Cohort Study Of Cancer Incidence And Mortality Amongst Women Treated For Subfertility

Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.

Objective for processing

[1 paragraph unchanged] “Cancer Cancer Incidence and Mortality in Women Treated for Subfertility.” Subfertility. The University of Oxford hold NHS England data that was supplied by predecessor service providers up until 2013. Due to the closure of the University of Oxford's Childhood Cancer Research Group (CCRG) in March 2014, the processing was never completed on the data received. The data has since been securely held and not processed due to not having a legal basis to do so. The University of Oxford have now gained support under section 251 of the NHS Act 2006 giving a legal basis in place to access process and analyse the data. The research team have determined that there is sufficient value in completing the study, with analysis of complete follow up to the end of cancer registration year 2012 (by March 2013) rather than extending follow up to more recent data. The following is a summary of the aims of the research project provided by University of Oxford: The following is a summary of the aims of the research project provided by the University of Oxford: Subfertility, defined as a reduced level of fertility characterized by unusually long time to conception, affects a significant proportion of women globally. In the UK, many women sought medical assistance for subfertility during the 1970s and 1980s, a period before the widespread use of modern Assisted Reproductive Technologies (ART) like In Vitro Fertilisation (IVF). Treatments during this era included hormonal therapies and surgical interventions, some of which are still in use today. However, long-term data on the health outcomes of women who underwent these treatments have been limited, especially regarding risks of cancer and overall mortality. "The study will use historical NHS hospital medical record data, already extracted for about 7000 subfertile women and linked to their vital event records at the National Health Service Central Registers (NHSCR), but without their individual consent (following regulatory advice in place at the time). This research study has CAG section 251 support. The following are the aims of the research project: There were 2 main data sources from which the cohort was identified. The most important were the computerised maternity datasets covering (at the time of the study's conduct) deliveries from 1973-89 in Oxfordshire/West Berkshire, on which a history of prior infertility (treatment) was coded as such. The other source was the paper copy of the infertility clinic booking records in the two health districts, from about 1970 to 1990, when we started preparations for assembling the cohort. Those women who were investigated/treated/delivered in the late 1980s, who appeared to have undergone some form of ART around that time, were effectively not included in our cohort because we did not further seek to inspect their records. The oldest woman recruited to the cohort was born around 1930 and was probably identified from the infertility clinic booking records. They would have been about 83 if still alive in 2013 when our follow up ended. In a large sample of the women, of the women's records we inspected 20 years ago, the median age at resolution of the women's (first) infertility episode in the period 1970-1990 was about 31.5 years. - Assess long-term cancer and mortality risks in women treated for subfertility between 1970 and 1990 in Oxfordshire and West Berkshire. The study’s main purpose is to assess whether the particular reproductive history and/or treatments experienced by this Oxford-based cohort affected some of their cancer and mortality risks. The women experienced difficulties in conceiving in the 1970s/1980s for a wide range of reasons, and were often treated successfully with the drug regimes used to aid conception at the time. Although this period preceded the advent of widespread use of Assisted Reproductive Technology (ART) from the 1990s onwards, the medical conditions underlying problems with conceiving have little changed and the drug regimes used to stimulate egg production in subfertile women, are still in active use so the results of the study would still be relevant to current ART practice. - Determine whether reproductive history and fertility treatments used in the pre-ART era influenced cancer and mortality outcomes. The Oxford-based cohort study that the Research Team wish to resume is similar in design to two earlier studies, which were conducted in London, but has some important advantages. It is larger, with more cancer cases accruing during more complete follow-up to 2013. It is at least as representative of the general population of subfertile women seeking help to conceive than the previous two studies. Our definition of subfertility was failure to conceive despite adequate attempts to do so within one year when menstrual history was within normal limits, or within six months if there was substantial menstrual irregularity. It also has more detailed information about the subfertility diagnoses (including for a subgroup who, though perhaps investigated and treated, did not satisfy the study’s criteria for being considered subfertile) and contains more detail about a wider range of treatment regimes used over the pre-ART period to 1990 (including a subgroup who conceived during the process of subfertility investigations only, without any treatment at all). Some subfertile women in the Oxford cohort also failed to conceive or deliver a term pregnancy, despite investigation and treatment. - Evaluate the safety and long-term effects of drug regimes used to stimulate egg production, many of which are still in use today. Perhaps most importantly the present study has more complete and longer term follow-up to older ages, when most cancer cases occur than the other two studies. All women in the Oxford cohort were followed up for vital events until 2013 from the time of their subfertility episode. That means a minimum of nearly 25 years cancer surveillance (to a time by which the national cancer registration process had been optimised and was considered very complete) for those of the 7000 most recently investigated/treated before 1990. The drug treatments used in the 1970s/1980s to aid conception are still in use today worldwide, including as part of some ART regimes. There remains considerable uncertainty about whether the cancer risks observed in some studies of subfertile women are a consequence of some of the medical conditions underlying the difficulties in conception