Assisted Reproductive Technology Clinic Report

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2019

Assisted Reproductive Technology Clinic

Annual Report

Contents

List of Tables ...... iv

List of Figures ...... v

Preface ...... vi

Message from the Responsible Person ...... vii

Message from the Lead Clinician ...... ix

I Introduction ...... 1

II Our Mission ...... 1

II Regulatory Aspects ...... 1

2.1 Inspections ...... 1

2.2 Licensed Activities ...... 2

2.3 Objectives of ART Clinic and Policies...... 2

2.4 ART Clinic Principles ...... 3

2.5 New Services introduced in 2019 ...... 3

2.6 Cycle at ART Clinic...... 3

2.7 The Workflow – Continuous programme vs Cycles in Batches ...... 4

III Personnel ...... 5

3.1. Changes in personnel ...... 5

IV The Organizational Structure ...... 5

V Quality and Safety ...... 7

5.1 Introduction ...... 7

5.2 Major Changes 2019 ...... 7

5.2.1 Changes in the Premises ...... 7

5.2.2 Extension of services ...... 9

5.3 Managing Change ...... 10

5.4 Qualifications ...... 10

5.4.1 The premises ...... 10

5.4.2 Equipment ...... 10

5.4.3 Materials ...... 11

5.5 Quality Management System (QMS) ...... 12

5.5.1 QMS improvements ...... 12

VI Communication ...... 13

6.1 Internal Communication ...... 13

6.2 Team Building ...... 13

6.3 Communication with Regulatory Authorities...... 14

6.4 Communication with patients ...... 14

VII Patients’ feedback on ART Clinic - 2019 ...... 15

7.1 Reception Service ...... 15

7.2 Nursing, Midwifery and Carers Service ...... 15

7.3 Embryology Service ...... 16

7.4 Medical Service ...... 16

7.5 Counselling Service ...... 16

7.6 Surgical Procedure ...... 17

7.7 General ...... 17

7.8 Follow-up ...... 17

VIII Counselling Sessions ...... 18

8.1. Breakdown of Sessions ...... 18

8.2 Counselling related Telephone calls ...... 19

8.3 Individual Sessions ...... 19

8.4 Drop-Ins ...... 19

8.5 Welfare of the Child Assessment (WOC) ...... 19

8.6 Notes after each Counselling Session ...... 19

IX Embryology ...... 20

9.1 Activity report ...... 20

9.2 Overview of ART Clinic processing and outcomes ...... 21

X Genetics activities ...... 26

XI Clinical Activities ...... 27

XII License holder activities ...... 28

XIII Biovigilance and Surveillance ...... 29

XIV Challenges and Limitations ...... 29

iii

List of Tables

Table 1 - New Equipment ...... 11 Table 2 - Revision and Development of new Documents...... 13 Table 3 – Rating – Reception Service ...... 15 Table 4 - Rating Nursing Midwifery and Carers’ Service...... 15 Table 5 - Rating Embryologists’ Services ...... 16 Table 6 - Rating Medical Services ...... 16 Table 7 - Rating Counselling Service ...... 16 Table 8 - Rating Surgical Procedure ...... 17 Table 9 - Rating Overall Experience ...... 17 Table 10 - Rating Follow up ...... 17 Table 11 - Counselling Sessions March – December 2019 ...... 18 Table 12 – Breakdown of Counselling sessions ...... 18 Table 13 – Counselling Telephone calls ...... 19 Table 14 – Number of oocyte pickups, sperm collection, embryo transfers and cryopreservation procedures ...... 20 Table 15 – Pregnancy rates Fresh vs Cryopreserved embryos...... 22 Table 16 – Cryopreserved embryo transfer – Cleavage stage vs Blastocyst stage ...... 23 Table 17– Fresh embryo transfer – Cleavage stage vs Blastocyst stage...... 23 Table 18 - Survival % Rate – Embryos vs Oocytes ...... 25 Table 19 - Fertilisation % Rate – Fresh vs Cryopreserved oocytes...... 25 Table 20 – Life Births ...... 25 Table 21 – Clinical Activity ...... 27

List of Figures

Figure 1 - ART Clinic – Mater Dei – Organogram 2019 ...... 6 Figure 2 - Average monthly number of oocyte pickup procedures performed ...... 21 Figure 3– Overall Pregnancy Rate ...... 21 Figure 4 – Fresh vs Cryopreserved Embryo Transfer – Pregnancy Rate ...... 22 Figure 5 – Cryopreserved Embryo Transfer pregnancy rates...... 24 Figure 6– Fresh Embryo Transfer pregnancy rates ...... 24

Preface

According to The Human Blood and Transplants Act (Quality and Safety) Regulations, (S.L. 483.01), Article 7 (2), the ART Clinic shall submit to the Authority an annual report on these activities, which shall be publicly accessible.

This year the report format has been changed to provide a more comprehensive and user-friendly presentation of our activities and data results. Data on counselling session’s activities, Genetic Activities, Clinical Activities and Quality Management System activities are also included, for the first time in this annual report.

The ART Clinic management team has continued to focus on the ART Clinic’s risk profile and service offered with a number of key initiatives carried out by our team in support of our vision to provide the highest level of care and outcomes to our patients in the safest environment.

Message from the Responsible Person

ART Clinic team is pleased to present the 2019 Annual Report of its activities. Unprecedented interest is focused on ART.

On the one hand, the public deserves to be more informed about solutions to fertility problems. The purpose of this annual report is to inform the Regulatory Authorities, clinicians, government, researchers, and the public about ART treatment and the resulting pregnancy and birth outcomes; to provide ongoing monitoring of ART treatment practices, success rates. This report is also an opportunity to consider the issues and the challenges affecting ART services and to suggest changes to improve our services for the benefit of all patients and our society.

The amendments in The Embryo Protection Act (Cap.524) enforced in October 2018, raise new opportunities and challenges to existing activities of ART Clinic, mainly, direct donation between known- partners, donation between unknown partners, cryopreservation of embryos, fertilisation of 2 to 5 eggs, and introduction of Intra Uterine Insemination. As consequences, new activities may increase risks if they are not carefully monitored and controlled. Thus scrupulous donor selection, testing criteria, quality control at each step of our processes and comprehensive quality management system apply.

Our services are based, first of all, on a structured medical approach, touching at the same time the search for causes of infertility and the evaluation of the balance between benefits and risk incurred by taking into account the conditions which must be favourable to ART treatment.

Other significant projects were finalised such as the structural changes of the cryogenic room and its requalification, re-enforcement of the microbiological controls of the laboratories where the processing of gametes are performed, recruitment of new personnel , introduction of new equipment and work on a review of the quality management system in place.

The overall Intra Cytoplasmic Sperm Injection (ICSI) pregnancy success rate at ART Clinic for 2019 stands at: 23.7%

This compares with results presented at ESHRE on the 25th of June 2019 in Vienna, Austria[1], showing that in 2016, that success rates were at 24.3% following ICSI. This is very encouraging for the ART Team and gives the strength to persevere in our effort, based on the strong commitment, good collaboration and the rigorous work of all the ART Clinic team.

