MR76 - ORAL CONTRACEPTION STUDY

The University of Aberdeen requires cancer registration, embarkation/exit from the NHS and death data (from the Cancer Registration Data, Civil Registration -Deaths and Demographics datasets available via the DARS Cohort Management Service) for the next three years of continuing cohort follow-up of the Royal College of General Practitioners’ (RCGP) Oral Contraception Study.

The Royal College of General Practitioners’ Oral Contraception Study was initially funded by the Medical Research Council. The study subsequently received support from the Royal College of General Practitioners, Imperial Cancer Research Fund, British Heart Foundation, Cruden Foundation, Schering AG, Schering Health Care Ltd, Wyeth Ayerst International, Ortho Cilag, Searle and the Chief Scientist Office. None of these funders have contributed to the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review or approval of any publications. Currently the study has no sustained funding, although the University of Aberdeen provides some resource to support the dataset for analysis.

The University of Aberdeen is the sole data controller and also processes data for this study. No other organisations process the data for this purpose.

The Oral Contraception Study was established in 1968 with the aim of determining the health effects of oral contraceptives. The Oral Contraception Study is one of the largest on-going studies of women’s health and oral contraception in the world. The study is now in year 54 of follow-up of the women recruited and contains more than 1.5 million woman-years of observation, more than 13,300 deaths have occurred and over 22,500 incident cancers have been notified. The collection of comprehensive medical information and the prospective cohort design has allowed investigation of the health effects of oral contraceptives, hormone replacement therapy and a number of other women’s health issues. For instance, it was one of the first studies to indicate a link between pre-eclampsia (then known as toxaemia of pregnancy) and increased risk of cardiovascular disease in later life. It has also been able to look at the sequelae of common gynaecological operations and other epidemiological issues affecting women's health.

Importantly, the Oral Contraception Study can address questions regarding the very long-term effects of oral contraceptives particularly in relation to mortality and many different types of cancer, which become more common among women as they get older. It is estimated that 100-150 million women use oral contraceptives daily (and nearly half a billion women have ever used oral contraception) and therefore being able to investigate the lifetime effects of this method of contraception using prospectively collected data is crucial. The analyses of the data will be carried out in accordance with Article 6(1)(e) and 9(2)(j) of the GDPR - the processing is necessary to perform a task in the public interest in order to provide informed advice to the public about the safety and long-term risks associated with administration of oral contraceptives.

The cohort was established in 1968 by the Director of the RCGP Manchester Research Unit. The RCGP was the data controller at this time, when 1400 general practitioners (GPs) throughout the United Kingdom recruited 23,000 women who were using oral contraceptives and a similar number of women who had never done so. The women were all married or living in a relationship of the nature of marriage. The women were interviewed personally at recruitment when study recruitment cards were completed. Information collected at baseline included social class (as determined by husband/partner’s occupation which, at that time, was considered to be a reasonable indicator of the woman’s social class), number of cigarettes smoked daily, details of any previous use of oral contraceptives, parity and significant medical history (using a tick list of specified conditions, which included toxaemia of pregnancy).

At six-monthly intervals thereafter, using a specific study follow-up form, recruiting GPs provided details of any: prescriptions for hormonal preparations, pregnancies, surgery, new episodes of illness and deaths occurring in the women. Follow-up via the GP stopped if: the woman left the recruiting practice (an attempt early on the study to trace women who moved via the national registries, to invite her new doctor to continue follow up was not successful and so was abandoned in the early 1970s); if the woman received contraception from an alternative source (usually a community clinic); if the GP resigned from the study; or the woman died. By the mid-1970s, roughly a quarter of the cohort had been lost from GP follow-up.

Following the publication of a monograph detailing the protocol of the study and early results from follow-up 1, the decision was made to ‘flag’ the cohort at the NHS Central Registries in Southport and Dumfries, in the mid-1970s (75% of the cohort, approximately 36,000 women). Through the flagging process the study has been notified of any cancer registrations or deaths occurring among the women even among those no longer under GP observation.