and/or some of the range of treatments used. Analysing the present study’s data would meaningfully contribute to this debate." - Compare cancer/mortality experiences across subgroups defined by different causes of subfertility and treatment combinations. The following NHS England data, which is already held the University of Oxford, will be accessed: - Investigate whether pregnancies resulting from subfertility treatment offer similar protective effects against certain cancers as naturally conceived pregnancies. • Civil Registration Mortality - Analyse characteristics of babies conceived, including: Twinning occurrence, Secondary sex ratio at birth and Birthweights • Cancer Registration The following NHS England Data will be accessed: • Demographics - Cancer Registrations Data - Necessary because it provides detailed information on cancer diagnoses, including type, site, and timing, which is essential for assessing long-term cancer risks among women treated for subfertility. The data is necessary to compare the cancer/mortality experiences of groups within the Oxford cohort defined by different subfertility causes/treatment combinations. - Civil Registrations of Death - Necessary to evaluate overall and cause-specific mortality, helping to determine whether subfertility treatment is associated with increased or decreased risk of death. The level of the data obtained was: - Demographics - Necessary because it enables accurate linkage of historical patient records to national datasets, ensuring correct identification and follow-up of individuals in the cohort. • Identifiable – necessary because although the University of Oxford will pseudonymise the data before analysis, this data was collected in paper format during 1970 -1990 and then computerised, as this data has never been processed before initial checks and cleaning was never done. Identifiers will be removed and a data destruction certificate will have to be provided to NHS England once the data has been pseudonymised. The level of the Data will be: The Historic data was minimised to the following: - Identifiable – necessary because although the University of Oxford will pseudonymise the data before analysis, this data was collected in paper format during 1970 -1990 and then computerised, as this data has never been processed before initial checks and cleaning was never done. Identifiers will be removed and a data destruction certificate will have to be provided to NHS England once the data has been pseudonymised. Limited to a study cohort identified by University of Oxford, of women of reproductive age experiencing a period of subfertility between 1970-90, approximately 7000 women who had successful fertility treatment up to and including data till 2013, within the Oxfordshire and West Berkshire (Ox/WB) area. Data for Cancer was supplied from 1971 and data for deaths was supplied from the mid 1970’s. The Data will be minimised as follows: - Limited to a study cohort of approximately 7,000 women who experienced subfertility between 1970 and 1990 in Oxfordshire and West Berkshire. [2 paragraphs unchanged] Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller. controller; [3 paragraphs unchanged] The funding is provided by Nuffield Department of Women’s and Reproductive Health (NDWRH) in at the University of Oxford. The funding is specifically for the study described. Funding is in place until completion. The funding is specifically for the study described. Funding is in place until completion. Data will be accessed by Individuals holding an honorary contract under the supervision of a substantive employee of University of Oxford for the purposes described in this DSA only. There are two Honorary Researchers at the University of Oxford (Nuffield Department of Women and Reproductive Health NDWRH) who will be working with the data held under this Data Sharing Agreement (DSA), both of whom were previously employed by the University of Oxford, but have now retired. Both previously worked on this study. They have completed the relevant data protection and confidentiality training required and are subject to the University of Oxfords policies on data protection and confidentiality. University of Oxford (NDWRH) would be responsible and liable for any work carried out by the researchers . They will only be working on the data for the purposes described in this DSA. University of Oxford must maintain records in a single location that cover the following details of each individual given access under an honorary contract: A Public and Patient Involvement and Engagement group helped refine the purpose of the research. The group supported the collection of the data for the purposes described above. - Their substantive employer; Patient and Public Involvement work have been undertaken with 9 women aged between 22-74 years, but most were aged between 60 and 74. The group appeared as representative of the cohort as possible. Valuable insights have been gleaned from these interviews, and the women agreed that they were supportive of the use of confidential patient information without consent for the purposes of this DSA. The women also provided feedback on the notification content and method. - Their role in respect of the purpose for the processing specified in the DSA; - The start date and end date of the duration in which the Data will be accessed by the individual under an honorary contract; - The necessity for the Data to be accessed by the person(s) holding an honorary contract, instead of a substantive employee of an organisation named as controller or a processor in this DSA; - Confirmation that an appropriate contract is in place which follows the relevant guidance and is countersigned by the substantive employer of the honorary contract holder. Members of the public played a meaningful role in shaping the design and ethical framework of the research project. A dedicated Public and Patient Involvement and Engagement (PPIE) group was formed, consisting of nine women aged between 22 and 74, with most participants aged 60–74. These individuals were selected to reflect the demographic characteristics of the study cohort. Their involvement ensured that the research was grounded in public interest and aligned with the values and concerns of those potentially affected by the study. The PPIE group contributed by reviewing the study’s aims, supporting the use of confidential patient data without individual consent, and providing feedback on how the research should be communicated to the public. Their input helped refine the notification materials and methods, ensuring transparency and sensitivity in public engagement.

