Most women who choose to use oral contraceptives do not expose themselves to long-term cancer harms; instead, with some cancers, many women benefit from important reductions of risk that persist for many years after stopping.

There were 4661 ever users with at least 1 cancer during 884,895 woman-years of observation and 2341 never users with at least 1 cancer during 388,505 woman-years of observation. Ever use of oral contraceptives was associated with reduced colorectal (incidence rate ratio, 0.81; 99% confidence interval, 0.66–0.99), endometrial (incidence rate ratio, 0.66; 99% confidence interval, 0.48–0.89), ovarian (incidence rate ratio, 0.67; 99% confidence interval, 0.50–0.89), and lymphatic and hematopoietic cancer (incidence rate ratio, 0.74; 99% confidence interval, 0.58–0.94). An increased risk of lung cancer was seen only among ever users who smoked at recruitment. An increased risk of breast and cervical cancer that was seen in current and recent users appeared to be lost within approximately 5 years of stopping oral contraception, with no evidence of either cancer recurring at increased risk in ever users with time. There was no evidence of new cancer risks appearing later in life among women who had used oral contraceptives. Thus, the overall balance of cancer risk among past users of oral contraceptives was neutral with the increased risks counterbalanced by the endometrial, ovarian, and colorectal cancer benefits that persist at least 30 years.

The 46,022 women who were recruited to the UK Royal College of General Practitioners’ Oral Contraception Study in 1968 and 1969 were observed for up to 44 years. Directly standardized rates of specific and any cancer were calculated for “ever” and “never” users of combined oral contraceptives; data were standardized for age, parity, social class, and smoking. Attributable risk and preventive fraction percentages were calculated. Poisson regression that adjusted for the same variables was used to estimate incidence rate ratios between ever and never users and to examine effects by time since last oral contraceptive use.

The purpose of this study was to examine the very long-term cancer risks or benefits associated with the use of combined oral contraceptives, including the estimated overall life-time balance.

Oral contraceptives have been used by hundreds of millions of women around the world. Important questions remain regarding the very long-term cancer risks that are associated with oral contraception. Despite previous research, important questions remain about the safety of these contraceptives: (1) How long do endometrial, ovarian, and colorectal cancer benefits persist? (2) Does combined oral contraceptive use during the reproductive years produce new cancer risks later in life? (3) What is the overall balance of cancer among past users as they enter the later stages of their lives?

Since its introduction, first in the United States in 1960,combined oral contraceptives have been used by hundreds of millions of women around the world. Today, it is estimated that 100–150 million women use this contraceptive method on a daily basis.Concerns were expressed early on about the method’s carcinogenic potential.Cancer was of particular concern, given the likely high level of usage and the 11–22% lifetime cancer risk among women living in different parts of the world.These concerns and frequent media scares have left many women wondering whether they have exposed themsleves to long-term harm by using this method of contraception.

There have been many, mostly case-control, studies that have looked at combined oral contraception and different types of cancer. Collectively, the evidence suggests that current and recent users of combined oral contraceptives have an increased risk of breast and cervical cancer and that long-term users in regions at low risk of hepatitis B virus may have an increased risk of liver cancer.Conversely, users of combined oral contraceptives appear to have a reduced risk of endometrial and ovarian cancer, which is an effect that appears to persist for many years after stopping. Current users of combined oral contraceptives also appear to be protected from colorectal cancer, with uncertainty about the length of protection after stopping.

Even with this extensive body of evidence important questions remain: (1) How long do the endometrial, ovarian, and colorectal cancers benefits persist? (2) Does combined oral contraceptive use during the reproductive years produce new cancer risks that emerge later in life? (3) What is the overall balance of cancer among past users of combined oral contraceptives as they enter the later stages of their lives? These questions are best answered by large-scale, population-based studies with the prospective collection of exposure information and very long-term follow-up. We report here results from 44 years of follow up of the Royal College of General Practitioners’ Oral Contraception Study, the longest running study of the health effects of oral contraception in the world.

Materials and Methods

5 Royal College of General Practitioners

Oral contraceptives and health. 6 General Registrar’s Office

Classification of occupations, 1966. Between May 1968 and July 1969, 1400 general practitioners (GPs) throughout the United Kingdom recruited approximately 23,000 women who were using oral contraceptives and 23,000 women who had never used this method of contraception.All women were married or co-habiting; most were white, and their mean age at recruitment was 29 years. Information collected at recruitment included previous use of oral contraception, smoking habits, social class (based on partner’s occupation according to the Registrar General’s 1966 Classification of Occupations), parity, and significant medical history. Women remained under GP follow up until (1) they were no longer registered with the recruiting doctor (usually because the woman moved away; approximately 56% of total cohort), (2) their doctor left the study (13%), (3) they obtained contraceptives from another source (3%), (4) they died (2%), or (5) GP follow up stopped in December 1996 (26%). While under GP follow up, GPs provided, on a 6-monthly report form, information about any hormonal preparations prescribed, any pregnancies, new episodes of illness or surgery, and cause of death. All GP-supplied information was coded by a team of trained clerks, with queries returned to the GPs for clarification wherever necessary.

In the mid 1970s, approximately three-quarters of the cohort was “flagged” at National Health Service central registries in Scotland and England. This enabled subsequent cancers and deaths that occurred among flagged women to be reported to the study anonymously, including after women left GP follow up. The other one-quarter could not be flagged because the women already had left the study when flagging occurred.

