eLIXIR, Born in South London- Early Lifecourse data Cross-Linkage in Research

The King’s Health Partners (KHP) Academic Health Sciences Centre - comprimised of Guys’ and St Thomas’ NHS Foundation Trust (GSTT), Kings College Hospital NHS Foundation Trust (KCH), South London, Maudsley NHS Foundation Trust (SLaM) and King’s College London (KCL) - requires access to NHS England data for the purpose of the following research programme:

eLIXIR, Born in South London- Early Lifecourse data Cross-Linkage in Research

The following is a summary of the aims of the research programme:

The KHP Academic Health Sciences Centre aims to develop a research registry of a UK inner-city deprived population which provides a continuous link between maternal and paediatric clinical and mental health data.

The data database is to be used for the purposes of medical research projects that receive approval from the eLIXIR Oversight Committee. The projects will be for the purpose of research into the following areas:

• Women’s Health: investigation of a) relationships between pre-pregnancy physical and mental health, common disorders of pregnancy and pregnancy outcomes; b) the long term consequences of maternal physical and mental health disorders during pregnancy for the mother’s health; c) the efficacy of interventions at the population level arising from Randomised Control Trials (RCTs) e.g. lifestyle, pharmacological, medical devices, diagnostics to improve maternal physical and/ or mental health in the short and longer term.

• Paediatrics: by enabling investigation of a) relationships between maternal physical and mental health disorders in pregnancy and longer term consequences of the physical and mental health of the child; b) relationships between adverse events and exposures in the fetal and neonatal period and the long term consequences for physical and mental health of the child; c) the efficacy of interventions at the population level to reduce the adverse impact of early life events and exposures on the child.

• Mental Health: by enabling investigation of a) interrelationships between physical and mental health disorders during pregnancy and pregnancy outcomes; b) relationships between maternal and childhood mental health; c) associations between mental and physical health in women and in children.

• Implementation Science and Public Health: by enabling evaluation of new pathways of care/ guideline recommendations to improve maternal and/ or child physical and/ or mental health and determination of associated health care costs.

• Scientists in Clinical Research; through methodological approaches including the study of the epigenome, the metabolome and the microbiome in pregnancy and the early postpartum period to determine the mechanistic bases for the above relationships and interactions.

Researchers or research organisations will make requests through a formal application process to use the samples and clinical data. For each individual study, an application will be submitted on an eLIXIR Biobank Research Request Form. Applications need to justify reasons and relevance for requesting all data sources including linked eLIXIR-HES or eLIXIR-COVID-19 Vaccination Status data.

The Oversight Committee will decide on the scientific merit of the study and review any potential overlap with existing agreements. Applications must be for bona fide research or for educational purposes.

The Oversight Committee will consist of 10-12 people including the Chief Investigator (CI) and at least two co-Principle Investigators (PIs), internal and external scientists (e.g. molecular biologist, geneticist, ‘omics expert), an internal and external statistician, an external obstetrician, paediatrician, biobank personnel, and a Patient and Public Involvement representative. At least 6 members need to be present to make the meetings quorate.

The committee will consider:

• whether the purpose is covered under the current ethical approvals or whether it will require an ethics amendment.

• whether the intended use of eLIXIR is feasible, realistic and appropriate, and whether it may potentially and unintentionally identify individuals, e.g. information about rare diseases or other data that may be available to the applicant.

• the quality of the planned research and the likely benefit of the research including its clinical relevance and significance to patients and improving care

The Oversight Committee will not support sole or partial commercial uses of patient data. Commercial companies’ involvement as partners in applications will be reviewed in line with the public interest, the Trust’s strategic objectives, information governance standards and commercial interests.

Published minutes from the oversite committee and a publicly accessible data release register of approved projects will be available on the eLIXIR website (https://www.kcl.ac.uk/research/elixir-1) updated biannually.