In 1996, the six-monthly GP follow-up of women remaining with their recruiting practice ceased. The study continues to be updated with cancer and death registrations, occurring in the women who were flagged in the mid-1970s, from the NHS Central Registries. In September 1997, the RCGP Oral Contraception Study re-located along with the current Principal Investigator to the Department of General Practice & Primary Care (now Academic Primary Care, Institute of Applied Health Sciences) at the University of Aberdeen. At this point all data for this study ceased to be held by RCGP and was transferred to the University of Aberdeen.

Mortality and Cancer data continued to be supplied to The University of Aberdeen by ONS and subsequently the Health and Social Care Information Centre (which has since become NHS Digital) for the purpose of the Oral Contraception Study.

The research team cannot identify any of the women in the Oral Contraception Study (see 5b.). Any dissemination of study findings presents aggregated information. Thus, there is very low risk of potential harm to the public by the dissemination of findings from the study. Indeed, publication of results from the study tends to be associated with much interest in various media (print, social media, radio, TV), generating increased knowledge and debate among the public. Feedback from previous users of oral contraceptives has generally been favourable, with former users being grateful that there continues to be an assessment of the very long-term health risks and benefits associated with their choice of family planning.

Since the research team cannot identify any of the cohort members, the Oral Contraception Study can only continue follow-up via the DARS Cohort Management Service. The data requested has been minimised as far as possible (date and nature of event) to provide sufficient information to perform robust statistical analyses of outcomes.

The aim of the study is to analyse the cancers and deaths of the study subjects, comparing the experiences of users and non-users of oral contraceptives (e.g. by comparing the data of the respective subsets within the cohort). The data obtained from NHS Digital also enables the University of Aberdeen to determine whether there is a difference in incident rate between those patients who are still under observation by their GP and those who have left the practice (to assess whether systematic biases have occurred through loss to follow-up).

The study was established in 1968 before the introduction of research ethics committees in the UK. Even so, procedures were used to maintain the confidentiality of women. The research team are unable to identify any of the women in the Oral Contraception Study because from time of recruitment, the study has had procedures in place to maintain the confidentiality of the women. At recruitment, the GPs completed for each woman a recruitment form which contained a unique study number, the key to which was completed and held by the recruiting practice. All correspondence between the GPs and the study coordinating unit used this unique study number. In order to identify whom the correspondence (including follow-up forms) related to, the GP had to refer to the key that he/she held. When women still under GP follow-up in the mid-1970s were flagged at the NHS Central Registries in Southport and Dumfries, the GPs supplied identifying information and each woman’s unique study number directly to the central registries on the study’s behalf. Women registered with a participating GP in Scotland, England and Wales were then flagged for subsequent notification of Cancer Registrations and for Death registrations. The registries placed an indicator (‘flag’) on each woman’s registry entry showing that she was part of the Oral Contraception Study, as well as her unique Oral Contraception Study number. When NHS Digital are informed that a death or cancer has occurred in a flagged woman, it sends event details to University of Aberdeen using the unique study number after identifying information has been removed. The research team link this new information with that already held in the study using the individual’s unique study number. The flagging procedure was completed in the 1970s. There will not be new attempts to add to the cohort already held by NHS Digital.

For cohort members registered in England and Wales, NHS Digital (using the unique study number) supplies on a quarterly basis, relevant information received about: date and cause of death, date and site of cancer registration, exits from and re-entries into the NHS for the flagged cohort. The data supplied has previously included patient identifying data, however under this agreement no identifying data will be supplied.

The University of Aberdeen has been receiving data for the Oral Contraception Study since September 1997 when the study relocated with the current Director/Principal Investigator. Prior to that date, data were received, processed and stored within the original coordinating centre for the study, the RCGP Manchester Research Unit. RCGP no longer hold any data for this study.

