The Pill 'does not raise death risk'

“Women who use the Pill can expect to live longer,” according to The Times. The news is based on research looking at the long-term effects of taking the contraceptive pill.

From 1968 to 2007 the study followed 46,000 women that had either used or never used oral contraceptives, comparing their mortality rates. The four decades of data showed that there was a small decrease in the mortality rates of women who had taken the Pill, as well as a small decrease in the overall risk of developing cancer.

This study has shown that the Pill is not associated with long-term health risks and also presents some associations between taking the Pill and decreased cancer risk. However, the study has some limitations in that it did not look at other lifestyle factors, such as diet and exercise, that can affect health. It also failed to adjust for some medical factors that may have a bearing on using the Pill and mortality risk.

This study followed women who had taken the earliest forms of the Pill. Its results are not directly applicable to modern forms of the Pill, which differ in hormone composition.

Where did the story come from?

Professor Philip Hannaford and colleagues from the University of Aberdeen carried out this research. The study was funded by the Royal College of General Practitioners, the Medical Research Council, the British Heart Foundation, the Cruden Foundatio, and several pharmaceutical companies including Schering Healthcare, Wyeth Ayerst International, Ortho Cilag and Searle. The study was published in the peer-reviewed British Medical Journal.

Many media outlets correctly highlighted that the women in this study had taken the Pill approximately 20 to 40 years ago and that the composition of contraceptive pills available then may differ from those used today. They also highlighted that the decreased relative mortality rates were quite small and that the important message from this research was that there was not a long-term increase in death rates following the use of contraceptive pills.

The Times quoted from the study that younger women were at slightly higher risk of suffering heart attack, stroke or breast cancers while taking the Pill. This research study did not provide evidence for risk of these particular diseases, although its sub-analyses did reveal there to be a greater risk of overall mortality in Pill users recruited to the study at a young age (below 30). The reasons for these differences are unclear and need to be investigated further.

What kind of research was this?

This was a cohort study that looked at whether taking the contraceptive pill had any effect on mortality risk.

The Royal College of General Practitioners Oral Contraception Study is a continuing investigation into the health effects of contraceptive pills. The study has been following women who have used the Pill since 1968. In its early days, the Pill was reported to be associated with increased risks of mortality; however, the researchers note that further studies suggest that oral-contraceptive use is associated with a reduced overall risk of cancer. This study aimed to assess the risks over a period of several decades, and to see how these risks altered if women stopped taking the Pill.

What did the research involve?

In 1968 approximately 23,000 women who were using the oral contraceptive pill were recruited through 1,400 GP surgeries. These women were termed the “ever users”. The researchers recruited a similar number of women who had never taken the Pill, classed as the “never users”. All of the women were married or living as married. Most were white and their average age at recruitment was 29.

At this time, information about whether they had children, whether they smoked, their medical history and their social class (based on their husband’s occupation) were recorded. Every six months the women’s GPs supplied information about any prescriptions for the Pill, any pregnancies and any illnesses or deaths that had occurred.

The women were monitored until one of the following occurred:

They left the area of the recruiting doctor.
Their doctor left the study.
They obtained the Pill from a source other than their GP.
Follow-up by GP practices ended, which eventually happened in 1996.

Medical records were also flagged so that data on cancer or death would be gathered on women who dropped out of the study and after GP follow-up had ended. These flagged records were examined up until 2007.

The researchers analysed two different datasets. The first contained all of the information up until 1996 (when the GP follow-up ended), while the second also included data from the flagged records followed until 2007.

In total, 46,112 women were followed up. As women were followed for different lengths of time, the researchers analysed the data in terms of a measure called “women years”: the number of women in a group multiplied by the number of years that they each participated in the study. The full study up to 2007 contained more than 819,000 women years for women who had ever used the Pill, and 378,000 women years for women who had never taken the Pill. The GP follow-up only study had 343,000 women years for “ever” users, and 237,000 for “never” users.

What were the basic results?