Processing activities

There will be no data flowing to the University of Oxford and no will transfer data to NHS England. The data will flow consist of identifying details (specifically NHS Number, Date of Birth, Gender, Forenames, Surnames, Hospital Numbers and a unique person ID) for the cohort to be linked with NHS England for the purposes of this DSA. This DSA is to allow the processing and retention of the data previously flowed. data. The University of Oxford will securely upload the computerised cohort data from NDWRH servers to the Medical Sciences Division (MSD) High Compliance Facility (HCF). NHS England will provide the relevant records from the Cancer Registrations Data, Civil Registrations of Death, and Demographics datasets to University of Oxford. The Health and Social Care Information Centre and predecessor service providers previously provided the relevant records from the Demographics, Cancer Registrations and Civil Registration Mortality datasets to the Childhood Cancer research Group (CCRG) (University of Oxford). The Data will contain directly identifying data items including Names, NHS Number, Date of Birth, Gender, Hospital Numbers and Unique study numbers. The data contained directly identifying information which was used for linkage of the cohort to vital event records and have been retained because they would be needed in order to modify the records of some women in the cohort (in order to make them as accurate and complete as possible before further processing and pseudonymisation), these data are: 1. Women’s’ forenames (and initials), 2. Women’s’ surnames at birth and subsequently, 3. Women’s’ dates of birth 4. Gender 5. NHS numbers 6. Hospital numbers 7. Unique study numbers 8. Data received up until 2013: a. Cancer Registration data b. Mortality records c. Records of embarkation, exit/re-entry to the NHS, and current NHS posting at 2013. After correction of any record errors University of Oxford have identified, the computerised dataset will be pseudonymised, with removal of all names, NHS/Hospital/ Unique study numbers and contraction of all dates to at least month and year. Only then will the nominated members of the Research Team proceed to analyse the pseudonymised dataset. [2 paragraphs unchanged] The data Data will be accessed by authorised personnel via remote access. The data will remain on the servers at the University of Oxford at all times. The Controller(s) University of Oxford must confirm and provide evidence upon audit by NHS England that access [7 words unchanged] data security obligations within this DSA and the Data Sharing Framework Contract. [2 paragraphs unchanged] - Personnel are both prohibited and technically prevented from downloading or copying NHSE data to local devices; [4 paragraphs unchanged] - All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this agreement) DSA) and complies with the organisation’s remote access policy. [1 paragraph unchanged] The data will not leave England at any time. Remote processing will be from secure locations within England and Wales. Access is restricted to individuals within the Nuffield Department of Women & Reproductive Health at The University of Oxford. The Data will not leave England and Wales at any time. Data will be accessed by individuals with an honorary contract with the Nuffield Department of Women & Reproductive Health at the University of Oxford. The individual(s) will act as an agent of University of Oxford at all times under supervision from employees of University of Oxford. Aside from these individuals, access is restricted to employees of University of Oxford who have authorisation from the Principal Investigator. [1 paragraph unchanged] The data that the Research Team have received up to 2013, and would now like to analyse, will have all identifying information about the 7000 individual women removed. No new data have been collected since then, and will not be. There will be no further data