Under this Data Sharing Agreement (DSA), eligibility to apply for access to the Data provided by NHS England is restricted to:

• substantive employees of SLaM, GSTT, KCH or KCL

• students enrolled with KCL

• one individual employed by St. George’s University Hospital NHS Trust who has an honorary contract with SLaM

The eLIXIR team expect that a minimum of 5 projects per year would use the eLIXIR-HES and eLIXIR-COVID-19 Vaccination Status linkage with the numbers of interested projects to expand as awareness of this linkage becomes more widespread through presentations and publications.

Examples of how the eLIXIR-HES linkage will be used are listed below:

1. Long-term follow up of hypertensive disorders in pregnancy

Several studies have demonstrated that women who experience a hypertensive disorder of pregnancy are at increased risk of cardiovascular disorders in later life including hypertension, ischaemic heart disease and stroke. In addition, a recent study has demonstrated an increased risk of chronic renal disease following history of pre-eclampsia. However, little data exists on which factors (maternal demographics, comorbidities, socioeconomic status, ethnicity, obstetric history, duration of hypertensive disorder, booking blood pressure, maximum blood pressure in pregnancy, and antihypertensive agent treatment) may aid risk stratification in women who have experienced a hypertensive disorder of pregnancy, to determine which women are at greatest risk of developing adverse cardiovascular and renal outcomes and in what timescale. Linkage of detailed maternal demographic, medical and obstetric information from the eLIXIR cohort with cardiovascular and renal diagnoses from Hospital Episode Statistics (HES) will enable detailed investigation of which factors predict adverse medium- and long-term outcomes in these women, enabling postnatal interventions to be targeted cost-efficiently to the women at highest risk.

2. GDM and risk of life-long metabolic and cardiovascular disease

Gestational diabetes (GDM) is increasing in line with upward trends in obesity. Other than the well-recognised associations with adverse outcomes in pregnancy, including macrosomia (oversized baby), stillbirth and complications in labour. GDM is associated with long term metabolic and cardiovascular morbidities in the mother, and increased risk of obesity and diabetes in the child. These associations have not been explored in our multi-ethnic high-risk population living in the Lambeth and Southwark boroughs of South London. The eLIXIR linkage between maternal and childhood clinical (primary and secondary care) records in Lambeth and Southwark will enable to some extent allow evaluation of these long-term complications. However, further linkage of the eLIXIR registry, primary care and HES records will provide complete coverage of relevant maternal morbidities (e.g. Type 2 Diabetes, cardiovascular) and childhood multi-morbidities (e.g. diabetes and non-alcoholic fatty liver disease (NAFLD)).

3. Maternal and perinatal mortality among BAME women

In the UK, deaths during pregnancy or shortly following birth are substantially increased among women and babies from Black, Asian and Minority Ethnic (BAME) backgrounds. Research is urgently needed to understand the specific factors affecting maternal and perinatal mortality and morbidity in different ethnic groups. This study aims to investigate differences in maternal and neonatal outcomes among women from different ethnic backgrounds and risk factors for any observed variation. Using linked data from electronic healthcare records (hospital admissions, maternity and mental health notes) we will explore pregnancy and birth outcomes among women from different ethnic backgrounds in South London. Findings will help inform future intervention strategies to reduce mortality and morbidity in BAME groups.

4. Infant admission to neonatal intensive care units (NICU) and maternal mental health outcomes

It is predicted that 10-20% of women experience mental health problems during the perinatal period. There is evidence to suggest that mental health problems during pregnancy, particularly depression, is associated with increased risk of preterm birth, low birth weight (LBW) and increased admission rates to NICU. Over 100,000 infants are admitted to NICU every year in the UK. Time spent in NICU exposes both the infant and their parents to a wide range of stressors. Infants are exposed to invasive clinical procedures, frequent handling and high levels of visual and auditory stimulation during their admission. Parents can experience psychological distress during infant admission to NICU, which can be associated with their infant’s appearance and irregular behaviour, concerns over their infant’s health and survival, as well as, anticipated financial burden and perceived loss of parental control. It is therefore unsurprising that mothers of infants admitted to NICU report higher rates of anxious and depressive symptoms compared to mothers of full-term and healthy infants. Using linked data from mental health and NICU services, we will explore the relationship between infant admission to NICU and maternal mental health problems within a diverse inner-city South London population. Subsequent findings from this research will help to inform potential care pathways for the mothers experiencing an infant’s admission to NICU.