We used the GP-supplied data to determine each woman’s pill status and her contribution to the analysis. Most women in the study (91%) who used oral contraceptives did so before age 38 years. Ever users were women who were recruited as takers and subsequently prescribed oral contraception (nearly always a combined estrogen and progestogen preparation). For each calendar month that a woman used an oral contraceptive, 1 month was added to the period of observation (denominator) of ever users, as were periods after stopping. Women who were recruited as never users who subsequently were prescribed an oral contraceptive were included in the ever user group from the month of prescription. Never users who were lost to GP follow up before 1996 and were aged <38 years when lost contributed data (as never users) up to the point of their loss before being censored because of uncertainty about whether they subsequently used oral contraceptives. Never users who were lost to GP follow up before 1996 and were aged ≥38 years when lost were likely to remain never users and so continued to make a contribution to the never user group if flagged (otherwise they were censored at this point). Never users who were still in the study when GP follow up stopped in 1996 were deemed unlikely to change pill status and remained in the analysis. For a small number of ever users (2,690/28,983; 9.3%), we did not have a stop date notified by the GP. For these women, we assumed oral contraceptive usage stopped 1 year after the last recorded prescription. The effect of this assumption was to underestimate time slightly since stopping if a woman used oral contraception for <12 months after the last recorded prescription and to overestimate it if used for a longer period.

Figure Flowchart of the Royal College of General Practitioners’ Oral Contraception Study Show full caption The follow-up plan of the Royal College of General Practitioner’s Oral Contraception Study from recruitment in 1968–1969 to December 2012 is shown. GP, general practitioner; OCS, oral contraception study. Iversen et al. Lifetime cancer risk and combined oral contraceptives. Am J Obstet Gynecol 2017. The analysis included cancers and periods of observation up to (1) the date of first relevant cancer or the date that the women left the study for all nonflagged women and flagged never users who were lost from the study before 1996 and aged <38 years when lost and (2) the date of relevant cancer or December 31, 2012, for all flagged women still under GP observation at December 1996, for flagged never users who were lost before 1996 and aged ≥38 years when lost, and for flagged ever users who were lost from the study before 1996 ( Figure 1 ). Most cancers were notified through flagging by the central registries (ie, 5467/7002 [78%] of all cancers).

7 World Health Organization

International classification of disease, injuries and causes of death, 8th revision. The cancers were coded according to the International Classification of Diseases, 8th revisiongrouped into categories: esophagus and stomach (code 150-151), colon and rectum (153-154), gallbladder and liver (155-156), pancreas (157), lung (162), skin-melanoma (172), skin-other (173), breast (174), invasive cervix (180), endometrium (182), ovary (183), bladder and kidney (188-189), central nervous system and pituitary (191 and 1943), thyroid (193), site unknown (199), lymphatic and hematopoietic (200-208), other cancers (any code between 140-209 not already mentioned); and any cancer (140-209). If a discrepancy in event type or date occurred between GP and registry notification, clarification was sought from the GP whenever possible. If this was not possible, the GP-supplied information was used, because this was likely to be most accurate because it was often based on hospital-supplied information.

Direct standardization was used to estimate the rates of cancer among ever and never users. The standardization variables for the total study population were age (<30, 30–39, 40–49, 50–59, 60–69, ≥70 years), parity (0, 1, 2, ≥3) at the time of the event, smoking (0, 1–14, ≥15 cigarettes daily), and social class (nonmanual: social classes I-IIIa [professional, managerial and technical, and skilled non-manual occupations] and students; manual: social classes IIIb-V [skilled, partly-skilled manual occupations, and unskilled occupations] and armed forces) at recruitment. Poisson regression was used to estimate the incidence rate ratio (IRR) and its 99% confidence interval (CI) for ever vs never users for each of the cancer types, adjusted for the same categories of age, parity, smoking, and social class as mentioned earlier. The exception was when we stratified the data by a particular variable (eg, smoking habits at recruitment), when we adjusted the IRRs for the other 3 variables. We calculated 99% CIs to allow for the large number of comparisons, which indicated statistical significance at the 1% level.

We excluded women who were known to have the cancer before recruitment and events and periods of observation related to pregnancy. Only first events in each cancer category were included; subsequent periods of observation that related to the same cancer were removed from the denominator of analyses but were included in analyses of other cancers (because the women remained at risk of having another type of cancer). The analysis of any cancer risk included only the first cancer, with subsequent observation censored. In all analyses, women were censored at death. By the end of the follow-up period, 7248 deaths occurred: 3003 deaths in never users and 4245 deaths in ever users of oral contraception.

Attributable risk was calculated by subtracting cancer incidence in never users from that in ever users. When the IRR was <1, the preventive fraction percentage was estimated (ie, the percentage of cancer reduction in ever users that might be prevented by combined oral contraception). When the IRR was >1, the attributable risk percentage was calculated (ie, the percentage of cancers in ever users that might be attributable to combined oral contraception).

For our time since last use analysis, we divided the ever users into current and <5 years since last use, 5 to <15 years since last use, 15 to <25 years since last use, 25 to <35 years since last use, and ≥35 years since last use. We undertook adjusted Poisson regression as mentioned earlier to estimate the IRR in each category that was relative to never users. Because of the strong relationship between age and time since last use of oral contraception, we did not undertake standardization to obtain adjusted rates.

The study was established before the introduction of research ethics committees in the United Kingdom. Even so, procedures were used to maintain the confidentiality of women (ie, correspondence between participating doctors and the study and between the National Health Service central registries and the study used a unique study number, the key to which only the GPs knew).