exchanges in either direction between the University of Oxford and NHS England. The Data will be linked at person record level with computerised datasets obtained by University of Oxford. All the identifiers that were originally used to link the individual hospital clinical record data that were extracted onto case record forms (CRFs), to the women’s subsequent vital event data will be removed before analysis and All the identifiers that were originally used to link the individual hospital clinical record data that were extracted onto case record forms (CRFs), to the women’s subsequent vital event data will be removed before analysis and eventual anonymised publication. eventual anonymised publication. The information received until 2013 was imported into a database held securely by the University of Oxford. There will be no requirement and no attempt to reidentify individuals when using the Data. Until the process of pseudonymisation is complete at the end of 2024 (expected date only), if any woman enrolled in the cohort would like to have their data withdrawn, the Research Team will remove their data from the linked dataset. However no attempt will be made to contact the 7000 women in the cohort individually, not only because of the scale of effort/difficulty involved but also because that attempt itself might be considered a breach of confidentiality as the team do not have the permissions to contact the individuals directly. Posters and news articles will be published to advise the public of the current study purpose, which include guidance on how to opt out of the research if their data is included. [1 paragraph unchanged]

Expected output

University of Oxford anticipate anticipates that upon completion of the data processing, record correction, pseudonymisation pseudonymisation, and analysis, that the expected outputs of the processing will be: - Produce a A brief report about summarising the study’s main findings will be produced for distribution to the nine women who volunteered their time and effort to help support the chief Chief Investigator achieve some degree of in achieving Patient and Public Involvement (PPI) about regarding the continued holding and use of hospital records/vital records and vital event follow-up data without consent. consent - A version of this report will likely is expected to be distributed to the 2500 strong membership 2,500 members of the SilverStar charity (some charity—some of whose members helped whom contributed directly with to the PPI) through PPI—via the annual newsletter that is produced newsletter, typically published towards the end of each year. The University 2023 edition of Oxford the newsletter will use the 2023 newsletter, which is due to be published later in 2023, used to publicise the approach being taken to complete the study. - University of Oxford anticipate producing journal Journal publications about are anticipated, focusing on cancer incidence in within the cohort of women in relation to the causes of their subfertility and the treatments they received, and about as well as on the causes of deaths which occurred amongst death among the women. - University of Oxford also anticipate making at At least one report about some of the is expected to be produced on birth characteristics at birth of the babies conceived, specifically examining the women conceived, in particular the effect impact of subfertility medical treatments on: Twinning occurrence; Secondary on twinning occurrence, secondary sex ratio at birth; Birthweights of the babies conceived. birth, and birthweights. - University of Oxford anticipate presentation Presentation of these results is anticipated at internal seminars within the University of Oxford, in particular particularly within their the host department (NDWRH). They do not anticipate conference attendance Attendance or presentations presentation at conferences outside the UK. UK is not expected. [7 paragraphs unchanged]

