‘Recurrent media scares about combined oral contraceptive pills and venous thromboembolism risk create confusion and anxiety for women.’
Stewart M, Chaar B, Bateson D. Combined oral contraceptives. O&G Magazine 2014;16:14-17.1
The daughter of an Australian member of parliament recently made headlines when she developed a venous thromboembolism (VTE) after a long-haul flight. She was 21 years old and taking Diane-35 at the time.2
In Australia Diane-35 is approved for severe acne and hirsutism. However, due to its active ingredients, this medicine can provide contraception as well, although it is not recommended first-line as a contraceptive choice only. Diane-35 was temporarily suspended in France in 2013 following a number of deaths and is not approved in the United States.
All combined oral contraceptive pills (COCPs) carry a risk of causing VTE, but in absolute terms this risk is low, and lower than the risk of VTE for pregnant and postpartum women.3
Other adverse effects are also associated with COCPs, making it essential that health professionals provide clear, balanced, evidence-based information and discuss these risks as part of a thorough consultation when initiating a COCP.1,4
Safe prescribing of contraception
A woman’s choice of contraception will be based on many factors, including efficacy, potential side effects, non-contraceptive benefits, cost and personal preference.5
Contraceptive counselling can provide evidence-based information on the safety, efficacy, advantages and disadvantages of all methods of contraception. This enables women to make choices based on their personal preferences and medical suitability.6 Safe prescribing, taking each woman’s risk factors into account, is paramount in this consultation.1
Guidelines for the safe prescribing of contraception include the World Health Organization (WHO) medical eligibility criteria (MEC). The MEC considers the safety of various contraceptive methods in the context of specific health conditions. These conditions are graded 1-4 and can be viewed as a quick reference chart to facilitate decisions about the best contraceptive choice for an individual.
For COCPs, Table 1 identifies conditions that have been graded 3 or 4, and are considered contraindications.
|Condition||Severity||MEC 3 or 4a|
|Smoking and age ≥ 35 years||< 15 cigarettes/day
≥ 15 cigarettes/day
Stopped smoking < 1 year ago
|Body weight||BMI ≥ 35 kg/m2||3
Consistently elevated systolic between 140 and 159 mmHg or diastolic between 90 and 94 mmHg
Consistently elevated systolic ≥ 160 mmHg or diastolic ≥ 95 mmHg
|Past history of ischaemic heart disease, stroke or TIA||--||4|
|Complicated valvular and congenital heart disease||--||4|
|Migraine with aura||Current|
Past history, with none for 5 years
a MEC 3 & 4 conditions are considered contraindications to the COCP.
MEC 3 is a condition where the theoretical or proven risks generally outweigh the advantages of using the method. The provision of a method requires expert clinical judgement and/or referral to a specialist contraceptive provider, since use of the method is not usually recommended unless other more appropriate methods are not available or acceptable.
MEC 4 is a condition that represents an unacceptable risk if the contraceptive method is used.
There has long been a hypothesis that use of the COCP is linked with depression. A 2016 prospective cohort study of 1,061,997 women reported that the relative risk (RR) of first time antidepressant use is 23% higher in COCP users (RR 1.23, 95% confidence interval [CI] 1.22 to 1.25) when compared with non-users. Adolescents had a RR of 1.80 (95% CI 1.75 to 1.84).7
The study was based on registry data in Denmark, and concluded that the use of hormonal contraception, especially among adolescents, was associated with subsequent use of antidepressants and a first diagnosis of depression, suggesting depression as a potential adverse effect of hormonal contraceptive use.7
The authors suggest further studies are needed that investigate depression as a possible side effect of hormonal contraception to see if the results can be repeated in other populations.7
What is the combined oral contraceptive pill?