[1] ESHRE 2019. Review of the 35th European Society of Human Reproduction and Embryology (ESHRE) Congress 2019 - European Medical Journal EMJ Repro Health.2019:5 [1]:10-19

vii

I am grateful to ART Clinic staff for their commitment and their willingness to provide the best care to the patients. In the course of its work programme in the period this report covers, ART Clinic staff has worked closely with the License Holder, Ministry for Health and Authorities and the engineers services at Mater Dei Hospital. Input from these sources is of considerable assistance to ART Clinic for its development.

Finally, I wish to express my deepest appreciation to all the staff at ART Clinic-Mater Dei Hospital who took time to contribute to the elaboration of this report. Their input is a valuable contribution to the ART Clinic work.

Dr. Fewzi Teskrat Responsible Person ART Clinic Mater Dei Hospital

viii

Message from the Lead Clinician

The year 2019 brought about major changes in the services offered at ART clinic and has heralded the start of reforms aimed at revolutionizing our infertility practices

The main reforms in The Embryo Protection Act (524) law, enforced in October 2018 provide, that clinicians are allowed to freeze embryos as part of the provision of services and not only in extraordinary situations provided authorization from the Embryo Protection Authority is granted for the fertilization of up to 5 oocytes.

The primary outcome of all this is that we have been able to aim to achieve an OHSS free clinic. In fact, we have not had any case of ovarian hyper stimulation syndrome (OHSS) in the last year. Freezing when there is a risk of OHSS is fundamental to preserving the health of the mother but also that of the embryo. In the case of the latter, we are electing to freeze when the progesterone/oestradiol is high as this improves the outcome by 30%. Being able to freeze has also allowed us to “risk assess” over stimulating in anticipated poor responders thus diminishing the chances of failed/abandoned cycles.

Being allowed to attempt to fertilize 5 oocytes also had significant positive implications. When we manage to achieve having more than 2 embryos, this translates into better success rates per stimulated cycle. For the patient, this means she needs to be exposed to less gonadotrophin cycles and in the older age groups also means that it limits the risks inherent to aging. In the case of successful cycles, it also gives the patient the opportunity of having future siblings in the future, again limiting the need for further stimulations and increasing risks with age.

2019 also saw the start of our continuous service. We are not batching patients anymore, a practice that limited services and created situations that were far from ideal as it gave peaks that would have a negative impact on the success rates. Having embryologist available daily also allowed us to introduce our Intrauterine Insemination (IUI) service. This has provided a service, free of charge, one that was only till now available in private practice.

On the downside the ongoing service, and IUI have put a tremendous strain on our human resources, since the number of embryologist, nurses, administrative and support staff is not sufficient to meet the demand. This has critical implications and pose the risk of failure to deliver the expected service to our patients or worse risk of error. The issue was brought to the attention of the authorities and efforts are being made to address this matter, however the rigid and centralised system does not support our cause in a timely manner. Our doctors have to do the ART services in addition to their normal duties, thus once

ix again, causing major disruptions. All of the above will be made even worse once the donor service is introduced. A fact that might make the introduction of this service impossible until the Human Resources issue is addressed adequately

The future presents more challenges. By no means are we satisfied with the status quo with regards to the law and what it offers our infertile population. In the light of developments occurring in other European countries, and with the aim to improve, we raise new questions to our legislators: Is it right that the Maltese are restricted to having only 5 oocytes fertilized? Is a complete ban on preimplantation genetic diagnosis (PGD) right? Is it acceptable to be obliged to donate ones embryos once you cannot make use of them?

We also have some reservations regarding the entitlement within NHS practice. Topmost of these is the fact that currently, a cycle that normally is defined as one that involves retrieval of oocytes and subsequent transfer of all fertilized embryos, from the entitlement perspective, itis considered as three cycles if 5 oocytes were fertilised, because embryo transfer of subsequent 3 embryo transfers from original oocyte pickup is considered as 2 other cycles. We believe that this -needs to be revised, for the benefit of our patients.

The last year has brought about a significant step forward with preliminary results showing a significant improvement in pregnancy rates. It has also allowed us to achieve an OHSS free practice. Hopefully this is just the start of further major achievements in the coming years.

Mr. Mark Sant Lead Clinician ART Clinic Mater Dei Hospital

I Introduction

ART clinic started its activities in 2014. Our Tissue Establishment was first licensed by the Licensing Authority (The Superintendence of Public Health -SPH) in 2015 under the License number MT000002.

II Our Mission

Our mission is to provide medically assisted procreation procedures to prospective parents facing fertility challenges to achieve pregnancy and life births.

The activities at ART Clinic-Mater Dei Hospital revolve round two types of services, which although related, differentiate in scope. Firstly is the provision of medically assisted reproduction (MAR) services to prospective parents facing infertility issues and secondly fertility preservation to patients undergoing chemotherapy.

MAR involves, the identification, collection, processing, storage and/or distribution of at least one of the following tissues and cells: oocytes, sperm, testicular tissue and embryos and includes procedures of ovarian stimulation; intra uterine insemination (IUI); in-vitro fertilization; intra cytoplasmic sperm injection (ICSI); and embryo transfer into the uterus.

II Regulatory Aspects

The work is regulated by The Human Blood and Transplants Act (Cap 483), The Embryo Protection Act (Cap 524) and related subsidiary legislations. The renewal of the license is commonly given every 2 years after an inspection on site.

2.1 Inspections

Several inspections took place since the opening of the ART Clinic:  October 2014  December 2014  January 2015  December 2015  December 2016  The last inspection took place in July 2019

On the 28th of November 2019, a request was made by ART Clinic-MDH to Superintendence of Public Health (SPH) to apply for an extension of the license for the collection, processing, storage and distribution of known non-partner donations.

ART Clinic ensures that donors understand that donating gametes and embryos is voluntary and unpaid. Only Oocytes donors may be compensated for the costs and expenses of the Stimulation treatments. Paying of substantial fees to obtain human egg cells is against the principles expressed in the Directive 2004/23/EC on Tissues & Cells and National legislation, which seeks to ensure the quality and safety aspects of human tissues and cells used in therapies.

2.2 Licensed Activities

The current licensed activities are the following:  Procurement of oocytes and sperm  Donor testing  Processing of semen and oocytes  In Vitro fertilisation without and with micromanipulation  Intracytoplasmic sperm injection (ISCI)  Mechanical assisted hatching  Embryo culture  Preservation and storage of sperm, oocytes and embryos  Transfer of embryos for implantation  Distribution of autologous sperm and oocytes  Collection, processing storage and distribution of known non-partner donations

2.3 Objectives of ART Clinic and Policies.

The ART Clinic continues, under the leadership of its Responsible Person, to develop a quality management policy in order to meet the requirements of its patients and thus strengthen their confidence. Organize the ART Clinic to ensure daily management and continuity of service. Define the strategy and objectives in line with direction from the Ministry for Health to ensure patients satisfaction. Communicate internally and externally with the Authorities. The Ministry for Health and the License Holder provide the means to achieve the objectives.

