Recent developments in oral contraception

Contributed by Dr Anne Szarewski, clinical consultant and honorary senior lecturer, Cancer Research UK, Wolfson Institute of Preventive Medicine, London.

Section 1: Combined oral contraception
The combined oral contraceptive pill (COC) fulfils a number of the criteria for an ideal contraceptive.

It is close to 100 per cent effective (see box), is taken independent of sex, easily reversible, easy to take, relatively low cost and the woman can guarantee its use.

It is only available on prescription, but this does not usually entail more than two surgery visits a year for most women.

New combined Pill
Yaz is a new combined pill containing 20 microgram ethinylestradiol with 3mg drospirenone in a 24/4 regimen, ie 24 days of active hormone tablets followed by four days of hormone-free tablets.

Yaz has not yet been launched in the UK, but it is now available elsewhere in Europe and in the USA, where it has proved popular. We are bound to see women who are using it in the UK.

The shorter pill-free interval is beneficial to those who suffer hormone withdrawal symptoms, such as pelvic pain, headaches, bloating and breast tenderness.

In addition, a study comparing a 21/7 regimen with the 24/4 regimen has shown that the risk of ovulation was much higher in women on the 21/7 regimen.1

Even with the normal seven-day break and no missed pills, one woman in 50 of that group ovulated. When the pill-free interval was increased to 10 days, four women in 50 ovulated. No ovulations occurred with a four-day interval.

The 24/4 regimen may therefore improve efficacy in the real world, where we know women often forget to take their pills.

Failure rates of different methods
Method Failure rates per 100 women-years
Sterilisation male0.0 to 0.2
Sterilisation female0.0 to 0.3 (1.8% at 10 years)
Implanon0.0
Mirena0.0 to 0.2
Depo-Provera
0.0 to 0.2
Combined pill0.2 to 3 (3 with poor compliance)
Progestogen-only pill
(second generation)
0.3 to 4 (0.5 over age 35)
IUDs 0.3 to 2
NuvaRing
0.64 to 1.39
Diaphragm/cervical cap
5 to 20
Condom (male, female)
5 to 15
Coitus interruptus
8 to 17
Natural methods5 to 25
Spermicides
5 to 25
Levonelle
1 to 3% (best within 24 hours)
Postcoital
IUD <1%

 

Section 2: Risks of oral contraception

Venous thromboembolism
The combined pill (of whatever generation) carries a small, but real risk of venous thromboembolism (VTE), and this should be explained to women. We should be aware of the risk factors for VTE, in particular a family history in a first-degree relative under the age of 45.

Thrombophilia screening is helpful, but a negative result is not conclusive, as even among women who have had a VTE, only about 50 per cent will demonstrate a thrombophilia using the tests currently available.

Risk of venous thrombosis is increased in pill users, particularly those who are obese and/or smoke (photograph: I LAZARETH, ISM / SCIENCE PHOTO LIBRARY)

Other risk factors
Obesity (BMI over 30) and increasing age (over 35) are both significant risk factors.

Results from a large post-marketing surveillance study suggest no difference in VTE rates between second- and third-generation pills, or Yasmin.2

The same study suggests all VTE rates are higher than previously thought: around 90 per 100,000 women-years for the COC, and on average 290 per 100,000 women-years in pregnancy.

For women with a BMI over 30, the risk was 230 per 100,000. Increasing age was also a significant risk factor.

It has generally been held that the risk factors for arterial and venous thrombosis are different, although in recent years it has been recognised that obesity is an important risk factor for both conditions.

Recent research
Three papers have recently been published from a systematic review/meta-analysis3 and a case-control study,4,5 which suggest that smoking, hypertension and diabetes (as well as obesity) are significantly associated with VTE.

They found that smokers who did not take the pill were at twice the risk of VTE of non-smoking, non-pill users, while smokers who took the pill had eight times the risk (OR 8.79; 95% CI 5.73-13.49), suggesting a synergistic relationship between the two.