The COCP contains synthetic forms of both oestrogen and progesterone (progestogen). The COCP was introduced to Australia in 1961, and women rapidly adopted it as a reliable way to separate sex and reproduction and help them plan their children.4,6
Despite the wide range of contraceptives currently available in Australia, the combined oral contraceptive pill remains the most commonly used method.1
If a woman wishes to try the COCP, a number of things need to be considered before prescribing. It is important to allow enough time in your consultation (at least 20 minutes) to undertake a thorough medical and sexual history and discuss key points of information the woman needs to know.4
Ask your patient
Medical and family
Do you have personal or family history of factors that increase the risk of:4
- venous thromboembolism (VTE)
- coronary artery disease
- migraine with aura
- transient ischaemic attack
What concurrent medicines are you on?4
Do you have conditions that might benefit from a particular sort of contraception like acne, hirsutism and heavy bleeding or pain?4
If she is sexually active, and you can clarify that this includes vaginal intercourse, ask about:4
- sexual and reproductive health
- current or previous use of contraception
- previous gynaecological procedures
- risk of sexually transmitted infections (STIs)
- previous pregnancies and outcomes
- plan for future pregnancies
- cycle length
- date of last period to rule out pregnancy
If she is a smoker, which category is appropriate?
- < 15 cigarettes/day
- ≥ 15 cigarettes/day
- Stopped smoking < 1 year ago
Ask your patient:
Examine your patient
- Measure blood pressure
- Assess body weight
- No other routine investigations are necessary
Discuss with your patient
How the COCP works
- Brief explanation of the menstrual cycle and ovulation if necessary4
- COCP supresses ovulation and failure rate is 0.3% when used correctly4
- Advice on condoms to protect against STIs5
- Difference between hormone and inactive pills in the chosen pill pack5
- Differences between brands
How to start the pill
- General side effects
- More serious side effects
- Concurrent use of liver enzyme-inducing medications
- What constitutes a missed pill
- Availability of emergency contraception4
Pills that are listed on the PBS are more affordable
Initiating the combined oral contraceptive pill
Consider prescribing a COCP if there are no medical contraindications. A COCP can be continued until the age of 50 years.4
A low-dose pill containing 35 micrograms or less ethinyloestradiol (EE) and levonorgestrel or norethisterone is the recommended first choice in Australia.5 This combination is considered to have the ‘gold standard’ safety profile, with a low risk of VTE.5,6
Most low-dose pills (30/35 micrograms EE) are listed on the PBS and are cost-effective options.5
There are also even lower dose pills containing 20 micrograms EE. These are not listed on the PBS and are less likely to have good cycle control, with an increase in unscheduled bleeding.5,6
The COCP is contraindicated for women:4
- less than 6 weeks postpartum and breastfeeding (MEC 4)
- breastfeeding ≥ 6 weeks to 6 months, fully or mostly breastfeeding (MEC 3).
Discuss the package directions with each patient as packaging in Australia varies. Some packaging directs women to start with an ‘active hormone pill’ and older packaging instructs women to start with either a placebo pill or an active pill depending on the time of their menstruation. These variations also result in a difference in when the COCP is effective, which can be immediate or up to 12 days.4,5
Pills containing cyproterone with 35 micrograms EE are reserved for women with the androgenic side effects of severe acne and hirsutism.
However, they are not first line for acne. The oestrogen in any COCP may improve acne, even at low dose or combined with an androgenic progestogen.5
Discuss the increased risk of VTE with all COCPs and that pills containing cyproterone with 35 micrograms EE are in a higher risk bracket.
Only prescribe pills containing cyproterone with 35 micrograms EE for a limited period of time, and review and discuss VTE risk if the prescription is repeated.
If you are seeing a woman on a pill containing cyproterone with 35 micrograms EE that was prescribed elsewhere, discuss the risk of VTE and note that this medicine is only recommended for short-term use. Provide the opportunity to change to another COCP.
In the past few decades, new progestogens have been introduced to help improve the androgenic effects of acne and hirsutism. These include cyproterone, dienogest, drospirenone, desogestrel and gestodene.
Diane-35 contains 35 micrograms EE with cyproterone, and is TGA-approved for severe acne and hirsutism in women, but is not PBS-listed. It is only approved for short to medium-term treatment of these conditions, and is not recommended first-line as a contraceptive choice only.3,8
Diane-35 is also available in Australia under the trade names Brenda-35, Juliet-35, Estelle-35, Laila-35, Carolyn-35 and Jene-35.3,5,6
The evidence for benefit of the newer progestogens remains limited, and they are not PBS-listed. Further, they have an increased risk of VTE, compared with levonorgestrel and norethisterone pills,5,6 and are more expensive.