2.4 ART Clinic Principles ART Clinic Principles based on the National Legislations are the following:  Quality and safety of the products and services  Confidentiality  Anonymity (measures regulating the disclosure of the identity of the donor)  Voluntary and Unpaid Donation  Transparency  Customers focus

2.5 New Services introduced in 2019

 Follicle tracking  Intra Uterine Insemination (IUI)  A continuous programme – centred on the clinical needs of each patient not in batches as was previously provided.  Potential to fertilise up to 5 oocytes (eggs) upon authorisation from The Embryo Protection Authority.  Extension of embryo culture from cleavage to blastocyst stage  Cryopreservation of embryos  Donation of gametes by known non-partners

2.6 Cycle at ART Clinic

An ART procedure is typically referred to as a cycle of treatment rather than a procedure at a single point in time. A full cycle of ART treatment covers ovarian stimulation (when a woman begins taking drugs to stimulate egg production or starts ovarian monitoring with the intent of having embryos transferred), egg collection, sperm collection, fertilisation and embryo transfer into the uterus. One full cycle of ART can take about two to three weeks. Sometimes these steps are split into different parts and the process can take longer. According to the entitlement criteria issued on DH Circular 84/2018 at ART Clinic -Mater Dei Hospital, patients are entitled to 3 cycles. A full cycle is considered by the Embryo Protection Authority as an attempt to pregnancy,. Sometimes IVF cycles need to be cancelled by the clinicians before egg collection for medical reasons which may include any of following:  Inadequate number of follicles developing or premature ovulation  Too many follicles developing, creating a risk of ovarian hyper stimulation syndrome (OHSS)

2.7 The Workflow – Continuous programme vs Cycles in Batches

The change in practices from batched cycles to a continuous programme and the introduction of follicle tracking, testing for potential risk of ovarian hyper stimulation syndrome (OHSS), dummy runs and Intra Uterine Insemination (IUI) all have added to the safety of our patients and aim at improving success rate. On the downside these has brought an increased workload on our members of staff since staff compliment has remained constant. Following is a workflow comparing the process steps of cycles in batches with those currently offered.

Workflow (Before) Workflow (Current) Patients called in Patients called in

Investigations Investigations

Consents/Authorization Consents/ Authorization

Stimulation (All patients Together) Stimulation /individual (following menses)

Sperm Collection/processing Follicle Tracking (Gynae & ART) all at the clinic

Oocyte pickup Sperm Collection/processing

Oocyte Processing IUI

Embryo Transfer Stimulation /individual (following menses)

Follicle Tracking

Sperm Collection/processing

Oocyte pickup

Oocyte Processing

Testing for potential OHSS Risk

Dummy Run

Embryo Transfer/Cryopreserve

Embryo Transfer

III Personnel

The ART Clinic workforce is composed of a multidisciplinary clinical-scientific team, led by the Responsible Person in liaison with the Clinical Chairperson and Lead Clinician. The team consists of Gynaecologists specializing in infertility, Medical Doctors, Urologists, Geneticist, Embryologists, Sonographers, Anaesthetics, Quality Manager, Midwives, Nurses, Counsellor, Administrative Officer, Clerks and carers.

3.1. Changes in personnel

In 2019, two nurses and one midwife joined the ART Clinic team, replacing members who either requested a transfer, or were transferred following a promotion to other departments or retired. The trainee embryologist who was also performing duties of a laboratory manager asked for transfer to another department. To date this vacancy has not been filled. Requests to fill the vacancies of, a laboratory manager, another embryologist, 1 counsellor, 1 midwife and 2 nurses, have been made to the authorities, due to increased workload as a result of increased services and to ensure continuity of service.

IV The Organizational Structure

The ART Clinic organisational structure aims to establish accountability, information flow, authority and distribution of responsibilities. It is a top down flowchart, starting with the Chief Medical Officer, who has the overall responsibility. This is, shared with Clinical Chairperson, Responsible Person and Licence Holder and followed through the Lead Clinicians, Quality Manager, Consultant Gynaecologist, Midwife in Charge, Medical and Clinical staff, Counsellor, Embryologists, Administrative Officer and support staff. They report directly to the Clinical Chairperson for the Clinical/Medical activities and to the Responsible Person for the organisational elements, laboratories activities and quality assurance.

Figure 1 - ART Clinic – Mater Dei – Organogram 2019

V Quality and Safety

5.1 Introduction

Quality is about consistently producing products and services that fulfill a specific set of standards, characteristics and requirements rendering them fit for their purpose. Thus ensuring that they are safe and effective to give clinical benefit which in medically assisted reproduction (MAR) is to achieve pregnancy and life births.

Safety is concerned with preventing risks of: infection; contamination; mix-ups; and harm to the health of the donors, recipients and the unborn child. Whilst effectivity is concerned with preservation of biological and structural functionality of cells to give clinical benefit.

Traceability, quality and safety of products and services are the three pillars on which MAR builds.

5.2 Major Changes 2019

The year 2019, was a very challenging year for the ART Clinic- MDH Team, characterized by several major changes brought about by, implementation of amendments in The Embryo Protection Act (Cap 524), mainly; restructuring of laboratory premises; widening of the entitlement criteria, extension of services, and activities; and introduction of new equipment to allow extension of embryo culture from cleavage to blastocyst stage and to meet the envisaged increase in capacity.

5.2.1 Changes in the Premises The great effort put in by the Responsible Person, in 2018, to, identify areas for improvement; meet the envisaged increase in cryopreservation capacity; and to establish requirements; followed by identification of solutions; planning; and seeking funding and authorization; yielded its fruit. This was a multidisciplinary effort, involving the license holder, CMO, Engineering Department, administrative Officer and the whole ART Clinic Team.

By December 9, 2018, the physical restructuring works to, enlarge the cryopreservation room and re- organize storage and office space were finalized. This resulted in a cryopreservation room which:  Is double the original size, to allow space for extra cryogenic tanks and offering an environment whereby topping up of cryogenic tanks can be carried out without moving the stored tissues and cells and with minimal risk to the users  Has two doors for ventilation and as an escape route during topping up  Is lined with seamless industrial steal metal to prevent trapping or infiltration of liquid nitrogen to lower floors.

Between January and May 2019, the:  The gas supply manifold was upgraded to ensure a controlled flow of gases to the incubators, for two reasons, firstly due to addition of a new incubator and secondly due to the requirement to extend embryo culture from cleavage to blastocyst stage whereby gases supply plays a critical role.  The cryopreservation room was equipped with, an oxygen sensor, attached to an external alarm to ensure health and safety of personnel and extra alarm connecting points, so that all cryogenic tanks will be individually attached to designated remote alarm system  Four new cryogenic tanks were procured.  Standard operating procedures for topping up and maintenance of cryogenic tanks and for daily monitoring of ambient environment and liquid nitrogen levels were developed and implemented.  An emergency plan in the case of spillage (worst-case scenario) was developed and is in place, after authorisation from Engineering and the Fire Department was granted.  Environmental microbiology control was stepped up, with Responsible Person providing training to the embryologists followed by the development of standard procedures, to ensure regular monthly monitoring.  Additional new equipment was procured and installed and the existing equipment was relocated according to new layout design, to allow work to proceed in a logical manner while minimising risk of error.