Women with a BMI over 30 who took the pill had an OR of 23.78 (95% CI 13.35-42-34) for VTE, while those with a BMI over 30 who did not take the pill had an OR of 3.04 (95% CI 1.66-5.57).

Following publication of the interim results of the EURAS study in 2004, the UK Committee on Safety of Medicines issued a statement confirming that VTE rates for all COCs are similar, and also that the COC should be prescribed with caution to women whose BMI is over 30.6

It is therefore difficult to justify a four-fold risk in women with a BMI over 30 taking the COC when other methods of contraception are available.7

Breast cancer
The risk of breast cancer in oral contraceptive pill users has been discussed at various times over the past 15 years. A large overview of studies published in 1996 suggested a small increase in risk (relative risk 1.24) for women who are current users.8

However, more recent studies of low dose COC use suggest there is no increase in risk of breast cancer for women without a family history.9,10 The same is probably true for those with a family history, but the evidence is less consistent.

Progestogen-only methods are not associated with an increased risk of breast cancer in either group, but non-hormonal methods remain the first-line option in women who have had breast cancer.

Section 3: Benefits of oral contraception
The data on cancer risk have to be viewed in the overall context of benefits as well as risks.

In addition to its high efficacy as a contraceptive, the oral contraceptive pill has many health benefits, including reductions in menstrual cycle disorders and almost complete protection against benign breast disease and benign ovarian cysts.

In addition, it protects against pelvic inflammatory disease and ectopic pregnancy.

Associated benefits
There is some evidence that third-generation COCs are safer for women at risk of arterial disease, adding another layer to the risk-benefit analysis, because some risk factors (now including smoking) for arterial and venous disease overlap.7

Third-generation oral contraceptive pills have benefits in terms of quality of life, but this aspect is difficult to quantify.

Third-generation progestogens, while still giving good cycle control, are less androgenic than second-generation products and therefore tend to be better for women who have problems with acne, hirsutism and weight gain.

Women using COCs are at reduced risk of cancer of the ovary and endometrium. The long-term risk of ovarian cancer is reduced by 40 per cent after four years of use, 54 per cent after eight years and 60 per cent after 12 years.

Importantly, the protective effect is similar for both high- and low-estrogen dose pills.11

The risk of endometrial adenocarcinoma is reduced by 56 per cent after four years of use, 67 per cent after eight years and 72 per cent after 12 years.12

Protection against these two forms of cancer continues for many years (at least 15) after discontinuing use of the oral contraceptive pill.

Evidence is also mounting that COCs offer a similar level of protection against ovarian cancer for carriers of the BRCA1 and BRCA2 mutations.13

Age limitations
Healthy non-smoking women who have no risk factors for cardiovascular disease can take the oral contraceptive pill until they are 50. This is of benefit to many women who may have estrogen-deficiency symptoms in their forties, but who are not yet frankly menopausal and still need contraception.

However, smokers should stop taking the oral contraceptive pill at the age of 35, and women with other cardiovascular risk factors should receive careful assessment above that age.

There is now a good choice of alternative methods that may prove as suitable, without the associated risks.

Section 4: Progestogen-only pills

Cerazette
Cerazette is a relatively new progestogen-only pill (POP) providing 75 microgram desogestrel per day, designed to inhibit ovulation. A study comparing it with Microval showed that 1.7 per cent of cycles were ovulatory in Cerazette users, compared with 40 per cent in Microval users.14

In a randomised trial of Cerazette against Microval, the Pearl Index was 0.5 (user failure) for Cerazette, compared with 1.9 for Microval in non-breastfeeding women.15

Although the bleeding pattern in Cerazette users is more variable than with Microval, there is a greater tendency towards infrequent bleeding and amenorrhoea by the end of year one.

Because of the ovulation inhibition, Cerazette has a 12-hour safety margin, rather than the three hours for conventional POPs.16 This, combined with its higher efficacy, makes it a more attractive proposition for many.