Benefits reported

The NHS England data previously disseminated has never been processed or analysed so there are no yielded benefits to date. Building on earlier work involving the extraction of clinical infertility (treatment) and maternity information to assemble the initial cohort of women and the babies delivered, the process of further cleaning this information regarding exposures around the time of pregnancies has commenced. Finalisation and analysis of the effects of these exposures on baby outcomes remain ongoing, with completion expected in the coming months. The NHS England data previously supplied concerning cancer and mortality outcomes in the women has not yet been processed or analysed, but this is anticipated to begin shortly. As a result, no direct benefits have been yielded to date. Publicly available national data for England, Wales, and Scotland has been analysed to provide contextual background information and reference rates for evaluating local cohort baby outcomes. This analysis offers valuable insights into trends in these outcomes, relevant to the study and not previously available in the public domain, building on a prior publication from the cohort in 2006.

Unchanged: Expected measurable benefits.

Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.

Datasets: + Cancer Registration Data; + Civil Registrations of Death; + Demographics · − MRIS - Personal Demographics Service

Objective for processing

This Data Sharing Agreement permits the retention of the data provided under previous iterations of this Agreement but no further processing, for an interim period. This is a pragmatic approach to provide an active Agreement whilst enabling the University of Oxford to complete the necessary actions to enable a subsequent application to extend the Agreement meeting all applicable data sharing standards as published in NHS Digital’s website (see: https://digital.nhs.uk/services/data-access-request-service-dars/dars-guidance). The University of Oxford requires access to NHS England data for the purpose of the following research project: The data supplied by NHS Digital to Childhood Cancer Research Group will be used only for the approved Medical Research Project. “Cancer Incidence and Mortality in Women Treated for Subfertility.” The University of Oxford hold NHS England data that was supplied by predecessor service providers up until 2013. Due to the closure of the University of Oxford's Childhood Cancer Research Group (CCRG) in March 2014, the processing was never completed on the data received. The data has since been securely held and not processed due to not having a legal basis to do so. The University of Oxford have now gained support under section 251 of the NHS Act 2006 giving a legal basis in place to access process and analyse the data. The research team have determined that there is sufficient value in completing the study, with analysis of complete follow up to the end of cancer registration year 2012 (by March 2013) rather than extending follow up to more recent data. The following is a summary of the aims of the research project provided by the University of Oxford: "The study will use historical NHS hospital medical record data, already extracted for about 7000 subfertile women and linked to their vital event records at the National Health Service Central Registers (NHSCR), but without their individual consent (following regulatory advice in place at the time). This research study has CAG section 251 support. There were 2 main data sources from which the cohort was identified. The most important were the computerised maternity datasets covering (at the time of the study's conduct) deliveries from 1973-89 in Oxfordshire/West Berkshire, on which a history of prior infertility (treatment) was coded as such. The other source was the paper copy of the infertility clinic booking records in the two health districts, from about 1970 to 1990, when we started preparations for assembling the cohort. Those women who were investigated/treated/delivered in the late 1980s, who appeared to have undergone some form of ART around that time, were effectively not included in our cohort because we did not further seek to inspect their records. The oldest woman recruited to the cohort was born around 1930 and was probably identified from the infertility clinic booking records. They would have been about 83 if still alive in 2013 when our follow up ended. In a large sample of the women, of the women's records we inspected 20 years ago, the median age at resolution of the women's (first) infertility episode in the period 1970-1990 was about 31.5 years. The study’s main purpose is to assess whether the particular reproductive history and/or treatments experienced by this Oxford-based cohort affected some of their cancer and mortality risks. The women experienced difficulties in conceiving in the 1970s/1980s for a wide range of reasons, and were often treated successfully with the drug regimes used to aid conception at the time. Although this period preceded the advent of widespread use of Assisted Reproductive Technology (ART) from the 1990s onwards, the medical conditions underlying problems with conceiving have little changed and the drug regimes used to stimulate egg production in subfertile women, are still in active use so the results of the study would still be relevant to current ART practice. The Oxford-based cohort study that the Research Team wish to resume is similar in design to two earlier studies, which were conducted in London, but has some important