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Learning from incidents in medically assisted reproduction: the Notify Library as a learning tool

      Abstract

      Biovigilance is the systematic monitoring of serious adverse reactions and events (SARE) that ensures the quality and safety of tissues and cells for human application in medically assisted reproduction (MAR). The Notify Library is an open access database launched by the World Health Organization and supported by the Italian National Transplant Centre (CNT) that has collected information on documented adverse occurrences in transplantation, transfusion and MAR. It is not a SARE register, but rather a collection of SARE types identified primarily by review of published articles and case reports from national or regional vigilance programmes. The Notify Library includes many well-documented records of adverse occurrences in MAR treatment, representing a useful tool for MAR operators in the evaluation of the risks associated with the clinical application of reproductive tissues and cells. It is updated with new records when a new type of incident is reported for the first time. All incident types described might have teaching value during the risk management carried out by a MAR centre. Sharing lessons learned from these incidents represents an important didactic opportunity that can help MAR centres to improve their processes and to achieve higher standards of quality and safety.

      Keywords

      Introduction

      Medically assisted reproduction (MAR) refers to reproduction brought about through various strategies aimed at treating different forms of fertility impairment and infertility. These strategies include ovulation induction, ovarian stimulation, ovulation triggering, assisted reproductive technology (ART) procedures, and intrauterine, intracervical and intravaginal insemination with the semen of husband, partner or donor (
      • Zegers-Hochschild F.
      • Adamson G.D.
      • Dyer S.
      • Racowsky C.
      • de Mouzon J.
      • Sokol R.
      • Rienzi L.
      • Sunde A.
      • Schmidt L.
      • Cooke I.D.
      • Simpson J.L.
      • van der Poel S.
      The International Glossary on Infertility and Fertility Care, 2017.
      ).
      Although MAR helps millions of people to achieve a pregnancy, it is associated with potential health risks for both the mother, e.g. risks associated with a multiple-birth pregnancy or from ovarian hyperstimulation syndrome (OHSS), and the infant, e.g. preterm birth and low birthweight (
      • Sunderam S.
      • Kissin D.M.
      • Zhang Y.
      • Folger S.G.
      • Boulet S.L.
      • Warner L.
      • Callaghan W.M.
      • Barfield W.D.
      Assisted Reproductive Technology Surveillance - United States, 2016.
      ). Moreover, fertility treatments are complex as each MAR cycle consists of several steps that, if incorrectly executed, could result in the loss of a chance of a viable pregnancy (
      • Farquhar C.
      • Marjoribanks J.
      Assisted reproductive technology: an overview of Cochrane Reviews.
      ).
      Gametes, embryos and gonadal tissues can be included under the term ‘medical products of human origin’ (MPHO) intended for clinical use. This term covers a wide range of substances of human origin, from cells and tissues to blood and organs, all donated by a human with the goal to benefit others, with shared exposure to risks through breaches of ethical, legal and safety standards, leading to a potential undesirable outcome (
      • Strong D.M.
      Tissue banking, biovigilance and the notify library.
      ).
      Biovigilance is a set of surveillance procedures covering the entire process chain from the donation of organs, tissues and cells to the follow-up of recipients, living donors and offspring. It aims to collect and assess information on unexpected or undesirable effects resulting from the therapeutic use of MPHO and to prevent their occurrence or recurrence. Biovigilance in MAR involves vigilance in terms of tissues and cells, but also pharmacovigilance, e.g. OHSS, vigilance of medical devices, e.g. media, incubators, aspiration needles, and potential adverse outcomes on the donor, the recipient and the offspring (
      European Directorate for the Quality of Medicines & HealthCare of the Council of Europe
      Guide to the quality and safety of tissues and cells for human application.
      ).
      European Union legislation requires member states to have in place a system for the reporting of serious adverse reactions and events (SARE) relating to the application of the aforementioned substances of human origin (European Union Directives 2004/23/EC and 2006/86/EC) (

      European Commission. Directive 2004/23/EC. European Parliament and Council Directive of the 31st of March 2004 for establishing types of quality and safety for donation, procurement, testing, processing, maintenance, storage, and distribution of human tissues and cells. Official Journal of the European Union L102/48, 7.4. 2004.https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32004L0023&from=EN (last accessed on 11 March 2021).