These works involved a significant active participation of the Quality Manager (QM), from the initial stages of drafting the protocols, which included impact and risk assessments, identification of means for measuring and monitoring and the development of an action plan, endorsed by Responsible Person. This was followed by QM’s active oversight in process to ensure that changes are, implemented in a controlled and risk based manner; testing, data analysis, interpretations and reporting as part of the quality

8 management system, to ensure they are fit for intended use. The embryologists and technical persons from license holder supported testing procedures.

5.2.2 Extension of services The period between May - July 2019, was characterised by the Licensing Inspection taking place in July 2019, entailing a substantial effort to prepare the documented evidence, requested by the Licensing Inspection Team.

In parallel with the above, the Quality Manager in liaison with the Responsible Person was involved in the preparation for the extension of services in line with the amendments in The Embryo Protection Act (Cap 524), to provide services for known and unknown non-partner gamete donations. These services are highly regulated and demand significant preparation in terms of interpretation of the regulating legislation and establishment of the quality and safety specifications as per legal requirements.

By October 2019, ART Clinic was ready to provide the service of known non-partner donation. Notification to the Authorities was submitted and license was granted. Testing of known donors entails a completely different protocol than that for prospective parents and their partners. Screening tests need to be performed:  In an anonymous manner  Urgently - results to be delivered within hours  Additional NAT testing to serology is required This required thorough planning and liaison with several sections within the Pathology Department. This was concluded with a joint working protocol with Pathology Department. Moreover, internally a Policy and relevant standard procedures, information sheets and consent forms, were developed, sent for legal approval and disseminated to all staff to an ensure; a co-ordinated effort; minimisation of errors; and for inspection purposes.

By the end of December 2019, all the preparatory work for provision of unknown non-partner sperm donation had reached an advanced stage. A European Tissue Establishment was identified. ART Clinic’s requirements and specifications were developed and ascertained that they will be met, a joint working protocol and a Third Party Agreement were developed, followed by associated Standard operating procedures for selection, reporting to the Authorities, ordering, accepting and managing non- conformities and serious adverse reactions and /or events were created and are in place. Notification to the Authorities and signing of TPA will follow early January 2020.

During this period a similar process was initiated for the provision of oocyte unknown non-partner donation. This is more challenging since availability of such a product is very limited. However a foreign Tissue Establishment was identified and negotiation is still at the preliminary stage.

5.3 Managing Change

All these major changes were performed within a Change Control Framework, so that, impact of changes were risk assessed; options were identified and appraised; and actions were implemented in a controlled manner with minimal disruptions and in a cost effective manner while ensuring that all quality and safety standards and requirements are met in compliance with local legislation. Change control process was documented.

5.4 Qualifications

5.4.1 The premises Once the restructuring works were completed, current and new equipment were re-located and installed to suit the new design. Then the laboratories and the cryopreservation room were qualified. Qualification proceeded by first demonstrating that, layout minimizes the risk of error, processes can proceed in a logical sequence and effective cleaning and maintenance are facilitated. Then installation and operation of equipment, gas supply systems, alarms, sensors, access control and other engineering services were checked and tested for conformance to specifications. Finally, air monitoring and bacteriological environmental control were performed and were reinforced to verify and support an operating environment suitable for intended use. Health & Safety Measures for the personnel were implemented and SOPs developed.

5.4.2 Equipment Processing, storage and distribution of tissues and cells require the use of different types of equipment, many of which are considered as critical since they have direct impact on quality and safety of the tissues and cells. Processing of gametes and culture of embryos need to be performed in an environment which mirrors physiological conditions, mainly pH and temperature, and these are performed under aseptic conditions to prevent risk of contamination.

ART Clinic MDH is equipped with:  Incubators to safely, incubate gametes and culture embryos up to cleavage stage;  Incubators to provide optimal and constant environmental conditions suitable for embryo culture from cleavage to enable development of blastocyst stage;

 Workstations that provide a confined workspace for protection of tissues and cells against particulate contamination from the surroundings and the operator.  Advanced micromanipulation equipment attached to inverted microscope for intracytoplasmic sperm injection  Centrifuges for processing of sperms  Biological safety cabinets designed to protect the operator, the laboratory environment and work materials from exposure to infectious aerosols.  Cryogenic tanks designed for storing human cells at very low temperatures to preserve their viability.  Other equipment mainly, incubator for plates and media, hot plates and pipettes.

Table 1 - New Equipment Equipment Quantity Incubator for culturing embryos up to blastocyst stage 1 Incubator for media and plates 1 Centrifuge 1 Hot plate 1 Cryogenic tanks 4

Following the restructuring of premises all equipment in use were re-qualified, together with new equipment, listed in Table 1. Equipment Qualification for new equipment proceeded in three stages, Installation qualification (IQ), Operation Qualification (OQ) and Performance Qualification (PQ), to ensure that the Equipment is, installed and operates according to manufacturer's specifications and performs by delivering results as per intended use. The re-qualifications entailed PQ. The objective of PQ is to challenge the critical aspects through a series of controlled tests representing the conditions under which they are expected to operate to demonstrate that they achieve the predefined quality and safety criteria for our processes of gametes and culture of embryos.

5.4.3 Materials Materials that come in contact with tissues and cells are registered and procured from qualified manufacturers and suppliers, to ensure they meet the required specifications for intended use and in compliance with regulations. Delivery of materials is accompanied by provision of certificate of compliance with every batch and undergoes a batch acceptance procedure. This is documented and records are kept as per specified retention periods dictated by law. Traceability of materials used is

11 recorded in every procedure carried out. Materials are stored under conditions as recommended by manufacturer, in designated spaces which are monitored and adequately labelled.

5.5 Quality Management System (QMS)

Quality management in ART Clinic – MDH is a key element in ensuring Good Manufacturing Practice (EU cGMP). A QMS is implemented covering all critical processes starting from Patient/Donor evaluation, through screening, processing of gametes and embryos, transfer and/or storage. It takes into account legal requirements, technical aspects and respects cost-benefit analysis in order to achieve and sustain safety and quality of the products. Each process is divided in sub processes and all are monitored and controlled.

Risk management procedures are key elements in developing Validation protocols, handling non- conformance and Incident Reports and Change Control to establish Corrective and Preventive actions (CAPA) as necessary. These procedures and practices are managed through generation of reports, documents, forms and standard procedures. Excel sheets are used to; record incidents, generate change control, report findings, establish CAPA and monitor follow-ups. The objective of ensuring standardisation of procedures and traceability of all steps in the procurement, processing, transfer and/or storage is achieved through Document Control. This provides a system that controls, monitor and record all activities which directly or indirectly affect quality of products.