advantages. It is larger, with more cancer cases accruing during more complete follow-up to 2013. It is at least as representative of the general population of subfertile women seeking help to conceive than the previous two studies. Our definition of subfertility was failure to conceive despite adequate attempts to do so within one year when menstrual history was within normal limits, or within six months if there was substantial menstrual irregularity. It also has more detailed information about the subfertility diagnoses (including for a subgroup who, though perhaps investigated and treated, did not satisfy the study’s criteria for being considered subfertile) and contains more detail about a wider range of treatment regimes used over the pre-ART period to 1990 (including a subgroup who conceived during the process of subfertility investigations only, without any treatment at all). Some subfertile women in the Oxford cohort also failed to conceive or deliver a term pregnancy, despite investigation and treatment. Perhaps most importantly the present study has more complete and longer term follow-up to older ages, when most cancer cases occur than the other two studies. All women in the Oxford cohort were followed up for vital events until 2013 from the time of their subfertility episode. That means a minimum of nearly 25 years cancer surveillance (to a time by which the national cancer registration process had been optimised and was considered very complete) for those of the 7000 most recently investigated/treated before 1990. The drug treatments used in the 1970s/1980s to aid conception are still in use today worldwide, including as part of some ART regimes. There remains considerable uncertainty about whether the cancer risks observed in some studies of subfertile women are a consequence of some of the medical conditions underlying the difficulties in conception and/or some of the range of treatments used. Analysing the present study’s data would meaningfully contribute to this debate." The following NHS England data, which is already held the University of Oxford, will be accessed: • Civil Registration Mortality • Cancer Registration • Demographics The data is necessary to compare the cancer/mortality experiences of groups within the Oxford cohort defined by different subfertility causes/treatment combinations. The level of the data obtained was: • Identifiable – necessary because although the University of Oxford will pseudonymise the data before analysis, this data was collected in paper format during 1970 -1990 and then computerised, as this data has never been processed before initial checks and cleaning was never done. Identifiers will be removed and a data destruction certificate will have to be provided to NHS England once the data has been pseudonymised. The Historic data was minimised to the following: Limited to a study cohort identified by University of Oxford, of women of reproductive age experiencing a period of subfertility between 1970-90, approximately 7000 women who had successful fertility treatment up to and including data till 2013, within the Oxfordshire and West Berkshire (Ox/WB) area. Data for Cancer was supplied from 1971 and data for deaths was supplied from the mid 1970’s. University of Oxford is the research sponsor and the controller as the organisation responsible for ensuring that the data will only be processed for the purpose described above. The lawful basis for processing personal data under the UK GDPR is: Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller. The lawful basis for processing special category data under the UK GDPR is: Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. This processing is in the public interest because it adheres to the UK Policy Framework for Health and Social Care Research, which protects and promotes the interests of patients, service users and the public, and aims to produce generalisable and publicly available information to inform future decisions over patients’ treatments or care. The funding is provided by Nuffield Department of Women’s and Reproductive Health (NDWRH) in the University of Oxford. The funding is specifically for the study described. Funding is in place until completion. There are two Honorary Researchers at the University of Oxford (Nuffield Department of Women and Reproductive Health NDWRH) who will be working with the data held under this Data Sharing Agreement (DSA), both of whom were previously employed by the University of Oxford, but have now retired. Both previously worked on this study. They have completed the relevant data protection and confidentiality training required and are subject to the University of Oxfords policies on data protection and confidentiality. University of Oxford (NDWRH) would be responsible and liable for any work carried out by the researchers . They will only be working on the data for the purposes described in this DSA. A Public and Patient Involvement and Engagement group helped refine the purpose of the research. The group supported the collection of the data for the purposes described above. Patient and Public Involvement work have been undertaken with 9 women aged between 22-74 years, but most were aged between 60 and 74. The group appeared as representative of the cohort as possible. Valuable insights have been gleaned from these interviews, and the women agreed that they were supportive of the use of confidential patient information without consent for the purposes of this DSA. The women also provided feedback on the notification content and method.