A 2017 systemic review of 39 studies reported that COCPs led to significant reductions in acne lesion counts compared to placebo, however with increased odds of VTE. The review concluded that COCPs are safe and effective in patients with adult-onset acne refractory to conventional treatments. However, appropriate clinical examination, screening and individual risk assessment for VTE must be conducted.9
Many side effects are attributed to COCPs, but evidence of direct cause and effect is limited. General side effects include headache, nausea, breast tenderness, amenorrhoea, bloating, mood changes, reduced libido and weight gain.5
Breakthrough bleeding (BTB) is common in the first 1–2 packets but should settle. Lower dose pills containing 20 micrograms EE are more likely to cause BTB as they may give poorer cycle control than those containing 30 micrograms. Persistent BTB when the pill is taken correctly needs investigation.5
These general side effects usually settle with time.5
As a prescriber you should be aware of the serious risks, including the absolute risk for women of reproductive age. Serious risks include VTE, ischaemic stroke and myocardial infarct.4
COCPs increase the risk of VTE, but the absolute risk of VTE remains low, particularly for those without other risk factors, and is much lower than the risk during late pregnancy or the postnatal period. The risk is greatest in the first 4 months after initiation.1,5,6
Oestrogen and VTE risk
The first COCPs contained relatively high doses of oestrogen, which was associated with a relatively high risk of VTE, due to the effect of oestrogen on the synthesis of clotting. The development of COCPs with lower doses of oestrogen, equivalent to 35 micrograms of EE or less, have since reduced this risk, without an apparent loss of contraceptive efficacy.1,6
However, a lower risk of VTE for pills containing 20 micrograms EE is unproven for formulations available in Australia.4
Progesterone and VTE risk
On the basis of published studies, the TGA has concluded that the risk of VTE with use of products containing cyproterone acetate with EE, such as Diane-35, appears to be around 1.5 to 2 times higher than for COCPs containing the progesterone levonorgestrel, and may be around 4 times the risk for non-users of COCPs.3
However, evidence of this risk with cyproterone acetate is based on relatively small case-control studies.1 Internationally, Diane-35 was temporarily suspended in France in 2013, following a number of deaths, and then reintroduced after 8 months when the European Commission evaluated it to be safe for use.10,11
In Australia, although the TGA concluded that there is an increased risk of VTE in women prescribed pills containing cyproterone acetate with EE, it determined that the medicine’s benefits continue to outweigh the risks when used for the indications approved by the TGA and outlined in the Product Information (such as acne and hirsutism).3
Prescribers should be mindful of the contraindications and precautions outlined in the Product Information for products containing cyproterone with EE, and should:3
- weigh the clinical needs of each woman against the possible slight increase in the risk of VTE
- inform women about the increased risk of VTE
- educate women to recognise the signs and symptoms of VTE.
There is also an increased VTE risk with the third-generation progestogens desogestrel, gestodene and drospirenone, compared with the more androgenic second-generation progestogens levonorgestrel and norethisterone, however the evidence is limited.4-6
A 2017 systematic review and meta-analysis assessing risk of VTE, focussing on drospirenone, concluded that VTE risk was, at worst, very small, and that choice of progestin should not be the sole factor considered when choosing the ‘right’ COCP for each woman.12
Assess for VTE risk as part of your history
A thorough history is important to assess individual patient risk. MECs for VTE and risk factors include:4
- history of VTE (MEC 4)
- current VTE (on anticoagulant) (MEC 4)
- VTE in first degree relative at age < 45 years (MEC 3)
- major surgery with prolonged immobilisation (MEC 4)
- immobility, unrelated to surgery, such as a long flight (MEC 3)
- known thrombogenic mutation (MEC 4).
Women should be advised of the risks of VTE with a COCP and be aware of the signs. Inform them that the risk increases with:13
- smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age)
- obesity (body mass index over 30 kg/m2)
- valvular heart diseaseb
- atrial fibrillation.b
If a woman is about to start a COCP but is travelling in a few weeks, consider delaying until she returns. For a woman already established on a COCP, provide general advice to reduce risks and mention compression stockings.
If a woman has a significant risk factor for VTE, no combined hormonal method will be suitable for her. Progestogen-only methods are safer for women with risk factors for VTE.1,6
Provide general advice on the risk of VTE when starting the COCP. Advise women to contact their doctors immediately, or go to the nearest Emergency Department, if they develop any symptoms of blood clots, such as:3
- persistent leg pain or tenderness
- swelling, warmth and redness of the leg
- severe chest pain
- sudden shortness of breath or difficulty breathing.
b You are unlikely to have to discuss this risk with younger women.