When the NHS Digital data are received, the University of Aberdeen’s NHS Digital Gateway Manager will add the data to the study’s password protected file space stored in the secure storage servers (Dell EMC Isilon data centre) inside the Edward Wright Building. This is a separate system from the main University data storage facility. The data replicates constantly between the data centres and a file saved in the Edward Wright Building would replicate to the Aberdeen Business School seconds later. Although the Aberdeen Business School data centre is located within a Robert Gordon University building, the data centre itself is operated and maintained by a University of Aberdeen, Robert Gordon University and North East Scotland College partnership. No staff employed by Robert Gordon University and North East Scotland College will have access to the NHS Digital data. The University of Aberdeen NHS Digital Gateway Manager is a substantive post which is responsible for arranging the secure receipt of NHS Digital data, it’s storage within a study specific file space, managing the access of University of Aberdeen approved users to the NHS Digital Data and any requests for data deletion and for maintaining the University of Aberdeen’s NHS Digital Information Asset Register. The study's password protected secure file space is accessible to only named individuals. The new data received are then cleaned (all notifications are manually back-coded to International Classification of Disease (ICD) version 8 as this was the classification system in use when the study commenced) and the date and code of event are linked to the study dataset using the unique study numbers.

Access to the Oral Contraception Study database is controlled by username and password and only those personnel identified by the Principal Investigator as working on the study have access to the data. All staff agree, as part of their terms and conditions of employment, to abide by the University’s Information Security Policy. All personnel authorised to access the Oral Contraception Study data received are trained in Good Clinical Practice and have completed Information Governance Training (Data Security Awareness Level 1).

All organisations party to this agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract i.e.: employees, agents and contractors of the Data Recipient who may have access to that data).

Approval to receive death and cancer registration data for cohort members registered in Scotland has been granted by the NHS Scotland Public Benefit and Privacy Panel for Health and Social Care (prior to May 2015 known as the Privacy Advisory Committee, PAC) (application number 1617-0244 granted 12 May 2017). There are no other new data collected by or linked to the Oral Contraception Study.

To address the common law duty of confidentially, The University of Aberdeen will destroy all fields that NHS Digital have classed as 'identifying'. This includes identifying details in both the data that NHS Digital (including any predecessor organisations) has provided to University of Aberdeen and fields that University of Aberdeen have obtained from other sources. Only pseudonymised will be held by University of Aberdeen and University of Aberdeen will have no means of re-identifying the individuals.

NHS Digital as a trusted party will retain the cohort identifiers as provided under historic Agreements. There is no requirement to re-identify individuals. Further access to the identifiers held by NHS Digital will only be permitted in future, if the applicant can provide evidence that they meet the Common Law Duty of Confidence.

Since its inception in 1968, the Oral Contraception Study has contributed significantly to the worldwide evidence-base regarding the safety and prescribing of combined oral contraceptives. To date, the Oral Contraception Study has led to over 100 publications in peer-reviewed journals and textbooks and more than six BSc/MSc/MD/PhD degrees - many of these have included analysis of the cancer and deaths registration data supplied by the NHS Central Registries.

When papers are published, the University of Aberdeen disseminate these via press releases, social media and interviews with internet, print, radio and television journalists. Results from the Oral Contraception Study have also been used as exemplars during undergraduate and postgraduate teaching of epidemiological topics. Results have been presented at national and international conferences, used in television documentaries and discussed at public engagement events. In addition, dissemination of study results has directly informed national and international clinical guidelines for the safe prescribing of combined oral contraceptives; including the World Health Organization’s Medical Eligibility Criteria for Contraceptive use, and its UK version. The Oral Contraception Study intends to continue to publish its high-quality work, including a new analysis of most-available mortality data.

The University plans to publish at least biennially with the next paper from the Oral Contraception Study being planned and prepared for statistical analysis in 2022 with publication following as soon as possible thereafter in late 2022/ early 2023.

All outputs will only contain results in highly aggregated format and as statistical summaries and measures of association. Small numbers will be suppressed in line with the HES Analysis Guide. Record level information will not be released to any third party.