5. Neonatal infection

Neonatal infection is a common presentation at admission to NICU. Without prompt antibiotic treatment, infection can lead to sepsis which accounts for over 1,500 deaths per day worldwide and 10% of all neonatal mortalities in the UK. Using the linked data between NICU and HES, we shall investigate longitudinal changes within a cohort of neonates admitted to NICU with sepsis. The use of Hospital Episode Statistics (HES), primary care records and access to full blood count specimens will enable detailed investigation in to identifying the onset of sepsis. Findings will help inform future intervention strategies to reduce mortality caused by sepsis.

An example of how the eLIXIR-COVID-19 Vaccination status linkage will be used is listed below:

1. Impact of COVID-19 related maternity care reconfiguration on vaccination uptake in pregnancy

The rapid roll-out of the COVID-19 vaccination programme has dramatically altered the trajectory of the pandemic and given considerable hope; however, we will continue to deal with the pandemic and its aftermath for the foreseeable future. For example, questions remain about lasting immunity after vaccination beyond six months, effectiveness against new variants, vaccination uptake, and whether annual vaccination (as for influenza) will be required. Substantial service reconfiguration was undertaken in Maternity services during the pandemic, in response to local infection rates and lockdown measures. While there were adverse pregnancy outcomes related to COVID-19 infection, there are indications of indirect effects on outcomes, good and bad.

Acceptance of COVID-19 vaccination by pregnant women has been suboptimal, as they were excluded from all vaccine trials, and are risk-averse, even when those risks are unlikely but unknown.

Moreover, acceptance of vaccination in the general community is not uniform, and is particularly low among Black, Asian and Minority Ethnic populations who are at heightened risk of severe infection. Guidance has changed rapidly, and the precautionary principle of needing evidence of no harm before recommending COVID-19 vaccination in pregnancy has weighed heavily in some recommendations.

Objectives include to study the impact of COVID-19 vaccination on maternity care quality, maternal and child health outcomes, and costs related to service provision and uptake; and how we can build back the system, post-pandemic to reduce inequalities in maternity care and COVID vaccination. Analysis will be conducted to ascertain if COVID-19 vaccination magnified or diminished existing inequalities in maternity care for minority ethnic group women or those living with social or medical complexity, including subfertility or mental health.

The following NHS England Data will be accessed:

• The HES Admitted Patient Care (APC) is required as delivery and birth records provide a good account of a maternity episode. When these records are coupled to general inpatient episodes it provides: -

a) A clear picture of pre-existing clinical risk factors for adverse pregnancy outcomes.

b) A picture of the long-term post-delivery health trajectories of the mother and infant. In addition, some fields such as parity, are badly reported by some NHS Trusts.

Having a long run of HES APC data is thus crucial in the estimation of parity using historical data. In addition, it is also frequently desirable to be able to see how indicators change with time so as to be able to assess data quality.

• HES Accident & Emergency (A&E), HES Critical Care and Emergency Care Data Set (ECDS) are required as records provide information on conditions both pre- and post-delivery that are not serious enough to warrant admission but never-the-less form an integral part of the whole medical picture.

It is important that researchers can be informed of woman’s previous pregnancy outcomes and underlying medical conditions which may complicate their pregnancy. The primary source for this information is the diagnosis and procedural codes found in both a woman’s past and present delivery records along with her non-delivery inpatient records and A&E attendances.

• COVID-19 Vaccination status are required as records will be used to study the impact of COVID-19 vaccination on maternity care quality, maternal and child health outcomes, and costs related to service provision and uptake; and how the system can be built back, post-pandemic to reduce inequalities in maternity care and COVID vaccination.