Ischaemic stroke and myocardial infarct
Although COCP use is associated with an increased risk of ischaemic stroke and myocardial infarct, the absolute risk is very low for most women of reproductive age. Risks are highest in older women and in those with additional risk factors for cardiovascular disease.4
The myth about antibiotics
A COCP is not considered missed until it is more than 24 hours late, equivalent to 48 hours since the last pill was taken.4 Advise women to take the pill as soon as they remember and take the next one at the usual time. Highest risk of lack of contraceptive efficacy occurs if the active pill-free week is extended, for example forgetting to start a new packet.5
Family Planning NSW have a fact sheet on the COCP, which includes information on what to do after missing a pill. The PI and CMI for each individual medicine will also provide guidance on how to manage missed pills.4
It is important to discuss doubling up with condoms and access to emergency contraception with all pill users.4
Cost can be an important factor for women when selecting contraceptive methods.
Be mindful that not all COCPs are subsidised under the PBS.5
For example, only one of the low-dose 20 microgram EE and levonorgestrel (Femme-Tab ED 20/100) is currently PBS-listed.5
Since 2010, newer formulations containing oestradiol or its prodrug oestradiol valerate in place of EE have been available.1 These are not PBS-listed.1,5,6 None of the newer progestogens are listed on the PBS.c,5
Out-of-pocket cost for newer non-PBS-listed pills can be up to $120 for 4 months.6
c Newer progesterones include desogestrel, gestodene, cyproterone acetate, drospirenone, dienogest, and etonogestrel.
The evidence for one COCP over another in relation to troublesome side effects is limited, and it may take trial and error to find the most appropriate formulation to suit an individual woman.1
Providing a short, 4-month prescription gives you the opportunity to review any adverse effects with patients after commencing the pill and to recheck blood pressure.
If a woman is experiencing adverse effects, trying another formulation may be helpful, but another form of contraception may be necessary.6
Strategies for managing common ‘general’ adverse effects of the COCP are outlined in Table 2 of Stewart M, Black K. Choosing a combined oral contraceptive pill. Aust Prescr 2015;38:6-11.
- Stewart M, Chaar B, Bateson D. Combined oral contraceptives. O&G magazine 2014;16:14-7.
- Smethurst A. Contraceptive pill led to blood clot and deep vein thrombosis, nearly killing MP’s daughter. Daily Telegraph 23 July 2017 (accessed 12 October 2017).
- Therapeutic Goods Administration. Cyproterone: Products containing cyproterone with ethinyloestradiol, such as Diane-35. Canberra: TGA, 2013 (accessed 12 October 2017).
- McNamee K, Harvey C, Bateson D. A practical guide to contraception. Part 1: Contraceptive pills and vaginal rings. 2013 (accessed 9 October 2017).
- Family Planning New South Wales, Family Planning Victoria, True Relationships and Reproductive Health. Combined hormonal contraceptives. In: Contraception: an Australian clinical practice handbook. 4th edn. Sydney, 2016;83-122.
- Stewart M, Black K. Choosing a combined oral contraceptive pill. Aust Prescr 2015;38:6-11.
- Skovlund CW, Morch LS, Kessing LV, et al. Association of hormonal contraception with depression. JAMA Psychiatry 2016;73:1154-62.
- Arowojolu AO, Gallo MF, Lopez LM, et al. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev 2012:CD004425.
- Trivedi M, Murase J, Anderson A. A review of hormone-based therapies in the treatment of adult acne: Safety and efficacy [2A]. Obstet Gynecol 2017;129:9S.
- Reuters staff. Bayer says reintroducing Diane-35 in France. Reuters 2014 (accessed 3 November 2017).
- Scott S. Australian women still being prescribed Diane-35 as contraceptive pill despite regulator warnings. ABC News 2013. (accessed 3 November 2017).
- Bateson D, Butcher BE, Donovan C, et al. Risk of venous thromboembolism in women taking the combined oral contraceptive: A systematic review and meta-analysis. Aust Fam Physician 2016;45:59-64.
- Bayer Australia Ltd. Dianne-35 ED Product Information. 2017 (accessed 12 October 2017).