5.5.1 QMS improvements In 2019 the QMS was improved with the development of:  Site Master File – that highlights the quality management policies, activities and operations carried out at ART Clinic (MDH)  Validation Master Plan – Highlighting key elements of the Qualification/Validation programme.  Qualification/Validation Protocols – provide a step-by-step support to plan a qualification process.  Change Control Form – to provide a step-by-step support to perform risk and impact assessment, action planning, implementation and monitoring.  A substantial number of Policies, SOPs and Forms were developed and/or revised as listed in Table 2.

Table 2 - Revision and Development of new Documents Document Revised New Policies 2 out of 5 (40%) 7 SOPs 27 out of 48 (56%) 28 Forms 26 out of 53 (49%) 64

VI Communication

6.1 Internal Communication

To ensure that the ART Clinic’s policy, objectives and associated results are known and understood by all the staff, awareness-raising and internal communication actions are carried out by the Responsible Person and the Clinical Chairperson by various means:  Management reviews  Internal communication through ad hoc meetings, by e-mail and social media groups  Monthly strategic meeting with top management: License Holder, Clinical Chairperson, Responsible Person, Lead clinician, Consultant Gynaecologist, Quality Manager, Midwife in charge and Administrative officer- the current organogram is attached to the present report  Weekly meeting of multidisciplinary staffs (geneticist, medical doctors, embryologists, counsellor, nurses and midwives)  Quality assurance meetings where new policy, SOPs and forms are presented to the staff  This review makes it possible to assess the functioning of the Management System, and to revise the quality policy and the associated objectives. The actions defined are integrated into the improvement plan.

6.2 Team Building

March 2019. Team building session meeting was planned and organised. Team building sessions create the time to focus on the importance of teamwork and what is needed to make us a better team. Learning how to work together effectively will create efficiency and knowledge on how to manage each other’s strengths and weaknesses. The ART Clinic team suggested examples of great teamwork and discussed what factors influence the best teams. Discussion was initiated to identify strengths and weaknesses within the team, and how behaviours and strengths can complement one another to strengthen and develop the team.

6.3 Communication with Regulatory Authorities

The Authorities (The Licensing Authority and The Embryo Protection Authority) are constantly informed of the activities carried out as well as of the changes made to the activities. This includes information relating to:  The quality or safety of gametes and embryos  The traceability of gametes and embryos  Serious adverse events and serious adverse reactions (SARE) According to the national legislation ART Clinic: a) Requests:  Authorisation for any substantial changes in activities or extension of services from the Licensing Authority and notifies the Embryo Protection Authority  Authorisation for fertilisation of oocytes, cryopreservation of embryos and transfer of products from or to other tissue establishments prior to each procedure, from the Embryo Protection Authority. b) Notifies:  The Embryo Protection Authority of gametes preservation in cases of oncology and subsequent embryo transfers following the initial transfer. c) Keeps:  A confidential register with full details of every medically assisted procreation procedure and forwards this information to The Embryo Protection Authority in a timely manner.

6.4 Communication with patients

Patients are constantly informed of, details of procedures, benefits and risks by the various specialists at each session held by the team. Information is also provided in writing with dedicated information sheets. Additionally our patients are kept constantly informed, by phone with outcome of each procedure and followed up with letters.

The communication strengthens the understanding and ownership by all staff of the objectives, expectations of patients and results linked to the ART Clinic’s performance. Clinical-biological communication is also essential for the care and monitoring of patients, particularly within this framework.

VII Patients’ feedback on ART Clinic - 2019

We introduced a new standard global patient satisfaction survey tool to measure our services in order to enhance service standards for all patients. This tool is also the method by which we measure our performance against patient expectations. The expectations and needs of the patients are identified, translated into requirements and are the subject of rigorous attention throughout the ART Clinic's services in accordance with our policies. The number of couples who did the IVF process from the period of June 2019 till December 2019 amounted 91 fresh cycles. Out of this number, Art Clinic received a total of 22 Feedback questionnaires. The Questionnaire consisted on the feedback from patients on 8 services that are used by them during the IVF process. Following we will go through each of these services and the satisfaction gradient from our patients. Satisfaction gradient went from very good to good, to fair, to poor. Comments written by our patients will be also listed at the end.

7.1 Reception Service

There are 2 questions related to this services asking patients if they felt adequately supported when calling and when coming to Clinic if they were welcomed in a friendly manner.

Table 3 – Rating – Reception Service

Total Respondents Excellent Good Fair Poor 22 17 3 2 0

7.2 Nursing, Midwifery and Carers Service

There are 4 questions as regarding this service asking patients if they were shown attention and consideration, clear explanation of things, whether they were given the opportunity to ask questions, and if the mode of delivering the pregnancy test was appropriate.

Table 4 - Rating Nursing Midwifery and Carers’ Service

Total Respondents Excellent Good Fair Poor 22 (Qsts.1 - 3) 19 3 0 0 22 (Qst.4) 10 7 5 0

7.3 Embryology Service

There are 2 questions related to this service asking patients if they were shown courtesy and attention and if their questions were handled to their satisfaction.

Table 5 - Rating Embryologists’ Services

Total Respondents Excellent Good Fair Poor 22 9 7 6 0

7.4 Medical Service

There are 5 questions related to this service. Asking patients, if they were given enough time to ask questions (Q1); if they were given a complete assessment of their situation and the treatment options (Q2); if they had enough contact with their specialist at the initial visit (Q3); if they were given, comprehensive information by the specialist (Q4); and if they were shown courtesy and attention (Q5). Table 6 - Rating Medical Services

Questions Excellent Good Fair Poor 1 14 8 0 0 2 9 12 1 0 3 11 11 0 0 4 16 6 1 0 5 15 7 0 0

7.5 Counselling Service

There are 4 questions as regarding this service. Patients were asked to rate their overall counselling experience, if the counsellor offered clear information regarding the process, if the service was offered in a supportive non-judgmental way and how was the Counsellor’s availability.

Table 7 - Rating Counselling Service

Total Respondents Excellent Good Fair Poor 22 19 3 0 0

7.6 Surgical Procedure

There are 3 questions as regarding this service and the questions ask patients if they were shown courtesy and attention by theatre staff (Q1), if they were comfortable in the Procedure area (Q2), and if they were satisfied with the care given post procedure (Q3). Table 8 - Rating Surgical Procedure

Questions Excellent Good Fair Poor 1 18 3 1 0 2 16 5 1 0 3 17 1 4 0

7.7 General

Here the patients were asked 2 questions. They had to rate their overall experience at ART Clinic and if the services were given with respect, empathy and support. Table 9 - Rating Overall Experience

Question Excellent Good Fair Poor 1 12 10 0 0 1 15 7 0 0

7.8 Follow-up

Here the patients were asked if they felt adequately supported after the process was finished. They had to score with a ‘yes’ or ‘no’ or ‘fair’ Table 10 - Rating Follow up

Total Respondents Yes No Fair No answer 22 18 0 3 1

In this same section patients were asked if ART Clinic could have done anything else to make their experience better. The following are some of the comments:  Shorter waiting times for appointments.  The option that medications are bought from Mater Dei.  A more comfortable waiting area.  Result of Pregnancy not given by phone.  Some informative leaflets in the waiting area.  More continuity with doctors (some patients wanted to be followed by one doctor throughout process). Most patients who commented had words of praise for the service provided.

VIII Counselling Sessions

ART Clinic opened its doors to patients once again in March 2019, after a period of closure due to necessary changes and updates after the introduction of the revised IVF Law back in November 2018. The amount of Counselling Sessions between the period of March 2019 and December 2019 is 544. Each counselling session takes approximately 1hr.

Table 11 - Counselling Sessions March – December 2019

Total Number of Counselling sessions 544 Total number of couples 205 First timers 51 Follow-up 151

These counselling sessions were provided to 205 couples, of which 51 couples had done the IVF process before with ART Clinic-MDH. Although the offer for counselling is given each time a couple/individual is doing IVF, it must be noted that it is obligatory for first timers, as specified in the Protocol established by the Embryo Protection Authority and is approved in the Parliamentary Health Committee, in line with The Embryo Protection Act Chap. 524.

8.1. Breakdown of Sessions

Table 12 – Breakdown of Counselling sessions Number of couples Number of hours Couples attending 3 sessions 95 285 Couples attending 2 sessions 49 98 Couples attending 1 Session 44 44

The 49 Couples who did not show up for the last Counselling Session, which falls after the final pregnancy result is out, were contacted by phone to check about their well-being. The 44 couples who came for only 1 counselling session consisted of 30 couples who did IVF already with ART Clinic and wanted to come for one session. The remaining 14 couples were clients who dropped from IVF (couple separated, natural pregnancy etc.).

8.2 Counselling related Telephone calls

From the period of March 2019 till December 2019 a total of 518 calls were done. Table 13 – Counselling Telephone calls Breakdown of Telephone Calls – March – December 2019 Calls to book 1st Counselling Session – after acceptance to proceed with 216 treatment Calls to book 2nd Counselling Session – after initiation of treatment 136 Calls to book for “Welfare of the Child” Assessment 16 Calls to follow up prospective parents after Pregnancy results or termination 150 of process due to medical reasons

8.3 Individual Sessions

Nine individuals kept using the counselling service after doing the IVF process. These sessions amounted to 92 hours.

8.4 Drop-Ins

Nine couples/Individuals dropped in without appointment amounting to 9 hours. These individual/couples were undergoing preliminary tests at ART Clinic-MDH and were identified as very anxious, distressed or in some kind of difficulty, by the nurses/medical staff. These were immediately directed for counselling.

8.5 Welfare of the Child Assessment (WOC)

As from November 2019 ART Clinic started doing the WOC assessment as a session on its own, prior to client’s file is referred for Prioritization A total amount of 16 couples were seen and assessed amounting to 16 hours.

8.6 Notes after each Counselling Session

A total of 544 sessions were done therefore an approximate of 90 hours were spent to record notes. The ‘Welfare of the Child Assessment’ in every couple’s file, takes approximately 1hour per week for a total of 48 hours.

IX Embryology

The embryologist has advanced academic background in, human reproductive biology; embryology; infertility studies; and assisted reproductive technology (ART). They are competent in using sophisticated gamete micromanipulation associated with ART. The activities performed within this area are, receipt and control of gametes, processing and testing for suitability of gametes, micromanipulation to perform intra cytoplasmic sperm injection (ICSI) in oocytes, monitoring of fertilisation and embryo development, cryopreservation and thawing of gametes and embryos and preparation of embryos for transfer in prospective parents.

9.1 Activity report

Table 14 – Number of oocyte pickups, sperm collection, embryo transfers and cryopreservation procedures May - December 2019 Procedure Number of procedures Oocyte pick up 88 Sperm cryopreservation from ejaculate 55 TESE / TESA 8 Cryopreservation of sperm from TESE 3 IUI 117 Fresh embryo transfer 48 Cryopreserved embryo transfer 23 Cryopreserved oocyte cycle 3

Table 14 depicts number of procedures. Each procedure of oocyte pickup is followed by several other procedures, firstly oocyte denudation on each oocyte collected, then followed by ICSI or cryopreservation as medically indicated. Number of oocytes collected can vary depending on patient. Out of these 88 procedures, there was only one procedure resulting in no oocyte collection and in another 31 oocytes were collected. Generally, the number of oocytes collected was 8.

Testicular Sperm Aspiration (TESA) is a procedure whereby fluid containing sperm is aspirated from the testis and Testicular Sperm Extraction (TESE) involves the extraction of testicular tissue biopsies. These procedures are performed under general anaesthesia by a specialist urologist. The specimen is processed and cryopreserved by the embryologist. Sperm and oocyte cryopreservation includes both ART and oncology cases.

Oocyte pickup procedure Monthly Mean 18 17 16 16 15 15 15 14 13 13 12 12

11 Number of procedures 10 2014 2015 2016 2017 2018 2019 2020 Year

Figure 2 - Average monthly number of oocyte pickup procedures performed

Fig. 2 Shows that the average monthly oocyte procedures performed in 2019, was on the same level with that of 2018, albeit marginally lower than in 2016, but relatively higher than 2015 and 2016.

9.2 Overview of ART Clinic processing and outcomes

Pregnancy % Rate 30.0 25% 23.7% 25.0 23% 20.5% 19.8% 20.0

15.0 Pregnancy Pregnancy Rate %

10.0 2014 2015 2016 2017 2018 2019 2020 Year

Figure 3– Overall Pregnancy Rate

Fig.3 Shows the overall pregnancy % rate, which includes all embryo transferred procedures performed (fresh embryos from fresh oocytes, embryos from thawed oocytes and transfer of cryopreserved embryos) following ICSI. The pregnancy rate in 2019 is marginally lower than that of 2016 but relatively higher than that of 2015, 2017 and 2018. This year’s rate 23.7% compares with results presented at ESHRE on the 25th of June 2019 in Vienna, Austria[1], showing that in 2016, the success rates were at 24.3% following ICSI.

Table 15 – Pregnancy rates Fresh vs Cryopreserved embryos

Fresh Cryopreserved

Embryo Transfer No. of procedures 48 23 Number of pregnancies 11 7 Pregnancy Rate 22.9% 30.4% Average female age 36.18 34.39

Table 15 – The average female age in the two groups is comparable and embryo maturity within each group varied between cleavage stage and blastocyst stage thus pregnancy rates can be compared.

Pregnancy %Rate Cryopreserved vs Fresh Embryo transfer 35.0

30.0

25.0

20.0

15.0 30.4 % 22.9 %

Pregnancy Pregnancy %Rate 10.0

5.0

0.0

Figure 4 – Fresh vs Cryopreserved Embryo Transfer – Pregnancy Rate

Fig. 4 shows that the pregnancy rate in cases when cryopreserved embryos are used is 7.5% higher than when fresh embryos are used. This compares with results presented at ESHRE on the 25th of June 2019 in Vienna, Austria [1], showing that in 2016, the success rates using frozen embryos were at 30.5%.

Table 16 – lists number of cryopreserved embryo transfers having different maturity stages. The cleavage stage which is normally reached between day 2 and day 3 and the blastocyst stage normally reached on day 5 or day 6. The female average age is comparable and pregnancy rate of cryopreserved embryo at Day 5 is 45% which is relatively higher than in other groups, with Day 6, having the lowest score. This can be due to the fact that only embryos showing a slow development rate are kept until day 6.

Table 16 – Cryopreserved embryo transfer – Cleavage stage vs Blastocyst stage

Cryopreserved Embryos Cleavage Stage Blastocyst Stage Blastocyst Stage Day 2 - 3 Day5 Day 6 Number of Embryo transfer procedures 7 11 5 Number of pregnancies 3 5 1 Pregnancy Rate 42% 45% 20% Average female age 33.85 36.09 31.4

Table 17 – lists number of fresh embryo transfers having different maturity stages and provides the pregnancy rates. Day 5 fresh embryo transfer has the highest pregnancy rate. Day 3 embryo transfer has the highest number of procedures. Day 2 and Day 3 embryo transfers are usually performed when number of available embryos is low. However the final decision on embryo transfer is based on embryo morphological aspects, stage of development, female age, ovarian response and rank treatment. The decisions are made by clinician in liaison with embryologist.

Table 17– Fresh embryo transfer – Cleavage stage vs Blastocyst stage Fresh Embryos Cleavage Stage Cleavage Stage Blastocyst Stage Day 2 Day 3 Day 5 Number of Embryo transfer procedures 15 29 4 Number of pregnancies 3 9 2 Pregnancy Rate 20% 31% 50% Average female age 38.1 35.48 34.75

Frozen Embryo Transfer Pregnancy % Rate - Compared on embryo development 50 45 40 35 30 25 45% 42 % 20 15 Pergnancy Pergnancy Rate % 20% 10 5 0

FROZEN ET DAY 5 FROZEN ET DAY 3 FROZEN ET DAY 6

Figure 5 – Cryopreserved Embryo Transfer pregnancy rates

Fig. 5 and Fig. 6 show that in both cases the highest pregnancy rate is when Blastocyst stage Day 5 embryos are transferred into the female.

Fresh Embryo Transfer Pregnancy % Rate - Compared on embryo development 50 45 40 35 30 50 % 25 20 31% 15 Pregnancy Pregnancy Rate % 20% 10 5 0

FRESH ET DAY 5 FRESH ET DAY 3 FRESH ET DAY 2

Figure 6– Fresh Embryo Transfer pregnancy rates

Table 18 - Survival % Rate – Embryos vs Oocytes % Survival Rate post-thaw - Embryos vs Oocyte Number of embryos thawed 37 Number of embryos survived 36 Survival Rate of frozen embryos 97%

Number of oocytes thawed 28 Number of oocytes survived 18 Survival Rate frozen oocytes 64%

Table 18 Shows that out of 37 embryos thawed 36 survived, resulting in a 97% survival rate, which is 33% higher than oocyte survival, where out of 28 only 18 survived.

Table 19 - Fertilisation % Rate – Fresh vs Cryopreserved oocytes % Fertilisation Rate – Fresh vs Cryopreserved Oocytes Number of fresh oocytes injected 314 Number of fresh oocytes fertilised 282 Fertilisation Rate of fresh oocytes 89.8%

Number of thawed oocytes injected 13 Number of fertilized eggs from thawed oocytes 10 Fertilization rate of cryopreserved oocytes 76.9% Percentage of pregnancy rate (from thawed oocytes) 0%

Table 19 summarises that out of 314 fresh oocytes, 282 fertilised post ICSI, resulting in a fertilisation rate of 89.8% which is 12.9% higher than when ICSI was performed on thawed oocytes. No pregnancy resulted out of these fertilised eggs. Table 20 – Life Births Live Births Cycles of Total 2015 37 2016 48 2017 44 2018 44 Table 20 summarises the number of life births resulted from medically assisted procreation every year since 2015. Since there were no cycles in the first five months of 2019, the 18 pregnancies resulted from 2019 cycles have expected date of delivery post March 2020.

X Genetics activities

181 couples were tested for Thalassaemia, Cystic fibrosis, Phenylketonuria and Gangliosidosis. 1 couple was identified to be at risk for cystic fibrosis and another were identified to be at risk of gangliosidosis.

76 males were tested for Y microdeletions and karyotyping for oligospermia or azoospermia – 2 cases had a balanced chromosomal translocation and 5 had at least one Y microdeletion that identified the cause of the male infertility.

Though these tests are covering the majority of recessive single gene disorders in Malta, there are at least another 3 disorders that should be included; these are Familial Mediterranean Fever (carrier rate of around 10%), Finnish Nephrotic Syndrome[2] (carrier rate of around 2%) and Tufting Enteropathy[3] (carrier rate 2%0. At the moment, these tests are not being offered due to a lack of personnel in the laboratory. It is hoped that within the next two years these tests shall be included in the list of genetic tests offered to couples undergoing IVF.

It might also be pertinent to note that these tests should also be offered to couples undergoing any other ART procedures.

[2] Defined by the presence of heavy albuminuria, hypoalbuminemia and oedema. It is classified as congenital if it presents at birth or appears during the first months of life.

[3] Is a rare genetic disease of the intestine that causes severe diarrhoea and an inability to absorb nutrients

XI Clinical Activities

The ART clinic activities listed below are coordinated by the Lead clinician, the nurses and midwives with the help of the clerk and carer at the clinic. The coordination of the clinic consists of the scheduling of appointments, preparation of files as at the Art Clinic patients have personal files apart from their personal files at MDH. Each file has to be adapted according to the type of clinic appointment they have.

Table 21 – Clinical Activity Period Number of patients New cases January –December 2019 216 Follow up cases January –December2019 193 Consents for IVF March – December 2019 383 IVF cycle patients seen March – December 2019 796 Bloodletting for IVF & Genetics January –December 2019 1267 Referral/introduction with nurse/midwife January –December 2019 287 Follicle tracking done February –December 2019 1239 HYCOSI April – December 2019 49 3D Ultrasound May –December 2019 67 Genetic clinic January – December 2019 389 Oncology Female oocyte retrieval January – December 2019 2 Oncology Males sperm banking January – December 2019 14 Pregnancies January – December 2019 19 Miscarriages January – December 2019 6 Telephone calls in/out January – December 2019 Average of 25 per day

Appointments for the above, clinics are done on daily basis and patients are called on individual basis by the member of nursing /midwifery staff responsible for the different clinics. This also includes the continuous calling of patients who are ready to start their IVF procedures according to the list compiled by the Prioritisation committee. This entails a substantial amount of time and is very time consuming.