      ;
      European Commission
      Commission Directive 2006/86/EC of 24 October 2006 implementing Directive 2004/23/EC of the European Parliament and of the Council as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells.
      ). In recognizing the need for the surveillance of such occurrences, in May 2010, the World Health Assembly, called the World Health Organization (WHO) to facilitate inter-alia member states’ access to ‘appropriate information on the donation, processing and transplantation of human cells, tissues and organs, as well as assisted reproductive technologies, including data on severe adverse events and reactions’. In 2011, in accordance with these resolutions, WHO, the Italian National Transplant Centre (CNT) and the EU-funded Project SOHO V&S (Vigilance and Surveillance of Substances of Human Origin, 2009–2012 - Grant Agreement 20091110) collaborated to organize a major global initiative that aimed at raising the profile of MPHO vigilance and surveillance called Notify Project (
      • Petrisli E.
      • Carella C.
      • Navarro A.
      • Fehily D.
      • Strong D.M.
      • Cardillo M.
      on behalf of the Notify Editorial Board. Vigilance for medical products of human origin - progress on the Notify Library's global effort to share information and learning.
      ).

      Notify Library

      The Notify Library is the major output of the Notify project. It consists of an open access database of published didactic cases of adverse occurrences arising with the donation, processing or clinical application of MPHO. The Notify Library aims to be comprehensive, describing all adverse occurrence types that might have teaching value and assist in the estimation of risk (
      • Fehily D.
      • Strong D.M.
      • Minutoli D.
      • Chatzixiros E.
      • Araya H.
      • Noel L.
      • Nanni Costa A.
      Sharing Vigilance experience and knowledge globally: a preliminary overview of the Notify Library.
      ).
      The work was initially conducted on a WIKI site where over 100 experts from across the WHO regions (regulators, clinicians, professional society representatives, scientists) gathered didactic information on documented types of adverse outcomes in transplantation and assisted reproduction (
      Notify group
      Exploring Vigilance Notification for Organs, Tissues and Cells.
      ). Subsequently, several international experts were asked to collaborate in editorial working groups to allow the uploading of the information to a new relational database hosted by the Notify Library website (https://www.notifylibrary.org). Between 2015 up to 31 December 2020, 84,125 users visited this website.
      The Notify Library is not a vigilance reporting programme, but a continuously updated compendium of information identified primarily by review of published articles in the scientific literature as well as case reports from national or regional vigilance programmes defined as grey literature (
      • Strong D.M.
      Tissue banking, biovigilance and the notify library.
      ). In fact, regulatory or professional vigilance programme reports represent a unique source of cases with teaching value that are usually not published in the medical literature. To promote the inclusion and dissemination of the information described in these cases, a work package of the European Union co-funded Joint Action VISTART (

      Vigilance and Inspection for the Safety of Transfusion, Assisted Reproduction and Transplantation (VISTART) Joint Action. Deliverable 5.1 - How to select and prepare SARE cases of didactic value for insertion in the Notify Library - a user guide for Competent Authorities. 2017.https://www.notifylibrary.org/sites/default/files/VISTART_WP5A_A%20User%20Guide%20for%20CA.pdf. (last accessed on 11 March 2021).

