Betensky, M.D., M.P.H., Johns Hopkins University/Johns Hopkins All Children’s Hospital; Joshua W. Branstetter, Pharm.D., Department of Pharmacy, Children’s Healthcare of Atlanta; Dina Ashour, M.S., Institute for Clinical and Translational Research, Epidemiology and Biostatistics Shared Resource, Johns Hopkins All Children’s Hospital; Pamela Williams, M.S., M.L.S., Medical Library, Johns Hopkins All Children’s Hospital; Arabela C. Stock, M.D., Heart Institute, Johns Hopkins All Children’s Hospital, Division of Cardiac Critical Care; Michael Silvey, D.O., Division of Hematology/Oncology/Bone Marrow Transplant, Department of Pediatrics, Children’s Mercy Hospital, Kansas City, Mo.; Therese M. Giglia, M.D., Division of Cardiology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania.