• Hormonal contraceptives: tailoring for the individual
  
• Contraception in special circumstances
• Missed pills
• Adverse effects
• Non-oral hormonal contraceptives
• Case study 50: Individualising hormonal contraception

Erratum (published December 2009)

In Table 1 we have provided information on the failure rates of various contraceptives. In this table the ‘typical use’ failure rate of both the combined oral contraceptive pill and the progestogen oral contraceptive pill were reported to be 8% during the first year of use. After review, NPS wish to clarify the comparative effectiveness of the combined pill and the progestogen only pill. The effectiveness of the progestogen only pill may be lower than the combined pill during typical use. We have added a footnote to the table to this effect.

The data in Table 1 were taken from a 1995 United States survey (the National Survey of Family Growth). However, this survey did not differentiate between the combined and progestogen only pills. Furthermore, it noted that that most women were expected to be using a combined pill rather than a progestogen only pill and that the failure rate was likely to reflect this. The failure rate of the progestogen only pill may be higher than that of the combined pill because of a higher likelihood of imperfect use. If the timing of a progestogen only pill varies by more than 3 hours, contraceptive efficacy may be reduced. In contrast, the combined pill should remain effective if taken within 24 hours of the usual time. In addition, a recent UK study (published in 2009) showed the risk of an unintended pregnancy among women taking a progestogen only pill was almost double that of the combined pill (hazard ratio 1.8, 95% confidence interval [CI] 1.6 to 2.4) although both progestogen and combined typical use failure rates were lower than those reported in the US survey — 0.43 per 100 woman years (95% CI 0.37 to 0.50) and 0.16 per 100 woman years (95% CI 0.14 to 0.17), respectively.

There are no similar data for the vaginal ring. Therefore, the failure rate is based upon that of the contraceptive pill as it is not expected to be any less effective.

Hormonal contraceptives: tailoring for the individual

When appropriate, discuss hormonal contraceptives in the context of sexual health and remind patients about safe sex practices.

More than one-third of Australian women aged between 16 and 60 years use some form of hormonal contraceptive.[1] With new products continually emerging on the market, health practitioners may find it difficult to keep up to date. This NPS News explores the range of hormonal contraceptives currently available in Australia and factors to consider when initiating or modifying prescribing.

Benefits of hormonal contraceptives

Hormonal contraceptives are very effective and have given women unprecedented fertility control. Most have well-defined safety profiles because of their long and widespread use. There are also some non-contraceptive health benefits associated with certain hormonal contraceptives. These include reduced risks of ovarian and endometrial cancers, benign breast disease and menstrual cycle disorders.[2–7]

Choosing the right hormonal contraceptive

Hormonal contraceptives encompass a variety of oestrogen/progestogen and progestogen-only formulations, delivered in several ways (see Table 1). Discuss the advantages and disadvantages of each modality with individual patients (Table 1), taking into account:

• age (give special consideration for adolescents and women over 35)
• risk for sexually transmitted infections
• adherence issues
• parity
• time frame for returning to fertility after contraceptive use
• suitability when breastfeeding
• smoking
• regular use of enzyme-inducing drugs or complementary medicines (e.g. St John’s wort)
• comorbidities (e.g. metabolic syndrome, obesity, menstrual disorders, acne, etc)
• risk factors for cardiovascular conditions or cancer.

Long-term hormonal contraception

For women seeking long-term contraception, four long-acting methods are available:

• etonogestrel implant (Implanon)
• levonorgestrel-releasing intrauterine device (IUD; Mirena)
• depot medroxyprogesterone acetate (DMPA) injection (Depo-Provera)
• ethinyloestradiol/etonogestrel-releasing vaginal ring (NuvaRing).

These methods are effective and, except for the vaginal ring, are relatively independent of user adherence. Consider the merits of each of the long-acting contraceptives (see Table 1) and individual suitability (Figure 1).

Table 1: Hormonal contraceptive types, failure rates, risks and additional indications
(Click on the Table 1 graphic to see a larger version in PDF format)

Figure 1: Suitable candidates or conditions across the oestrogenic to progestogenic spectrum of oral contraceptives (A) and for the long-acting contraceptives (B).
(Click on the Figure 1 graphic to see a larger version in PDF format)

Hormonal contraceptives in special circumstances

Adolescents

Discuss the potential and perceived non-contraceptive effects of hormonal contraceptives (e.g. reduced premenstrual symptoms, regular menstruation, weight gain, headaches, etc.) with adolescents. As appropriate, prescribe a low-dose (20 microgram ethinyloestradiol) monophasic combined oral contraceptive.[8] Consider an implant or vaginal ring if adherence is likely to be a problem. Provide counselling about safe sex.

Women with cardiovascular risk factors

Cardiovascular risk is an important consideration in choosing an appropriate hormonal contraceptive. Combined oral contraceptives increase cardiovascular risk in women who have one or more cardiovascular risk factors including:

• smoking, in women over 35
• obesity (body mass index > 30 kg/m²)
• uncontrolled hypertension, hyperlipidaemia or diabetes with vascular disease
• family history of cardiovascular disease before age 50.[9,10]

Consider non-hormonal or progestogen-only methods (progestogen-only pill, DMPA, etonogestrel implant or levonorgestrel-releasing IUD) first in such women.

Women over 35

For women over 35, consider non-hormonal or progestogen-only methods first if there are other cardiovascular risk factors.[8–10] Combined oral contraceptives can be used by women over 35 without cardiovascular risk factors.[9]

Metabolic syndrome or diabetes

Consider non-hormonal contraceptives first in women with metabolic syndrome, as they have multiple cardiovascular risk factors.[11] Hormonal contraceptives can generally be prescribed in non-smokers who have diabetes without nephropathy, retinopathy or neuropathy, although evidence is limited.[10,12,13]

Smokers

Combined oral contraceptive use in heavy smokers substantially increases cardiovascular risk.[10,14]

Use of enzyme-inducing drugs

Hepatic enzyme–inducing drugs (e.g. phenobarbitone, phenytoin, carbamazepine, oxcarbazepine, topiramate, rifampicin, griseofulvin and St John’s wort) can interact with hormonal contraceptives and reduce their efficacy. Consider other contraceptives first (e.g. levonorgestrel-releasing or non-hormonal IUD or DMPA). Alternatively, tri-cycle[a] combined oral contraceptives (containing 50 microgram ethinyloestradiol) with a 4-day pill-free period after each 3-packet cycle.[9] Etonogestrel implants are not recommended for patients on hepatic enzyme–inducing drugs.[15,16]

Menstrual disorders

(Menorrhagia/dysmenorrhoea)

Initiate therapy with a monophasic combined oral contraceptive. If menorrhagia or dysmenorrhoea remains uncontrolled, tri-cycle pills to reduce the frequency of withdrawal bleeding.[17] The levonorgestrel-releasing IUD is an alternative for managing menorrhagia.[9]

[a] ’Tri-cycling’ involves continuous use of active pills for 2 months and only having an inactive pill or pill-free period in the 3rd month.

Missed pills and emergency contraception

If an active combined oral contraceptive pill has been missed, the missed pill should be taken as soon as possible and the remaining pills should be taken as usual. If the active combined oral contraceptive pill has been missed by > 24 hours, an additional method of contraception is needed or intercourse should be avoided for 7 days. Consider emergency contraception if the missed pill was from the first 7 days of the pack and the woman had unprotected intercourse in the previous 5 days.[9] If the missed pills were in the week before the inactive pill or pill-free week, the woman should finish the active pills in the current pack and begin with the active pills in the next pack (i.e. skip the inactive pills or pill-free week).[17]

If a progestogen-only pill has been missed by > 3 hours, the missed pill should be taken as soon as possible. An additional method of contraception is needed or intercourse should be avoided for 2 days (i.e. until 3 consecutive pills have been taken). Consider emergency contraception if the woman had unprotected intercourse during these 2 days.[9]

Adverse effects

Managing minor adverse effects

Adverse effects are often cited as reasons for discontinuation of hormonal contraceptives and occur across the oestrogenic to progestogenic spectrum.[18,19] The more common, relatively minor adverse effects can be managed by modifying the oestrogen and/or progestogen dose or type (Table 2) as long as the change does not increase the risk for more serious medical conditions.

Table 2: Managing common adverse effects of combined oral contraceptives[8,9]

Adverse effect	Action needed	Examples of pill change
Acne	Reduce or change progestogen to a less androgenic formulation	Microgynon 30/Brevinor to Diane ED/Marvelon
Amenorrhoea	Increase oestrogen or decrease progestogen	Nordette/Microgynon 30 to Microgynon 50
Breakthrough bleeding • early to mid cycle • late cycle	Increase oestrogen Increase progestogen or change type	Microgynon 30/Brevinor to Microgynon 50 Triphasil to Nordette Nordette to Norinyl-1
Breast problems • fullness/tenderness   • mastalgia	Decrease oestrogen   Decrease progestogen	Microgynon 30/Brevinor to Microgynon 20 Nordette/Microgynon 30 to Triphasil/Triquilar
Chloasma	Stop oestrogen Try progestogen-only pill Avoid direct sun (use sunscreen)
Depression	(No evidence to guide management, pill change may help)
Headache • migraine with aura • in pill-free week	Discontinue pill Add oestrogen daily during pill-free week Tri-cycle pills to avoid the pill-free week
Libido loss	(No evidence to guide management, pill change may help)
Nausea/vomiting	Decrease or change oestrogen or stop oestrogen or take pill at night	Change to Microgynon 20, Loette or progestogen-only pill
Weight gain • constant   • cyclic	Decrease or change progestogen   Decrease oestrogen	Nordette/Microgynon 30 to Brevinor or Marvelon Microgynon 30/Brevinor to Microgynon 20

Cardiovascular risks

Venous thromboembolism

Combined oral contraceptive users have a higher than baseline risk of venous thromboembolism (Table 3) but, as this is rare among reproductive-aged women, the absolute risk is small. Third-generation progestogens (desogestrel or gestodene) may further increase the risk of venous thromboembolism (Table 3) but the risk associated with pregnancy is higher.[20–23]

Table 3: Risk of venous thromboembolism among combined oral contraceptive users[58]

Comparator	Absolute risk (per year per 100,000 women)	Relative risk
Not using combined oral contraceptive	5	BASELINE
Combined oral contraceptive with levonogestrel or norethisterone	15	3-fold increase
Combined oral contraceptive with gestodene or desogestrel	25	5-fold increase
Pregnancy	60	12-fold increase

Note: Risk of venous thromboembolism using combined oral contraceptive with drospirenone (Yasmin) is similar to that of other combined oral contraceptives.[59,60] Risk of venous thromboembolism using combined oral contraceptive with cyproterone acetate (e.g. Diane-35 ED) was reported to be 4-fold higher, compared with combined oral contraceptive with levonorgestrel.[61]

Other factors that increase risk of venous thromboembolism include:

• age[24]
• obesity[24]
• high oestrogen dose[23]
• smoking>[24]
• prothrombotic conditions (e.g. thrombogenic mutations, immobilisation following major surgery)[9,10]
• a family history of venous thromboembolism.[9,10]

Venous thromboembolism risk is highest in the first year of combined oral contraceptive use, particularly in women with thrombogenic mutations.[23,25]

Myocardial infarction and ischaemic stroke

Choose hormonal contraceptives based on overall cardiovascular risk (see above), as this is the primary determinant of myocardial infarction and stroke risk in reproductive-aged women.[26]

Myocardial infarction and stroke are uncommon in non-smoking reproductive-aged women and there is only weak evidence that low-dose combined oral contraceptive use increases the risk of myocardial infarction and ischaemic stroke.[14,27–32] In studies that found an association, the absolute risks with combined oral contraceptive use were low — an estimated 3 extra cases of myocardial infarction per year per 100,000 non-smoking women over 35, and 4.1 extra cases of ischaemic stroke per year per 100,000 non-smoking, normotensive women.[28,30] The presence of other cardiovascular risk factors substantially increased the risk of both conditions.[14,28,29,31,32] Hormonal contraceptives can increase the risk of ischaemic stroke in women who suffer migraines with aura; consider progestogen-only or non-hormonal methods of contraception for these women.[33,34]

Cancer risk

Breast cancer

The small increase in risk of breast cancer in combined oral contraceptive users appears to revert to no excess risk 10 or more years after discontinuation.[35] In practical terms, any excess risk may not be clinically significant, as the incidence of breast cancer is much higher later in life. Indeed, a meta-analysis found little difference between users and never-users in the calculated cumulative number of breast cancers for women up to the age of 50.[35]

Cervical cancer

Current or recent use of hormonal contraceptives may slightly increase the risk of cervical cancer.[36,37] However, the evidence is inconsistent and the effects of other potentially confounding factors, such as sexual behaviour and persistence of human papillomavirus infection, remain unclear.[38–40]

Adverse effects of non-oral hormonal contraceptives

Most of the evidence on adverse effects and serious risks with hormonal contraceptives comes from observational studies. There is less evidence about long-term risks for the other methods. Nonetheless, as these methods also involve the administration of exogenous steroid hormones, the same general principles apply as for prescribing oral contraceptives.

Menstrual disturbances are common with progestogen-only methods. Usually this will manifest as amenorrhoea or infrequent short bleeds, but frequent and/or prolonged bleeding can occur in a minority of users. Counsel all women considering progestogen-only methods about menstrual disturbances before use.

Etonogestrel implant (Implanon)

Menstrual disturbances are a reason for discontinuation in up to 21% of etonogestrel implant users.[41,42] Menstrual disturbances are most likely during the first 3–6 months but may stabilise later.[41] The implant may also be associated with acne.[15,41]

Doctors must attend a training course before inserting or removing etonogestrel implants. Improper insertion can lead to implant expulsion and/or contraception failure. Also, if the implant is inserted too deeply it may be difficult to remove.

Levonorgestrel-releasing IUD (Mirena)

Menstrual disturbances are also common with the levonorgestrel-releasing IUD.[43–45] In an open-label study (N = 678) the cumulative event rate over 5 years for menstrual disturbances was 16.7%.[43] Other potential problems include expulsion (5.9%) pain (4.3%) and functional ovarian cysts (12%), which spontaneously regress.[43, 46]

The absolute risk of ectopic pregnancy with this method is low and is less than when using no contraception.[15] However, in the case of contraception failure, consider the possibility of an ectopic pregnancy.[46]

Depot medroxyprogesterone acetate (DMPA) injection (Depo-Provera)

Menstrual disturbances and weight gain are common reasons for discontinuation of this method.[47,48] Amenorrhoea can be expected in 50% of users after 12 months and 70% of users after 24 months.[49]

Loss of bone mineral density is the most significant risk associated with DMPA injections. This is particularly important in adolescents and very young women, who may not have reached their peak bone mass, and older women with risk factors for osteoporosis.[50–52] In most women bone mineral density returns to normal levels on discontinuation of DMPA.[53] Consider other methods first for long-term (i.e. > 2 years) contraception in these age groups.[52]

Ethinyloestradiol/etonogestrel-releasing vaginal ring (NuvaRing)

In a 1-year study, the incidence of break-through bleeding or spotting with the combined vaginal ring was comparable to that with drospirenone-containing combined oral contraceptives.[54] Vaginitis and vaginal discharge were more frequently reported by women who used the combined vaginal ring than by combined oral contraceptive users.[55,56]

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Useful Resources

Consumer medicine information leaflets
Faculty of Family Planning and Reproductive Health Care of the Royal College of Obstetricians and Gynaecologists
Family Planning NSW
National Institute of Health and Clinical Excellence Long-acting Reversible Contraception guidelines
WHO Medical Eligibility Criteria for Contraceptive Use

Expert reviewer

Dr Edith Weisberg
Director of Research
Family Planning NSW

Reviewers

Dr James Best, General Practitioner
A/Prof Nick Buckley, Clinical Pharmacologist, The Canberra Hospital
Ms Jan Donovan, Consumer
Dr John Dowden, Editor, Australian Prescriber
Ms Debbie Norton, Pharmacist
Ms Susan Parker, Head of Medical Affairs, Pfizer Australia
Ms Simone Rossi, Editor, Australian Medicines Handbook

Any correspondence regarding content should be directed to NPS. Declarations of conflicts of interest have been sought from all reviewers.

References

1. Richters J, et al. Aust NZ J Public Health 2003;27:210–6.
2. Lurie G, et al.Obstet Gynecol 2007;109:597–607.
3. Hannaford PC, Kay CR. Br J Gen Pract 1998;48:1657–62.
4. Rohan TE, Miller AB. Intl J Cancer 1999;82:191–6.
5. Borges LE, et al. Contraception 2006;74:446–50.
6. Davis AR, et al. Obstet Gynecol 2005;106:97–104.
7. Xiao B, et al. Fertil Steril 2003;79:963–9.
8. Murtagh J. Family Planning. In: General Practice. 3rd ed. Sydney: McGraw-Hill, 2003; p. 958-65.
9. Sexual Health and Family Planning Australia. Contraception: an Australian clinical practice handbook. Ashfield: Sexual Health and Family Planning Australia, 2006.
10. World Health Organization (WHO). Medical Eligibility Criteria for Contraceptive Use. Geneva: WHO, 2004.
11. Grundy SM. J Clin Endocrinol Metab 2007;92:399–404.
12. Shawe J, Lawrenson R. Treatments Endocrinol 2003;2:321–30.
13. Visser J, et al. Cochrane Database Syst Rev 2006:CD003990.
14. Rosenberg L, et al. Arch Intern Med 2001;161:1065–70.
15. National Institute for Health and Cinical Excellence (NICE). Long-acting reversible contraception. London: NICE, 2005.
16. Organon (Australia) Pty Ltd. Prescribing Information: Implanon, 1 November 2006.
17. Australian Medicines Handbook. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2007.
18. Huber LR, et al. Am J Obstet Gynecol 2006;194:1290–5.
19. Rosenberg MJ, Waugh MS. Am J Obstet Gynecol 1998;179:577–82.
20. Jick SS, et al. Contraception 2006;73:566–70.
21. Hennessy S, et al. Contraception 2001;64:125–33.
22. Kemmeren JM, et al. BMJ 2001;323:131–4.
23. Lidegaard O, et al. Contraception 2002;65:187–96.
24. Nightingale AL, et al. Eur J Contracept Reprod Health Care 2000;5:265–74.
25. Bloemenkamp KW, et al. Arch Intern Med 2000;160:49–52.
26. Lewis MA. Am J Obstet Gynecol 1998;179:S68–77.
27. Petitti DB, et al. Stroke 1997;28:280–3.
28. Anonymous. Lancet 1997;349:1202–9.
29. Tanis BC, et al. N Engl J Med 2001;345:1787–93.
30. Gillum LA, et al. JAMA 2000;284:72–8.
31. Chan WS, et al. Arch Intern Med 2004;164:741–7.
32. Siritho S, et al. Stroke 2003;34:1575–80.
33. Becker WJ. Neurology 1999;53:S19–25.
34. Chang CL, et al. BMJ 1999;318:13–8.
35. Anonymous. Lancet 1996;347:1713–27.
36. Moreno V, et al. Lancet 2002;359:1085–92.
37. Smith JS, et al. Lancet 2003;361:1159–67.
38. Kjellberg L, et al. Br J Cancer 2000;82:1332–8.
39. Syrjanen K, et al. Anticancer Res 2006;26:4729–40.
40. Castle PE, et al. J Natl Cancer Inst 2002;94:1406–14.
41. Funk S, et al. Contraception 2005;71:319–26.
42. Flores JB, et al. Int J Gynaecol Obstet 2005;90:228–33.
43. Cox M, et al. J Fam Plann Reprod Health Care 2002;28:73–7.
44. Baldaszti E, et al. Contraception 2003;67:87–91.
45. Hidalgo M, et al. s. Contraception 2002;65:129–32.
46. Bayer Schering Pharma. Prescribing Information: Mirena. 12 July 2000.
47. Heber KR. Aust Fam Physician 1988;17:199–201, 204.
48. Paul C, et al. Contraception 1997;56:209–14.
49. Therapeutic Guidelines. Endocrinology. 3rd ed. Melbourne: Therapeutic Guidelines Limited, 2004.
50. Scholes D, et al. Obstet Gynecol 1999;93:233–8.
51. Scholes D, et al. Arch Pediatr Adolesc Med 2005;159:139–44.
52. US Food and Drug Administration. Physician Information: Depo-Provera. 2004. (accessed 10 July 2007).
53. Kaunitz AM, et al. Contraception 2006;74:90–9.
54. Milsom I, et al. Hum Reprod 2006;21:2304–11.
55. Ahrendt H-J, et al.Contraception 2006;74:451–7.
56. Oddsson K, et al. Contraception 2005;71:176–82.
57. Trussell J. The essentials of contraception: Efficacy, safety, and personal considerations. In: Hatcher RA, Trussell J, Stewart FH, et al, eds. Contraceptive Technology. 18th Revised Edition. edn. New York: Ardent Media, Inc., 2004; p. 226–7.
58. Committee on Safety of Medicines (CSM) and Medicines and Healthcare products Regulatory Agency (MHRA). Curr Prob Pharmacovigilance 1999;25:11–2.
59. Heinemann LA, Dinger J. Drug Saf 2004;27:1001–18.
60. Dinger JC, et al. Contraception 2007;75:344–54.
61. Vasilakis-Scaramozza C, Jick H. Lancet 2001;358:1427–9.