      ) focused on providing instructions to facilitate European member states’ competent authorities in the selection and analysis of cases from their annual vigilance reports with didactic value for submission to the Notify Library.
      In the Notify Library, each record describes a specific type of adverse occurrence in one type of MPHO and can be linked to one or multiple different references. The selection and review of references for inclusion is carried out by international experts who collaborate in five topic-specific editorial groups (infections, malignancy, process-related incidents, clinical complications and living donor reactions). Expert analysis focuses on how the adverse occurrence was recognized and how it was associated with the donation, processing or clinical application of the MPHO. The records are enhanced didactically with expert comments, highlighting key informative points arising from the cases. To facilitate a structured database search, all records have been classified according to a taxonomy of two main groups, the adverse occurrence types and the MPHO types, both further subdivided according to standardized definitions and terminology (
      • Whitaker B.I.
      • Strong D.M.
      • Gandhi M.J.
      • Petrisli E.
      Hemovigilance and the Notify Library.
      ). Types of adverse occurrence include harm to a recipient, harm to a donor and harm to a fetus or offspring and risk of harm. In particular, the ‘risk of harm’ group is further categorized into five subgroups: donor disease without transmission, loss of a suitable MPHO, unsuitable MPHO released for clinical use - no harm, mix-up and other adverse occurrences. For MAR field, the Notify Library collects occurrences involving the partner donation and non-partner donation as well, using the term ‘donor’ in both cases.
      At present, the Notify Library contains 1718 records, 73 of which are related to reproductive tissues and cells and are linked to a total of 54 source references (
      • Petrisli E.
      • Carella C.
      • Navarro A.
      • Fehily D.
      • Strong D.M.
      • Cardillo M.
      on behalf of the Notify Editorial Board. Vigilance for medical products of human origin - progress on the Notify Library's global effort to share information and learning.
      ).

      Notify Library and medically assisted reproduction

      The Notify Library is of interest to all stakeholders in MAR. Many examples of serious adverse occurrences regarding reproductive cells and tissues have been reported. In the Notify Library, the occurrence of adverse effects related to MAR mainly concern the loss of a suitable MPHO (32/73), e.g. relating to inappropriate storage, packaging or shipment conditions, processing error, damage during procurement (Table 1). Moreover, the ‘Reproductive Cells’ section contains an overview of incidents involving spermatozoa, oocytes and embryos, and most cases described concern spermatozoa and embryos, 40% (29/73) and 36% (26/73), respectively (Table 1). Incidents associated with oocytes represent 21% (15/73) of the cases in the Notify Library.
      TABLE 1REPORTS IN THE NOTIFY LIBRARY OF MEDICALLY ASSISTED REPRODUCTION BY ADVERSE OCCURRENCE AND BY MPHO TYPE (AS OF END OCTOBER 2020)
      SpermatozoaOocyteEmbryoOvarian tissueCombinedTotal
      Harm to a recipient
      Infections5139
      Detrimental immunization112
      Harm to a fetus or offspring
      Genetic112114
      Harm to a donor
      OHSS22
      Infections22
      Insertion of needle11
      Risk of harm
      Loss of highly matched or autologous MPHO5817232
      Unsuitable MPHO released for clinical use415
      Mix-up336
      Total2915262173
      Source: Notify Library.
      MPHO, medical products of human origin; OHSS, ovarian hyperstimulation syndrome.
      The most important cases of risk of harm in MAR procedures involve the misidentification of a patient, gamete or embryo that could lead to dramatic consequences. High workload, lack of communication between team members, distraction, time pressure and complex procedures are the risk factors that could result in misidentification or a witnessing error, also called ‘mix-up’. Although the frequency is low, mix-up cases have been described worldwide. In the section ‘risk of harm’ in the Notify Library, the section ‘mix-up’ is available for both embryos and gametes. Reported cases of gamete and embryo misidentifications are sourced from National Registries such as the TRIP annual report from the Netherlands.
      In the Notify Library, cases of damage to gametes, embryos, and ovarian tissues caused by inappropriate freezing technique, failure of gas supply or equipment failure have been reported (

      Agence de la biomédecine (ABM). ART vigilance report 2009.https://www.agence-biomedecine.fr/AMP-Vigilance-914?lang=fr (last accessed 11 March 2021).

      ;

      TRIP Foundation (Transfusion Reactions In Patients). TRIP annual report 2009https://www.tripnet.nl/pages/en/documents/MicrosoftWord-TRIPAnnualReportTissuevigilanceweb.pdf (last accessed on 11 March 2021).

