Hyaluronic acid intraarticular injections are gel-like medical devices used in osteoarthritis. Patients may only experience modest improvement with these devices, which may be reclassified as medications in the United States (US). Medications may require more testing than devices, and device adverse event reporting in the US has come under scrutiny. We undertook an exploratory analysis of fatal adverse events for these injections in the US. We reviewed all adverse events reported to the US Manufacturer and User Facility Device Experience and Alternative Summary Reporting databases between 2014 and 2019 under the relevant product names and product codes. Reports assigned an outcome of “death” were retained, as were reports that were found to pertain to fatality after review. Of 3449 reports, 103 were found to pertain to 63 distinct fatalities. In 54 of these fatalities, the cause of death was stated to be unknown in narratives. We judged that eight fatalities may have had a logical nexus to device use; six of these fatalities were associated with infection. Low-quality information in reports suggests that the US should review its medical device adverse event reporting processes and providers who administer hyaluronic acid intraarticular injections should use meticulous aseptic technique.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Kux L. Intent to consider the appropriate classification of hyaluronic acid intra-articular products intended for the treatment of pain in osteoarthritis of the knee based on scientific evidence. Federal Register. 2018; https://www.federalregister.gov/documents/2018/12/18/2018-27351/intent-to-consider-the-appropriate-classification-of-hyaluronic-acid-intra-articular-products. Accessed 28 Jun 2020.
Aronson JK, Heneghan C, Ferner RE. Medical devices: definition, classification, and regulatory implications. Drug Saf. 2020;43(2):83–93.
Bowman S, Awad ME, Hamrick MW, et al. Recent advances in hyaluronic acid based therapy for osteoarthritis. Clin Transl Med. 2018;7(1):6.
Dhruva SS, Bero LA, Redberg RF. Strength of study evidence examined by the FDA in premarket approval of cardiovascular devices. JAMA. 2009;302(24):2679–85.
Garber AM. Modernizing device regulation. N Engl J Med. 2010;362(13):1161–3.
Hines JZ, Lurie P, Yu E, Wolfe S. Left to their own devices: breakdowns in United States medical device premarket review. PLoS Med. 2010;7(7):e1000280.
United States Food and Drug Administration. Premarket Approval (PMA) P950027. 1998; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P950027. Accessed 28 Jun 2020.
Newberry SJ, Fitzgerald JD, Maglione MA, et al. Systematic review for effectiveness of hyaluronic acid in the treatment of severe degenerative joint disease (DJD) of the knee. Rockville: Agency for Healthcare Research and Quality; 2015.
Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2020;72(2):149–62.
Jewett C. Hidden FDA reports detail harm caused by scores of medical devices. 2019; Kaiser Health Network. https://khn.org/news/hidden-fda-database-medical-device-injuries-malfunctions/. Accessed 28 Jun 2020.
Shuren JE. Statement on agency’s efforts to increase transparency in medical device reporting. 2019; https://www.fda.gov/news-events/press-announcements/statement-agencys-efforts-increase-transparency-medical-device-reporting. Accessed 28 Jun 2020.
Carico RL, Emmendorfer TR, Aspinall SL, et al. Review of purchases of unapproved medications by the Veterans Health Administration. Am J Health Syst Pharm. 2019;76(23):1934–43.
Meier L, Wang EY, Tomes M, et al. Miscategorization of deaths in the US Food and Drug Administration adverse events database. JAMA Intern Med. 2020;180(1):147–8.
Manfreda F, Rinonapoli G, Nardi A, et al. A fatal sepsis caused by hyaluronate knee injection: how much the medical history and the informed consent might be important? Case Rep Orthop. 2017;2017:1518401.
Virupannavar S, Guggenheim C. A patient with fatal necrotizing fasciitis following the use of intra-articular sodium hyaluronate injections: a case report. Case Rep Med. 2013;2013:531794.
MAUDE Adverse event report: Seikagaku Corp Supartz acid, hylauronic, intraarticular. 2015; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI__ID=4743252. Accessed 28 Jun 2020.
MAUDE Adverse event report: Didia Farmaceutici S.P.A. hyalart hyaluronic acid for intrarticular use. 2015; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI__ID=4734161. Accessed 28 Jun 2020.
MAUDE Adverse event report: Genzyme Biosurgery (Ridgefield) Synvisc One intra-articular hyaluronic acid. 2015; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI__ID=5328200. Accessed 28 Jun 2020.
MAUDE Adverse event report: Genzyme Biosurgery (Ridgefield) Synvisc One intra-articular hyaluronic acid. 2016; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI__ID=5469613. Accessed 28 Jun 2020.
MAUDE Adverse event report: Genzyme Biosurgery (Ridgefield) Synvisc One MOZ. 2018; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI__ID=7446087. Accessed 28 Jun 2020.
MAUDE Adverse event report: Genzyme Corporation(Ridgefield) Synvisc One MOZ. 2017; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI__ID=7036433. Accessed 28 Jun 2020.
MAUDE Adverse event report: Genzyme Biosurgery (Ridgefield) Synvisc One MOZ. 2018; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI__ID=7215126. Accessed 28 Jun 2020.
MAUDE Adverse event report: Sanofi-Aventis U.S. LLC Synvisc-One viscosupplement gel acid, hyaluronic, intraarticular. 2018; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI__ID=8128888. Accessed 28 Jun 2020.
MAUDE Adverse event report: Genzyme Biosurgery (Ridgefield) Synvisc One MOZ. 2018; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfMAUDE/Detail.CFM?MDRFOI__ID=8191030. Accessed 28 Jun 2020.
This article was produced without funding from any source.
Conflicts of interest/competing interests
The authors have no conflicts of interest to disclose.
Availability of data and material
This article was produced using only publicly available data, collected using procedures outlined in the article. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
This article uses data that are made publicly available by US regulatory agencies. This study was reviewed by the institutional review board of Marshall University and deemed to be not human subjects research for the purposes of ethical review.
Consent to participate/consent for publication
Data were analyzed with Microsoft Excel. No custom code was necessary.
RC was the primary author and was responsible for data collection and analysis. SA and CG provided technical and clinical feedback and assisted with manuscript revisions.
About this article
Cite this article
Carico, R.L., Aspinall, S.L. & Good, C.B. Fatalities possibly associated with hyaluronic acid injections: a review of events reported to the FDA. Drugs Ther Perspect (2021). https://doi.org/10.1007/s40267-020-00804-z