Oral contraceptives are used, often for prolonged periods, to prevent pregnancy, not as a treatment for a disease. With 100-150 million women using oral contraceptives daily (and perhaps half a billion ever exposed to these preparations), it is important to consider any health risks and benefits associated with their use and how these vary throughout a woman’s lifetime.

The cancer and death registrations supplied by NHS Digital allows the Oral Contraception Study to continue to assess the very long-term safety of oral contraceptives, as used by the first generation of users. This important information about the risks and benefits associated with combined oral contraceptives also continues to inform current evidence about the safety of this highly popular method of contraception. In addition, the breadth of the Oral Contraception Study dataset allows other possible influences of women’s health to be assessed and put into a public health context. The next analysis of the study is planned for in 2022 with publication and dissemination to follow as soon as possible in late 2022/ early 2023.

NHS Digital data allows follow-up of the Oral Contraception Study cohort to continue and has resulted in over 100 publications in medical journals. Our most recent analysis based on up to 44 years of follow-up of the cohort found that women who had ever used the pill were less likely to have colorectal, endometrial or ovarian cancer than women who had never used this contraceptive method. These protective effects first seen during the cohort’s reproductive years were long-lasting, persisting for at least 30 years after women stopped using the pill. Increased risks of breast and cervical cancer were found in current users but these risks disappeared within five years of stopping. There was no evidence of new cancer risks appearing in later life.

A 25 year follow-up of the study found that women who were current or recent pill users had lower rates of death from ovarian cancer but higher rates of death from circulatory diseases, cervical cancer and violent causes. However, 10 or more years after stopping the pill, mortality risks were similar in ever and never users. After 39 years of follow-up, the study found that use of the pill did not lead to a long-term risk of death. Compared to never users, women who had ever used the pill had a higher risk of violent death but lower risks of death from any cause, from cancer; specifically large bowel/rectum, endometrial and ovarian cancers, from circulatory disease, ischaemic heart disease and all other diseases. In other words, there was an overall net benefit.

The Oral Contraception Study identified that current pill users had an increased risk of stroke and current users who smoked had increased risks of myocardial infarction in comparison to women who never used oral contraceptives. The study did not find evidence of a relationship between pill use and risk of liver disease or multiple sclerosis or eye disease (except retinal vascular lesions). A small increased risk of fractures found among pill users followed until 1990 was no longer seen among the cohort in later life at a time when osteoporotic fractures were more common.

The cohort design means the Oral Contraception Study can also examine other women’s health issues. The study has confirmed the important prospective relationship between cigarette smoking and lung cancer, myocardial infarction, stroke and gallbladder disease in women. The study was one of the first to demonstrate that a history of toxaemia of pregnancy (now known as pre-eclampsia) increases the risk of cardiovascular disease and death later in life. The study has also shown that common gynaecological surgeries, hysterectomy and tubal sterilisation were not associated with an increased long-term risk of death. Continued follow-up of the cohort at a time when the incidence of cancers is high and death is common continues to be important to our understanding of oral contraceptives and women’s health.

The Oral Contraception Study was recognised as “world class” in the 2001 Research Assessment Exercise by the assessing Primary Care Panel. In addition to its intrinsic value regarding the assessment of the safety of oral contraception, The study has directly led to other research studies. For example, the publication Hannaford P, Ferry S, Hirsch S. Cardiovascular sequelae of toxaemia of pregnancy. Heart 1997; 77: 154-158 led to grant funding from the British Heart Foundation, to a research team in Aberdeen which included Professor Hannaford, to investigate the adverse role of pre-eclampsia in cardiovascular health in later life in a different cohort of women. Professor Hannaford and Dr Iversen also examine cancer issues associated with contemporary hormonal contraception use in Denmark, re-assessing associations first identified in the Oral Contraception Study (for example in relation to breast, endometrial, ovarian and cervical cancer).