      ).
      Other adverse events derive from preventable human actions, e.g. overlooking an embryo when carrying out assessments, dropping a dish, incorrect labelling, improper pipetting technique, unusually poor thawing, and inadvertent discard of sample.
      The Notify Library has described many medical complications related to oocyte retrieval procedure, include OHSS, ovarian torsion, thromboembolism, bleeding and urinary tract injury (
      • ESHRE Working Group on Ultrasound in ART
      • D'Angelo A.
      • Panayotidis C.
      • Amso N.
      • Marci R.
      • Matorras R.
      • Onofriescu M.
      • Turp A.B.
      • Vandekerckhove F.
      • Veleva Z.
      • Vermeulen N.
      • Vlaisavljevic V.
      Recommendations for good practice in ultrasound: oocyte pick up.
      ). In addition, viral or bacterial infections could potentially result in a reduction of the effectiveness, efficiency and, especially, the safety of MAR treatments. Infections can occur from vaginal puncture, with contamination from the vaginal bacteria into the intra-peritoneal space; from contamination in embryo culture medium; or through the introduction of contaminants into the uterine cavity during the procedure. Infections of women after insemination caused by pathogens present in ejaculated semen have also been demonstrated. The Notify Library includes some examples in this category.
      Another adverse reaction in donor cycles could be the birth of a newborn who has inherited a genetic disease that was undisclosed or undetected in the gamete donor. Offspring affected by a genetic disease after preimplantation genetic testing for aneuploidy represents another type of adverse reaction. The causes of misdiagnosis include human errors, such as mismatch of embryo diagnosis with the consequent transfer of the ‘affected’ embryo, instead of a healthy one.

      Strengths and limitations of the Notify Library

      The Notify Library does not only provide a register of adverse outcomes but describes all incident types that might have teaching value. It assists in the estimation of the risk, reporting also estimation frequency of each type of event, when available, the time of detection and the root cause of each case. For this reason, the major strength of the Notify Library is its usefulness as a tool when conducting risk management in the MAR field. This tool may increase awareness of risks and inform on the implementation of effective approaches necessary to decrease complication occurrence and errors in the MAR centres.
      On the other hand, the Notify Library presents some limitations. First, although analytics data showed a steady increase in access to the Notify Library, it is challenging to establish a direct correlation between library visits and improved clinical practices and outcomes. Second, it relies on the free and voluntary contribution of biovigilance experts from around the world. The bibliography and information are not guaranteed to be complete or to be fully up to date at any moment. Moreover, it may seem difficult to add new insights to the Notify Library because most adverse reactions and events are known to those working in the MAR field. Cases, however, are considered having instructive value when they describe in detail unusual signs or symptoms in the recipient or donor, as well as uncommon or unexpected causes or errors, an unforeseen level of severity or new corrective actions taken. Also, cases, that did not cause harm but had a significant potential to do so, can represent informative records in the Notify Library. Therefore, clinical and laboratory professionals are encouraged to search and review its content, propose information that might still be missing and support this didactic initiative. In this context, to promote the use of the Notify Library, international and national congresses, scientific meetings and dedicated vigilance workshops have been organized, generating an increased number of library visits worldwide. For instance, the Human Fertilisation and Embryology Authority has encouraged clinic staff to access the Notify Library, promoting it at various conferences and annual meetings and via their in-house publications.
      In conclusion, despite the improvements provided by the European Directives in terms of safety, unfortunately, some incidents in the MAR field have been detected and reported to regulatory or professional vigilance programmes. For this reason, MAR centres must implement risk analysis and risk minimization strategies, mostly through a proactive approach. In view of this, the Notify Library helps to identify what could go wrong in the process and in promoting learning from the experience of others. Indeed, it is wise to use mistakes to promote learning, but it is wiser and safer to learn from the mistakes of others.

      Acknowledgments

      The authors acknowledge the support of other members of the Notify team, in particular Claudia Carella of the Italian National Transplant Centre, Rome, Italy for her revision of the manuscript.

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