Venous thromboembolism
High-dose oestrogen preparations are associated with an increased risk of venous thromboembolism. It was previously thought that using low-dose preparations would substantially reduce this risk, but it has become apparent that the effect is also dependent on a complex interaction with the progestogen component. Second-generation COC pill use, compared with no use, shows a relative risk of 3.2; third-generation preparations demonstrate a relative risk of 4.8.

The incidence of venous thromboembolism in the general population is five per 100,000 per year. The incidence in second-generation COC pill users is 15 cases per year, and in third-generation COC pill users 25 cases per year. To put this risk into perspective, 60 cases per 100,000 occur in pregnancy each year. Despite this apparent association, however, a population screening approach for pro-coagulant conditions before prescribing the pill has been found to be neither feasible nor cost beneficial.
Cerebrovascular events

Ischaemic stroke occurs in five per 100,000 women per year in the population who are usually prescribed the pill. The use of COC pills is an independent risk factor for ischaemic stroke by a factor of 1.5. In patients who are also hypertensive the risk of stroke is doubled, and for patients who also smoke the risk is comparatively trebled.

The additional risk is apparent in the first six to 18 months but returns to normal after cessation, with no apparent benefit between second- and third-generation preparations. Patients who carry the Factor V Leiden mutation have a 13 times greater risk of ischaemic stroke on the contraceptive pill, while homocysteinuria patients have a nine-fold increase. There appears to be no increased risk of haemorrhagic stroke in patients under the age of 35 years without additional risk factors.

Cardiovascular disease
Oral contraceptive use is associated with an increased risk of myocardial infarction (RR=1.84). Many studies have attempted to attribute this as a direct causal effect. Several recent studies have shown that in patients younger than 35 years with an uncomplicated medical history and no additional risk factors (i.e. hypertension, smoking or obesity) there is no significant additional risk. But in women older than 35 there appears to be a two- to three-fold increase in the incidence of cardiovascular events amongst those who take combined oral contraception.

Several studies have looked at the role of differing formulations of progesterone and their cardiovascular effect. Although there is no conclusive evidence, it has been suggested that there may be a reduced cardiovascular risk associated with third-generation preparations over second-generation pills. Interestingly, there seems to be no accumulative incidence of myocardial infarction in patients with a prothrombotic condition who use the oral contraceptive pill and those who do not use it.

Hepatic disease
A recent meta-analysis of oral contraceptive use failed to prove a statistical link between such use and hepatic cancer, despite discrepancies in the literature suggesting increases ranging from two to twenty times. It has been suggested that further studies are required that focus on the duration, intermittency and recency of oral contraceptive use.

Gallstones
There remains a strong correlation between oral contraceptive use and incidence of gallstones, although this is dependent on age. In patients aged 21–30 years using the COC pill, 39% have ultrasound evidence of gallstones compared with 14% in non-users. In COC pill users aged 31–40 years, 40% have evidence of gallstone disease compared with 18% in non-users. An inverse pattern has been seen in older patient groups, although this may be explained by the small number of patients using COC at this age.

Conclusion
Although widely criticised, the Royal College of General Practitioners’ study observed a 12% overall reduction in cancer diagnosis in women taking the COC pill. However, as discussed, it took no account of the increase in breast cancer risk consistently observed in other studies. In spite of this, the important question remains: of the 30 to 40 deaths per year attributed to use of the pill, how many would not have died if they were not prescribed combined oral contraception?

Conversely, how many women would have died through conditions related to pregnancy and childbirth if they had not had access to this undeniably effective form of birth control? The design of a public health model becomes even more complex when adjusting for morbidity alongside mortality, particularly when considering the differing healthcare systems across the developing world. For now the crucial question looks likely to remain: is the oral contraceptive pill friend or foe?

References

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  7. International Collaboration of Epidemiological Studies of Cervical Cancer, Appleby P, Beral V, Berrington de Gonza’lez A et al. Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet 2007; 370(9599):1609–21.
  8. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Invasive squamous-cell carcinoma and combined oral contraceptives: results from a multinational study. Int J Cancer 1993; 55:228-36.}

Dr R Russell, Specialist Registrar, Liverpool Women’s Hospital, UK
Mr C Kingsland, Consultant gynaecologist, Liverpool Women’s Hospital, UK