Mode of action

CHCs work primarily by inhibiting ovulation. Exogenous oestrogen inhibits the secretion of follicle-stimulating hormone, while progestogens inhibit the development of the luteinizing hormone (LH) surge. The CHC also alters cervical mucus, rendering it hostile to the passage of sperm, and also causes endometrial atrophy.

CHCs are highly effective (Table 29.3). The failure rates associated with all forms of contraception depend on the inherent efficacy of the method, but also on the potential for incorrect or inconsistent use. Since ovulation is inhibited in most women who use the combined pill, failure rates of the method itself are low. However, as inhibition of ovulation depends on reliable pill taking, the overall failure rate of the COC, which includes user failure, is higher.

Table 29.3 Pregnancy rates for birth control methods (for 1 year of use)

^a Used without spermicide.

^b Used with spermicide.

Contraindications

In an analysis of 25 years of follow-up of 46,000 women who took part in the Royal College of General Practitioners’ (RCGP) Oral Contraceptive Study comparing 517,519 years of pill use with 335,998 years of never-use, the risk of death from all causes was similar in ever-users and never-users of oral contraception (Beral et al 1999). Among current and recent users (within 10 years), the relative risk (RR) of death from ovarian cancer was significantly decreased (RR 0.2), while the risks of dying from cervical cancer (RR 2.5) and cerebrovascular disease (RR 1.9) were increased.

Absolute contraindications to CHC use are listed in Box 29.1. They include either a past history of, or existing, cardiovascular disease, migraine and most liver diseases. Women often describe headaches as migraine. CHCs are contraindicated in migraine which is or may be associated with transient cerebral ischaemia. A recent study designed to investigate the risk between migraine and stroke in young women demonstrated a significant increase in the risk of ischaemic, but not haemorrhagic, stroke in women with a personal history of migraine both with and without aura (classic and simple). Concomitant use of the CHC further increased this risk (Chang et al 1999). It is important therefore to take a clear and detailed history before refusing to prescribe a CHC because the woman has an occasional migraine.

Relative contraindications to CHC use include the following:

Comprehensive discussions and lists of contraindications are available in most textbooks of contraception, and WHOMEC and UKMEC.

Side-effects of combined oral contraception

Debate continues over the increased risk of cardiovascular events in women taking CHCs. Until reliable data are available for non-oral routes of administration, it is sensible to assume that similar risks apply to all methods. Cardiovascular disease is very rare in women of reproductive age. Venous thromboembolism (VTE) is the most common cardiovascular complication of CHC use. Oestrogen and progestogen are both metabolized by the liver and alter the metabolism of most substances, including carbohydrates and lipids. Oestrogens also alter coagulation factors. A reduction in antithrombin III and alteration in platelet function increase the risk of VTE by up to seven-fold. A clear history of thromboembolism is a contraindication to CHCs. A possible history or a very strong family history are indications for investigating haemostasis, particularly circulating concentrations of antithrombin III and the factor V Leiden thrombogenic mutation. Population screening for inherited thrombophilias is not currently considered to be cost-effective.

Studies in the mid-1990s appeared to show a differential risk of VTE between the second- and third-generation progestogens, the latter being associated with double the risk of the former (Bloemenkamp et al 1995, Jick et al 1995, WHO 1995, Spitzer et al 1996). These findings prompted the UK Committee on Safety of Medicines to advise women at risk of thrombosis to avoid third-generation progestogens. Although well designed, criticisms of these studies include prescriber bias (whereby women with cardiovascular risk factors and new users would be more likely to be prescribed a newer brand) and attrition bias (existing users susceptible to VTE would be less likely to be using older brands). Latterly, the 2005 EURAS study, funded and designed as a postmarketing cohort study to demonstrate the safety of the combined ethinylestradiol/drospirenone pill, found an increased incidence of VTE across the categories (including pregnant women and non-pregnant, non-CHC-using women) with no difference between progestogen used (Dinger et al 2007). Whilst the large numbers in the study (58,674 women and 142,475 women-years) lend strength to its findings, data from the pharmaceutical industry must always be viewed with some reservation. Of additional interest was the reported three-fold increase in risk for women with a body mass index (BMI) above 30 compared with women with a BMI of 20–25. Table 29.4 shows the comparison of risk estimates of VTE from the two sources.

Table 29.4 Absolute risk of venous thromboembolism (VTE)

^a Levonorgestrel alone.