Processing activities

Under this Agreement, the data may be securely stored but not otherwise processed. No new data will be provided by NHS Digital under this Agreement. There will be no data flowing to the University of Oxford and no data will flow to NHS England for the purposes of this DSA. This DSA is to allow the processing and retention of the data previously flowed. The University of Oxford will securely upload the computerised cohort data from NDWRH servers to the Medical Sciences Division (MSD) High Compliance Facility (HCF). The Health and Social Care Information Centre and predecessor service providers previously provided the relevant records from the Demographics, Cancer Registrations and Civil Registration Mortality datasets to the Childhood Cancer research Group (CCRG) (University of Oxford). The data contained directly identifying information which was used for linkage of the cohort to vital event records and have been retained because they would be needed in order to modify the records of some women in the cohort (in order to make them as accurate and complete as possible before further processing and pseudonymisation), these data are: 1. Women’s’ forenames (and initials), 2. Women’s’ surnames at birth and subsequently, 3. Women’s’ dates of birth 4. Gender 5. NHS numbers 6. Hospital numbers 7. Unique study numbers 8. Data received up until 2013: a. Cancer Registration data b. Mortality records c. Records of embarkation, exit/re-entry to the NHS, and current NHS posting at 2013. After correction of any record errors University of Oxford have identified, the computerised dataset will be pseudonymised, with removal of all names, NHS/Hospital/ Unique study numbers and contraction of all dates to at least month and year. Only then will the nominated members of the Research Team proceed to analyse the pseudonymised dataset. The data will not be transferred to any other location. The data is stored on servers at University of Oxford. The data will be accessed by authorised personnel via remote access. The data will remain on the servers at the University of Oxford at all times. The Controller(s) must confirm and provide evidence upon audit by NHS England that access via any remote device complies with the data security obligations within this DSA and the Data Sharing Framework Contract. For remote access: - Remote access will only be from secure locations situated within the territory of use (as further restricted elsewhere within the DSA if so done) stated within this DSA; - Personnel are both prohibited and technically prevented from downloading or copying NHSE data to local devices; - Access controls granting users the minimum level of access required are in place; - Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data; - Multifactor authentication (MFA) is required for remote access; - Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access; - All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this agreement) and complies with the organisation’s remote access policy. The above applies in addition to any condition set out elsewhere within the DSA (e.g. who may carry out processing, and for what purpose). The data will not leave England at any time. Access is restricted to individuals within the Nuffield Department of Women & Reproductive Health at The University of Oxford. All personnel accessing the data have been appropriately trained in data protection and confidentiality. The data that the Research Team have received up to 2013, and would now like to analyse, will have all identifying information about the 7000 individual women removed. No new data have been collected since then, and will not be. There will be no further data exchanges in either direction between the University of Oxford and NHS England. All the identifiers that were originally used to link the individual hospital clinical record data that were extracted onto case record forms (CRFs), to the women’s subsequent vital event data will be removed before analysis and eventual anonymised publication. The information received until 2013 was imported into a database held securely by the University of Oxford. Until the process of pseudonymisation is complete at the end of 2024 (expected date only), if any woman enrolled in the cohort would like to have their data withdrawn, the Research Team will remove their data from the linked dataset. However no attempt will be made to contact the 7000 women in the cohort individually, not only because of the scale of effort/difficulty involved but also because that attempt itself might be considered a breach of confidentiality as the team do not have the permissions to contact the individuals directly. Posters and news articles will be published to advise the public of the current study purpose, which include guidance on how to opt out of the research if their data is included. Researchers from the University of Oxford (Nuffield Department of Women & Reproductive Health) will process and analyse the data for the purposes described above.