ART clinic nursing /midwifery staff assists the medical staff in the daily clinics, with 4 clinics running at one go on daily basis. Apart from the clinical activities, ART includes as well theatre procedures for oocyte retrievals and Embryo Transfers which are scheduled on daily basis at the operating theatre at MDH. The nursing/midwifery staff prepares and assist the medical team at the operating theatre during these procedures. During the IVF procedures nurses/midwives prepare patients for theatre and assist patients

27 during the postoperative recovery period till the patients are ready to be discharged home on the same day. Moreover the staff, in the absence of the care worker accompanies the male partners to and from the comfort room to the laboratory during the IVF procedures and even when males are referred for sperm banking. In addition the ART clinic coordinates the TESE male operations with the operating theatre and assists in the theatre during these procedures.

The clerk at the ART clinic has the responsibility of inputting and updating data, receiving clients at reception, inputting all appointments and helps all that is needed with clerical work, filing and answering telephone calls.

The care worker has the responsibility of keeping all clinics clean and updated for clinical use, the accompanying of males to and from comfort room to laboratory and all that is needed for the smooth running of the clinic. The carer is responsible also for the compiling of new files.

Regular weekly meetings are held with all the Clinicians, nursing staff, embryologists, Responsible Person, counsellor to discuss ART cases and other important issues related to the clinical practices.

XII License holder activities

The Licence holder in liaison with the Chief Medical Officer (CMO), the Clinical Chairperson (Obstetrics & Gynaecology) , the Responsible Person and Senior Manager (QA) contributes to the provision of services and assurance of quality and safety and assists in maintaining a Quality System. Additional duties include:  Cross checking the data and inputting the data in the system  Creating and filing IVF files  Preventive and Corrective maintenance of the equipment  Contributing to the TPA with foreign tissue establishments  Ordering and delivering of goods including media, consumables and gases  Reporting to authority

XIII Biovigilance and Surveillance

Adverse events can be detected at any stage in the process from donation/collection of sperm and oocytes to transfer of embryos. Directive 2004/23/EC defines Serious Adverse Event in terms of the potential to cause a Serious Adverse Reaction . Seriousness might relate to potential severity of an adverse reaction if the event had not been discovered or to the severity of an adverse reaction that might occur due to a repetition of the event in another place or time.

Serious adverse event and reactions (SARE) reporting and management are incorporated within the ART Clinic’s Quality Management System, with standard operating procedures and form that describe the process for acknowledgment of notifications, investigation, implementation and follow up on corrective and preventive actions and reporting to the Authorities. The procedures include the management of SARE detected within the art Clinic itself. The procedure enables rapid action to be taken by the ART Clinic to protect the safety of prospective parents of embryos. This may involve gametes or Embryos quarantine and look-back in patients who have already had transfer of embryos.

When it is not possible to confirm imputability, ART Clinic always takes preventive measures on the basis of the Precautionary Principle. No Serious adverse event and reactions occurred in 2019.

XIV Challenges and Limitations

The year 2019, was a very challenging year for the ART Clinic- MDH Team, characterized by several major changes brought about by the implementation of amendments in The Embryo Protection Act (Cap 524), mainly; restructuring of premises; widening of the entitlement criteria, extension of services with the introduction of Intra Uterine Insemination, Embryo culture up to blastocyst stage, embryo cryopreservation, follicle tracking, dummy runs, introduction of new equipment, refurbishment of laboratories, introduction of sperm donation by known donors and continuous programme – centred on the clinical needs of each patient not in batches as was previously provided.

The results obtained show improvement on all aspects mainly quality, effectiveness and capacity and while this encourages us to persevere, it presents the challenge to maintain the standards achieved and aspire to raise the bar. We look ahead to 2020, with two major projects in the pipeline, the introduction of sperm and oocyte donation from unknown donors. These services are highly regulated and demand significant preparation in terms of interpretation of the regulating legislation and ensuring that quality, safety, legal and ethical requirements are met. The Work for sperm donation from unknown donors are

29 at a concluding stage. Work for oocyte donation by unknown donors is underway, this is more challenging than sperm donation due to the limited availability of such products.

On the downside the continuous programme and extended services have put a tremendous strain on our human resources, since the number of embryologist, midwives, nurses, administrative and support staff is not sufficient to meet the envisaged increase in demand. This has critical implications and pose the risk of failure to deliver the expected service to our patients or worse risk of error. The issue was brought to the attention of the authorities and efforts are being made to address this matter, however the centralised system does not support our cause in a timely manner.

The continuous programme which is beneficial to the patient, along with the introduction of IUIs, Follicle tracking of both patients undergoing IVF and those referred from Obstetrics and Gynae, HYCOSI and 3 D ultrasound clinics, on top of the previous activities, demand that clinic sessions and theatre sessions are held concurrently on same days, meaning that midwives and nurses are needed on both sites. Whereas before, clinics and theatre sessions were held on separate weeks within one cycle. Hence the need to increase head count, because since all patients are being stimulated at different times according to their clinical needs, availability of sufficient staff has to be guaranteed at all times.

The trainee embryologist who was also performing duties of a laboratory manager asked for transfer to another department. To date this vacancy has not been filled. Requests for, a laboratory manager to fill this vacancy and another embryologist, have been made to the authorities. Moreover In 2019 three senior nurses left ART clinic, 1 left the service in March, 1 was deployed to another unit as Deputy Charge Nurse in May, and 1 retired in September. As a replacement one midwife joined the team in January 2019 and 2 nurses in May. An additional midwife joined in October 2019. As expected these new recruits needed induction training on ART. This proved to be quite a challenge because apart from having to train the new recruits, staff members were adapting to the provision of continuous programme.

Relievers from the Obstetric pool are sent to compliment the staff, however this service is not sufficient because relievers are not trained in ART treatment and secondly because availability is unsystematic, resulting in working on skeleton staff, most of the time, especially when staff is on vacation leave or sick leave, which is not commendable. Moreover, due to lack of both nursing and medical staff, when there are long sessions in the theatre, the clinics start later in the morning, with patients complaining of longer waiting hours. All staff involved does their utmost to keep the clinic in a smooth running process to achieve the expected results.

The premises at the ART clinic is also a limitation for the service. The space for clinics is limited, with no offices for the Consultants and the Midwife in charge. The present office of the Midwife in charge of the unit, is used for office work, meeting room for all the team and as a dining area. The waiting area as well has much to be desired. Patients who come to ART are very sensitive on data protection, especially if they are staff members of MDH. The waiting area is the corridor for changing rooms for staff, therefore it is very difficult for couples to keep confidentiality with people going in and out of the area.

Data Processing is managed by a semi manual system which is robust but labour intensive. Measures to address this issue are being discussed with Licence Holder especially in view of the widening of our activities.

Finally there is a significant need for regular staff training. Members of the team attended the 28th World Congress on Controversies in Obstetrics Gynaecology and Infertility (COGI) in November 2019, this was a very positive experience and the one of the Department’s challenges is to provide the whole team with frequent updates and training and work experiences in peer clinics abroad.

With its limitations the ART clinic team strives to provide the best quality of care and takes on challenges to provide best practices.