The level of the Data will be identifiable, required for the study team to link the eLIXIR Identifiers with patients who have received maternity or neonatal care and other record level data already held by the recipient.

The Data accessed for the purposes of medical research projects will be pseudonymised.

The Data will be minimised as follows:

• Limited to a study cohort identified by SLaM – SLaM Clinical Data Linkage Service (CDLS) create eLIXIR Identifiers Table which includes first name, last name, gender, date of birth, NHS number, postcode, and a unique pseudonymised eLIXIR ID (patient level anonym) for eLIXIR Programme patients who have received maternity or neonatal care at either GSTT or KCH NHS Trusts since October 2018.

• Cohort provided will include details for approximately 82,000 mothers and 45,000 babies.

• Limited to data beginning from October 1st 2018.

• Limited to records of all babies born between 2018 to latest available.

• Limited to patients who are female and have either an unknown Date of Birth or who are over the age of 16.

• Limited to the following geographic area - England.

GSTT, KCH, SLaM and KCL are the controllers as the organisations responsible for ensuring that the Data will only be processed for the purposes described above. Each act as data controller over the data they contribute to the eLIXIR database. The sponsor is King’s College London. The Chief Investigator has a substantive contract with KCL.

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 being undertaken for scientific research in the public interest so that the risk factors and care pathways that feed into both mothers’ and babies’ maternal outcomes can be better understood. Access to all of eLIXIR’s data (including proposed HES, ECDS and COVID-19 Vaccination Status data held within eLIXIR’s framework) is conditional on not attempting to re-identify individuals, not performing any unauthorised linkage and not sharing data with third parties.

The funding is provided by The Medical Research Council (MRC). The funding is specifically for the study described. Funding is in place until April 2028. The funder will have no ability to suppress or otherwise limit the publication of findings.

Data will be accessed by substantive employees of SLaM, GSTT, KCH and KCL.

Data is also accessed by:

i. Students enrolled with KCL – Any student working with the Data held under this Data Sharing Agreement (DSA) must have completed relevant data protection and confidentiality training and are subject to KCL’s policies on data protection and confidentiality. Any students accessing the Data will do so under the supervision of a substantive employee of KCL. KCL would be responsible and liable for any work carried out by students. These students would only work on the Data for the purposes described in this DSA.

ii. An individual with an honorary contract with SLaM. The individual is a substantive employee of St. George’s University Hospital NHS Trust and has an honorary contract with SLaM. This individual will access the Data under the supervision of a substantive employee of SLaM for the purposes described in this DSA only.

PPIE and Stakeholder Engagement:

Patients, service users and members of the public have been involved since the creation of the eLIXIR data resource, and this is intended to continue to do so moving forward. Firstly, the eLIXIR proposal was generated from extensive prior work at KCL Department of Women’s Health which has strong patient and public involvement. In addition, the technical and governance models of the use and linkage of health records data for research purposes have been derived from those pioneered at the SLaM BRC where patients have played a leading role in model design – in the setting up of CRIS in 2007-08, in administering data governance of projects using CRIS, in the subsequent data linkages involving CRIS, and in the development and continued running of SLaM’s CDLS.

Building on this original consultation, engagement with the public and patients have included ongoing consultation with specific stakeholders such as women using maternity services and those with lived experience of complex pregnancies by way of the eLIXIR Oversight Committee, described below, as well as deliberative engagement activities with community groups such as Lambeth Early Years Partnership (LEAP) an organisation in South London who provide a community for mothers residing in the catchment area, and for them to have a say in their healthcare.

In order to meet the requirements for fair processing of patients’ personal and confidential information for direct and indirect care uses, Fair Processing Notices have been produced. Patient Information Sheets are added to maternity booking packs and distributed in all maternity and child health care services. These include information on the purpose of the study, what data are collected, who can access the data and conduct research, and importantly the opt-out procedure should one wish to do so. These are also available on the study website (https://www.kcl.ac.uk/research/elixir-1), along with more detailed information about the study, the security model, the project privacy policy, and other resources.