In the full study up to 2007, the risk of death due to any cause was lower in the women who had ever taken the Pill compared with women who had never used it. The relative risks were adjusted to account for the influence of age, smoking, social class and whether the women had had children.

The researchers found a 15% lowered risk of any cancer in ever users than in never users (Relative Risk 0.85, 95% Confidence Interval 0.78 to 0.93). Ever users also had a decreased risk of cancers of the large bowel and rectum, uterus and ovaries. Ever users were also found to have a higher rate of accidental violent death (Relative Risk 1.49 95% Confidence Interval 1.09 to 2.05).

Age seemed to play a large role in the risk of death due to any cause. In women who were under 30 at the time of recruitment, the relative risk of death was three times greater in ever users compared with never users. However, if the women were over 50 at the time of recruitment, the rate of death was lower in ever compared to never users.

Analysis of the smaller dataset of GP follow-up data showed no difference between never or ever users of the Pill in terms of overall mortality or cancer.

The average length of time that women took the Pill in this study was 44 months. The length of time taking the Pill did not affect the risk of death.

How did the researchers interpret the results?

The researchers concluded that “oral contraception was not associated with an increased long-term risk of death in this large UK cohort; indeed, a net benefit was apparent. The balance of risks and benefits, however, may vary globally, depending on patterns of oral-contraception usage and background risk of disease”.

Conclusion

This study followed a large number of women who had taken the contraceptive pill over 39 years. It showed that there was a small decrease in mortality rates for women who had ever used the Pill compared to those who had never used it.

However, there are several things to consider when interpreting these results, many of which the researchers highlight:

Medical diseases and risk factors may have differed between the two groups of women but were not adjusted for in the analyses.
A lack of adjustment for medical history may have influenced the results as the oral contraceptive pill is not suitable for all women as a number of medical factors make taking the Pill undesirable or unsafe, including a history of vascular disease (e.g. deep vein thrombosis, DVT), past strokes or mini-strokes, heart disease and liver disease. Other women with risk factors for these diseases may only be cautiously considered for the Pill. On this basis, medical reasons may potentially have confounded any increase in mortality in the “never used” group.
Equally, “ever use” of the Pill in this cohort was associated with an overall decreased risk of death from any circulatory diseases. However, it is unclear whether differences in cardiovascular diseases or disease risk were already present at the time decisions were being made to prescribe the Pill.

There are a number of other points to consider when interpreting this research:

Although the analysis adjusted for whether the women smoked, the smoking data was not routinely updated throughout the study. Using only the information about smoking collected at the start of the study may have underestimated the effects of smoking.
Other lifestyle factors such as diet and exercise were not measured. This may have affected the outcome of the study.
There are many different formulations available, but the study did not assess whether the risk of death differed according to hormonal content of the contraceptive pill used. In the early 1970s there were few oral contraceptive pills available compared to the numerous brands there are today. The hormone content of the early contraceptive pills is likely to differ from those taken today, principally in that the oestrogen concentration in today’s tablets is often lower, and today’s combined pills contains the hormones oestrogen and progestegen rather than oestrogen alone.
The women in the cohort were all married and mostly white, so these results may not be applicable to other ethnicities and society as a whole.
The researchers’ subanalyses did reveal there to be a greater risk of overall mortality in pill-users recruited to the study at a young age (below 30). The reasons for these apparent differences in risk according to age need to be further investigated.
Although the overall risk of cancer was less in ever users, the specific cancers that did demonstrate an association with Pill use had relatively small case numbers (e.g. 19 cases of uterine cancer in the Pill group compared to 13 in the never used group). There is a high possibility that calculated differences between such small numbers have occurred by chance. Further research is needed to see whether there is a direct causal link between hormone treatments such as the Pill and cancer risk and the mechanism behind it.
As the authors say, there has been a substantial loss of subjects during follow-up, and their full dataset represents only two-thirds of their potential cohort.

Overall, this study demonstrates that use of the contraceptive pill is not associated with increased long-term mortality rates, as early research may have suggested.