Current CEU advice to prescribers acknowledges the continuing debate over progestogens, and suggests that individual risk of VTE should be a governing principle in choice of contraceptive method.

Arterial disease, including myocardial infarction (MI) and cerebrovascular accident, results from the (mainly) progestogen-related alteration to lipid profiles together with the oestrogen-associated changes in blood coagulation. A WHO expert group reviewed the data on MI, stroke and hormonal contraception; the conclusions are as follows (World Health Organization Scientific Group 1998).

Benefits of combined oral contraception

The CHC confers a number of health benefits. Withdrawal bleeds are usually more regular, lighter and less painful, and the CHC is often the treatment of choice for women with irregular heavy periods (resulting from anovulatory dysfunctional uterine bleeding), premenstrual syndrome, dysmenorrhoea and endometriosis, as ovarian suppression can be achieved without the need for additional contraception (in contrast to danazol). A Cochrane review also concluded that the CHC can improve acne (Arowojolu et al 2009). These benefits can improve compliance significantly (Courtland Robinson et al 1992).

CHC use is associated with a 70% reduction in the risk of endometrial cancer, which may be maintained for up to 15 years after discontinuation (Weiderpass et al 1999). There is a similar duration-dependent reduction in the risk of ovarian cancer (RR 0.64, 95% CI 0.57–0.73) in ever-users compared with never-users (Riman et al 2004), which probably acts through the inhibition of ovulation and lasts for at least 10 years after discontinuation.

Significant numbers of unplanned pregnancies result from women stopping the pill for a ‘break’. There is no evidence that breaks in pill taking reduce the long-term risks. It is not necessary to stop the CHC before planning a pregnancy. There is no evidence of any adverse effect on the fetus of CHC use prior to conception, neither is exposure during pregnancy associated with increased risk of fetal malformation.

Fertility is restored after a delay of 1–3 months, although some women take longer to resume normal cycles. So-called ‘post-pill amenorrhoea’ is almost always associated with cycle irregularity before starting the pill or with coincidental factors associated with secondary amenorrhoea, such as weight loss or stress.

Mode of action

While Cerazette inhibits ovulation in over 90% of cycles, approximately 50% of classical POP users continue to ovulate and menstruate regularly. In these women, the POP works by altering cervical mucus and probably by interfering with implantation. If follicle development is inhibited completely, amenorrhoea results (10–20% of women).

Side-effects

The mode of action of the POP explains its side-effects. Erratic bleeding is the most common cause for discontinuation of the pill; approximately 20% of women will stop using it for this reason.

Follicular growth without ovulation is associated with an increased incidence of functional ovarian cysts. Up to 20% of women using the POP will have a cyst identifiable by ultrasound. Most are symptomless and nearly all resolve spontaneously. A woman found to have a symptomless ovarian cyst should be reviewed after her next menstrual period.

POP use is associated with a slightly increased risk of ectopic pregnancy. Some 2% of pregnancies among POP failures will be ectopic, perhaps as a result of an effect of the progestogen on tubal motility. Since Cerazette inhibits ovulation in almost all cycles, the theoretical risk of ectopic pregnancy is less.

Due to its mechanism of action (50% of women continue to ovulate) and its relatively short half-life (approximately 19 h), the classical POP has a higher failure rate than the COC (see Table 29.3), with users of the established varieties having a 3-h window within which to remember to take their pill. This failure rate is dependent on age and is almost as low as the COC in women aged over 35 years. However, the ovulation-inhibiting Cerazette can be taken in much the same way as the COC with a 12-h window, making it a suitable and reliable choice for younger women as well. There is no direct evidence for advising women who weigh more than 70 kg to take two pills each day.

Injectable progestogens

Long-acting injectable progestogens are available in two forms: DMPA or Depo-provera (150 mg IM every 12 weeks) and norethisterone oenanthate (200 mg IM every 8 weeks). The latter is seldom used in the UK.

Worldwide, DMPA is a popular method of contraception used by some 9 million women in over 90 countries. DMPA appears to exert a powerful protective effect against endometrial cancer with an RR of 0.2. No association has been described between DMPA use and the risk of ovarian cancer, which is surprising if the protective effect of the COC is due to the inhibition of ovulation. The slight increase in the risk of breast cancer among users of both the POP and DMPA identified in the large meta-analysis (Collaborative Group on Hormonal Factors in Breast Cancer 1996) may be due to detection bias; however, there are some concerns that progestins alone may be associated with a real increase in risk.

Depo-provera is a highly effective (Table 29.3

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