SLaM will transfer data to NHS England. The data will consist of identifying details (specifically First Name, Last Name, NHS Number, Date of Birth, Postcode, Gender and a unique person ID) for the cohort to be linked with NHS England data.

NHS England will provide the relevant records from the HES, ECDS and COVID-19 Vaccination Status datasets to SLaM. The Data will contain no direct identifying data items but will contain the eLIXIR ID which can be used to link the Data with other record level data already held by the recipient.

The Data will not be transferred to any other location other than SLaM.

The Data is stored on the SLaM data safe haven provided by Microsoft Azure Cloud.

The Data will be accessed by authorised personnel via remote access.

The Controllers 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;

- 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 DSA) 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).

Remote processing will be from secure locations within England/Wales. The data will not leave England/Wales at any time.

Data will be accessed by substantive employees of SLaM, GSTT, KCH and KCL, enrolled students of KCL and an individual with an honorary contract with SLaM. The individual will act as an agent of SLaM at all times under supervision from employees of SLaM. Aside from these individuals, access is restricted to substantive employees of KHP (SLaM, GSTT, KCH & KCL) who have authorisation from the Chief Investigator.

Access to confidential patient identifiable data is restricted to employees of the Clinical Data Linkage Service (CDLS) team at SLaM. Identifiable data is not accessible to anyone besides specific named individuals for the purposes of linkage. After data linkage is completed, identifiers are removed and a unique pseudonym (eLIXIR ID) assigned. Identifiers are held within a separate secure folder, within the SLaM NHS Network but separate from where data is stored by CDLS. Researchers only have access to pseudonymised data. Confidential patient identifiable data is not accessible to any researchers.

Microsoft Limited are not permitted to access the Data. Microsoft Limited cannot access the data on the SLaM Azure Cloud. Access is granted via individual user accounts administered by SLaM Digital Services.

All personnel accessing the Data have been appropriately trained in data protection and confidentiality.

There will be no requirement and no attempt to re-identify individuals when using the Data.

Expected outputs of the new linkage of eLIXIR with HES and COVID-19 vaccination status data will include:

• Submission to peer-reviewed journals,

• Presentations at academic conferences, of which will be confirmed by the researchers at a later date but previous examples are: MARCE Society Conference and British Maternal and Foetal Medicine Society.

• Presentations to relevant charities and PPIE groups, policy labs and listening events.

All outputs will only include results with aggregate level data, and all numbers <10 suppressed, as is the existing protocol for all eLIXIR output. Specific details of dissemination and output plans are subject to individual projects using eLIXIR-HES and eLIXIR- COVID-19 Vaccination Status NIMS data, and their funding stipulations, as below:

1. eLIXIR needs to have reliable, coded outcomes for serious maternal complications, such as potentially life-altering or -ending complications (e.g., uterine rupture), and/or life-saving interventions (e.g., blood transfusion or intubation). These data currently come from the ‘maternal critical incident’ field in BadgerNet that is a hybrid of tick boxes and free text, and is variably completed.

o Specific eLIXIR project need: to assess prevalence of serious maternal complications within the South London cohort, associated risk factors and differences between groups such as different ethnicity, socio-economic status etc.

o Project- The impact of the COVID-19 pandemic on pregnancy for women with co-morbidity, belonging to ethnic minority or living complex social lives; peer-reviewed publication, conference, PPIE group presentation, policy lab, listening events with key stakeholders (target date 31.12.2025)

2. eLIXIR needs to have pregnancy outcome information for women who move and deliver outside of our Trusts (i.e., GSTT and KCH).

o Specific eLIXIR project need: to explore associations between maternal and child health for those seeking physical or mental health care beyond the scope of participating acute Trusts (e.g., further childbirth, hospitalisations, mental health crises, emergency care use, outpatient attendance)

o Project- Reducing perinatal mental health inequalities for women of racial and ethnic minority groups: a data linkage study; peer-reviewed journal, conferences, PPIE group presentation (target date 31.10.2025)