Prescribing in overweight
Doubling the daily dosage of conventional POPs has been suggested as a policy in women who weigh >70kg.

There is, however, no evidence relating to the POP itself to suggest that there is an increased failure rate in overweight women.17

The evidence that does exist relates to a progestogen-only vaginal ring (which was not marketed) and an early version of Norplant; for both of these devices, the failure rate was two to four times higher in women weighing >70kg.

The efficacy of Implanon also appears unaffected by weight. So there seems little justification for such a policy for the POP. In the case of young women using conventional POPs, it might be reasonable to err on the side of caution in view of the already higher failure rate.

It would appear that this will not be necessary with Cerazette, because blood levels are high enough to withstand any effect of increased weight.

  • Contraception Awareness Week 9-15 February. For more information visit www.fpa.org.uk

References
1. Klipping C, Duijkers I, Trummer D, Marr J. Suppression of ovarian activity with a drospirenone-containing oral contraceptive in a 24/4 regimen. Contraception 2008; 78(3): 218-25.

2. Dinger J C, Heinemann L A, Kuhl-Habich D. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance study on Oral Contraceptives based on 142,475 women-years of observation. Contraception 2007; 75(5): 344-54.

3. Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen P W. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation 2008; 117: 93-102.

4. Pomp E R, Rosendaal F R, Doggen C J M. Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use. Am J Haematol 2008; 83: 97-102.

5. Pomp E R, Le Cessie S, Rosendaal F R, Doggen C J M. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br J Haematol 2007; 139: 289-96.

6. Committee on Safety of Medicines. Combined oral contraceptives: venous thromboembolism. Curr Prob Pharmacovigilance 2004; 30: 7.

7. Szarewski A. Contraception and vascular disease. Gynaecology Forum 2005; 10: 23-5.

8. Beral V, for Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: reanalysis of individual data on 53,297 women with breast cancer and 100,239 controls. Lancet 1996; 347: 1,713-27.

9. Vessey M, Painter R. Oral contraceptive use and cancer. Findings in a large cohort study, 1968-2004. Br J Cancer 2006; 95(3): 385-9.

10. Hannaford P C, Selvaraj S, Elliott A M, Angus V, Iversen L, Lee A J. Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioner's oral contraception study. BMJ 2007; 335: 651-9.

11. Beral V et al. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet 2008; 371: 303-14.

12. Burkman R, Schlesselman J J, Zieman M. Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol 2004; 190: S5-22.

13. Elmasry K, Gayther S A. Ovarian cancer aetiology: facts and fiction. J Fam Plann Reprod Health Care 2006; 32: 82-6.

14. Rice C et al. A comparison of the inhibition of ovulation achieved by desogestrel 75mcg and levonorgestrel 30mcg daily. Hum Reprod 1999; 14: 982-5.

15. Korver T, for collaborative group. A double blind study comparing the contraceptive efficacy, acceptability and safety of two progestogen-only pills containing desogestrel 75mcg/day or levonorgestrel 30mcg/day. Europ J Contraception Reprod Health Care 1998; 3: 169-78.

16. Korver T, Klipping C, Heger-Mahn D et al. Maintenance of ovulation inhibition with the 75 microg desogestrel-only contraceptive pill (Cerazette) after scheduled 12-hour delays in tablet intake. Contraception 2005; 71: 8-13.

17. Vessey M. Oral contraceptive failures and body weight: findings in a large cohort study. J Fam Plann Reprod Health Care 2001; 27: 90-1.

Further resources

  • Szarewski A, Guillebaud J. Contraception: a User's Handbook (third edition). OUP, Oxford, 2002.
  • Szarewski A. Contraceptive dilemmas. Altman Publishing, St Albans, 2006.
  • Guillebaud J. Contraception: Your Questions Answered (fifth edition). Churchill Livingstone, Oxford, 2008.
  •  For an archive of all GP clinical reviews visit www.healthcarerepublic.com/clinical/GP

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