Expected output

This Agreement permits the secure retention of the data only and no other processing. University of Oxford anticipate that upon completion of the data processing, record correction, pseudonymisation and analysis, that the expected outputs of the processing will be: No new outputs will be produced under this Data Sharing Agreement. - Produce a brief report about the study’s main findings for distribution to the nine women who volunteered their time and effort to help the chief Investigator achieve some degree of Patient and Public Involvement (PPI) about the continued holding and use of hospital records/vital event follow-up data without consent. In any future application, the applicant will be required to provide details of the outputs that were produced and disseminated by the study as well as details of any future outputs planned. - A version of this report will likely be distributed to the 2500 strong membership of the SilverStar charity (some of whose members helped directly with the PPI) through the annual newsletter that is produced towards the end of each year. The University of Oxford will use the 2023 newsletter, which is due to be published later in 2023, to publicise the approach being taken to complete the study. - University of Oxford anticipate producing journal publications about cancer incidence in the cohort of women in relation to the causes of their subfertility and the treatments they received, and about the causes of deaths which occurred amongst the women. - University of Oxford also anticipate making at least one report about some of the characteristics at birth of the babies the women conceived, in particular the effect of subfertility medical treatments on: Twinning occurrence; Secondary sex ratio at birth; Birthweights of the babies conceived. - University of Oxford anticipate presentation of these results at internal seminars within the University of Oxford, in particular within their host department (NDWRH). They do not anticipate conference attendance or presentations outside the UK. The outputs will not contain NHS England data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived. The outputs will be communicated to relevant recipients through the following dissemination channels: - Journals - University of Oxford Internal seminars - Targeted charity newsletters - Reports aimed at PPI and targeted charity Target dates for publishing/presentation of results would be 2024 onwards.

Expected measurable benefits

This Agreement permits the secure retention of the data only and no other processing. The findings of this research study are expected to contribute to evidence-based decision-making for policy-makers, local decision-makers such as doctors, and patients to inform best practice to improve the care, treatment and experience of health care users relevant to the subject matter of the study. In any future application, the applicant will be required to provide details of the expected benefits resulting from the study. The use of the data could: • help the system to better understand the health and care needs of populations. • lead to the identification or improvement of treatments or interventions, or health and care system design to improve health and care outcomes or experience. • support knowledge creation or exploratory research (and the innovations and developments that might result from that exploratory work). University of Oxford anticipate that analysis of the cohort data will add to existing knowledge about some cancer risks that may be influenced by medical conditions underlying difficulties in conception and treatments for it, some of which are still in use today. University of Oxford expect to find evidence that a pregnancy resulting from subfertility treatment confers the same degree of protection against some adult female cancers as does a naturally conceived pregnancy. A particular benefit from analysing the cohort study maybe that it features very long-term follow up of all the women enrolled in the cohort, to ages when cancer risks rise steeply. Although ART is now generally the most popular method of aiding conception amongst the subfertile, long term follow up to older ages of large numbers of women has not been easily possible so far, because ART has only been in widespread use since the 1990s. The study should help to clarify what cancer risks exist at older ages for the women who were helped to conceive in the 1970s/1980s. There may also be a benefit from the study in clarifying whether drug doses or the duration of treatment before conception are linked to the likelihood of multiple ovulations and multiple births. The changes in the rates of multiple births worldwide are almost certainly influenced by subfertility treatment, even though the natural multiple birth rate may have declined over the last 50 years. There exists a tension in clinical practice between limiting the potential hazards associated with a multiple birth while nonetheless maintaining ovulation induction/conception success rates. Similarly, a possible benefit from analysing characteristics of the babies the women in the cohort conceived may help to clarify whether the Secondary Sex Ratio at birth is influenced by the drug treatments used in both past and present clinical practice. It is hoped that through publication of findings in appropriate media, the findings of this research will add to the body of evidence that is considered by the bodies, organisations and individual care practitioners charged with making policy decisions for or within the NHS or treatment decisions in relation to specific patients.

Benefits reported

In any future application, the applicant will be required to provide details of the actual benefits achieved as a result of the study. The NHS England data previously disseminated has never been processed or analysed so there are no yielded benefits to date.