3. eLIXIR needs to link pregnancy data with long-term health outcomes for mothers and babies.

o Specific eLIXIR project need: to understand long-term health impacts and quantify association of poor future health in mother and child with complications during pregnancy.

o Project- Management strategies in women at risk of premature birth; long term influences on the health of the child; peer-reviewed journal, conferences, PPIE group presentation (target date 28.02.2026)

4. eLIXIR needs to have information on COVID-19 vaccination status for mothers in the cohort, linked to pregnancy outcomes.

Specific need: To investigate immunisation trends amongst pregnant women from underserved groups in South London, to evaluate care-seeking behaviour and vaccine hesitancy.

Project- Care-seeking behaviour of pregnant women from underserved groups in South London; peer-reviewed journal, conferences, PPIE group presentation (target date 31.12.2025).

The development of an early life course register comprising routine clinical data from mother and children, including HES data, with links to research databases and a bioresource will be of potential benefit to academics and clinicians working in the health care sector. These include those in the fields of obstetrics, paediatrics, psychology, psychiatry, social science, implementation science, public health and primary care. The generation of 'big data' from the research platform will benefit a raft of different scientists including bioinformaticians, geneticists and those working in the field of, epigenetics, metabolomics and the microbiome. Neuroscientists will also gain from elucidation of early developmental pathways in the brain and associations with later mental and physical health. The potential of the platform to assess efficacy of health care pathways will interest policy makers in the field of Public Health.

Development of novel tools and interventions, testing of their efficacy at the population level, and health economic evaluation will be of benefit to NICE, and other opinion leaders including the Royal Colleges in the development of clinical guidelines.

The patient support groups and the many charities with which the members of the partnership work closely, it is hoped will benefit from evidenced based advice for dissemination to their specific subgroup of the population with whom they interact. Of paramount interest to the partnership is the impact and benefit to the South London population from whose data the research outputs will be derived.

The eLIXIR UK partnership will lead to outputs which will directly inform the early origins of health and disease. The following provide likely examples of how this will be achieved.

1. In Women's health; by enabling investigation of

a) relationships between pre-pregnancy physical and mental health and common disorders of pregnancy and pregnancy outcomes

b) the long-term consequences of maternal physical and mental health disorders during pregnancy for the mother's physical health

c) the efficacy of interventions at the population level arising from RCTs e.g. lifestyle, pharmacological, devices, diagnostics to improve maternal physical health in the short and longer term.

2. In Paediatrics; by enabling investigation of

a) relationships between maternal physical and mental health disorders in pregnancy, and longer-term consequences for the physical of the child

b) relationships between adverse events and exposures in the fetal and neonatal period and the long-term consequences for physical health of the child

c) the efficacy of interventions at the population level to reduce the adverse impact of early life events and exposures on the child.

3. in Mental Health; by enabling investigation of

a) interrelationships between physical and mental health disorders during pregnancy and pregnancy outcomes

b) relationships between maternal and childhood mental health, and

c) associations between mental and physical health in women, and in children.

4. In patient care pathways; by enabling evaluation of new pathways of care/guideline recommendations to improve maternal and or child physical and/or mental health, and determination of associated health care costs.

The benefits described are far reaching, long lasting and applicable to all sectors of the community. HES and COVID-19 Vaccination Status NIMS data augment the eLIXIR data to enhance these benefits.

Although UK maternity services are the prime recipients of the benefits derived from eLIXIR data, members of the King’s Health Partnership are internationally renowned, and the research can thus be expected to have a worldwide audience.

eLIXIR is currently already used as part of postgraduate study research, and several new projects have proposed the use of the requested HES-eLIXIR and COVID-19 Vaccination StatusNIMS-eLIXIR data. The data will provide an excellent resource for MSc and PhD Students at King’s College London, and from other universities in the coming years.

Yielded Benefits is not a requirement for new applications.