The Oral Contraception Study has influenced and continues to influence clinical guidelines across the world including the World Health Organization‘s Medical Eligibility Criteria for Contraceptive Use (WHOMEC, now 5th Edition 2015), the UK Medical Eligibility Criteria for Contraceptive Use (UKMEC, first published 2006 last updated September 2019) and the Faculty of Sexual and Reproductive Healthcare (FSRH) Guideline Combined Hormonal Contraception (January 2019, amended November 2020). Examples of key study publications included in several clinical guidelines are:

• Oral contraceptives, venous thrombosis, and varicose veins. Royal College of General Practitioners’ Oral Contraception Study. Journal of the Royal College of General Practitioners’ 1978; 28: 393–399.

• Croft P, Hannaford PC. Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners' Oral Contraception Study. British Medical Journal 1989; 298: 165-168.

• Hannaford PC, Croft PR, Kay CR. Oral contraception and stroke: Evidence from the Royal College of General Practitioners' Oral Contraception Study. Stroke 1994; 25: 935-942.

• Hannaford PC, Selvaraj S, Elliott AM, Angus V, Iversen L, Lee AJ. Cancer risk among oral contraceptive users: cohort data from the Royal College of General Practitioner’s Oral Contraception Study. British Medical Journal 2007; 335: 651-654.

• .Hannaford PC, Iversen L, Macfarlane TV, Elliott AM, Angus V, Lee AJ. Mortality among contraceptive pill users: cohort evidence from the Royal College of General Practitioners’ Oral Contraception Study. BMJ 2010; 340: c927 doi:10.1136/bmj.c927.

• Memon S, Iversen L, Hannaford PC. Is the oral contraceptive pill associated with fracture in later life? New evidence from the Royal College of General Practitioners Oral Contraception Study. Contraception. 2011;84(1):40–47.

• Iversen L, Sivasubramaniam S, Lee AJ, Fielding S, Hannaford PC. Lifetime cancer risk and combined oral contraceptives: the Royal College of General Practitioners’ Oral Contraception Study. American Journal of Obstetrics & Gynecology 2017; 216: 580.e1-580.e9 doi:10.1016/j.ajog.2017.02.002.

The US Agency for Healthcare Research and Quality health technology assessment of Oral contraceptive use for the primary prevention of ovarian cancer referenced 17 publications from the Oral Contraception Study in its Evidence Report. These examined risk of gallbladder disease, eye disease, carpal tunnel syndrome, fractures, stroke, myocardial infarction, multiple sclerosis, cancer, serious illness and mortality in pill users in comparison to never users, as well as other women’s health issues including impact of lifestyle, long-term effects of hysterectomy and determinants of menopause. The International Agency for Research on Cancer Monograph on the Evaluation of Carcinogenic Risks to Humans v100A (2008, Lyon, France) also referenced the Oral Contraception Study. In 2017, the James Lind Alliance Contraception Priority Setting Partnership also cited the Oral Contraception Study as evidence for Priority 3 (what are the long-term effects of using contraception on fertility, cancer and miscarriage?).

The Oral Contraception Study also informs the public in scientific issues not always directly related to the pill’s safety. For example, the cohort study is a case study of the Wellcome Trust’s Understanding Patient Data initiative, which illustrates the value of linking information supplied from GP records for the study with that (deaths and cancers) supplied from central NHS data sources- to assess the safety of oral contraceptives. The Oral Contraception Study results were also presented and discussed as a key element of the BBC Horizon documentary “The contraceptive pill; how safe is it?”. In this programme Professor Hannaford was interviewed by a combined oral contraceptive user with a family history of breast cancer and through careful explanation of absolute risk was able to reassure her that her contraceptive choice was not putting her at great harm. The programme had 610,000 viewers at first airing in 2018 with a high audience appreciation index of 80/100. During a number of radio interviews (including Radio 4 Today Programme and TV News Programme) we have been able to explain the importance of considering absolute as well as relative risk when explaining results from the study.