Published: July 1998

Publications

Advice on the Use of Combined Oral Contraceptives

Information on this subject has been updated. Read the most recent information.

Prescriber Update 12, July 1996
July 1998

Medsafe Editorial Team

The purpose of this article is to assist medical practitioners and midwives to evaluate the relative risk between products and the individual risk for women of venous thromboembolism when prescribing combined oral contraceptives. It may also help prescribers meet their informed consent obligations as outlined in the Health and Disability Commissioner (Code of Health and Disability Services Rights) Regulations 1996. The article is based on recent advice from the Medicines Adverse Reactions Committee (MARC). The Ministry will continue to monitor any new published information, seek advice from the. Committee and other experts, and keep prescribers informed.

In March 1996 the MARC reviewed the published studies^1-5 and discussion documents on the safety of combined oral contraceptives. The Committee concluded that combined oral contraceptives containing desogestrel or gestodene are associated with a relative risk of venous thromboembolism that is greater than that found for levonorgestrel containing contraceptives.  Although it has been suggested that these results could have been affected by bias and confounding, in the opinion of the Committee the difference in risk cannot be wholly explained by such factors.

When the results of these studies are put in the New Zealand context, it is estimated that the continued use of contraceptives containing desogestrel of gestodene at the current level (approx. 150,000 women) is resulting in approximately 40 women per year suffering from venous thromboembolism. If these women were taking a low dose contraceptive containing levonorgestrel, approximately 20 cases per year of venous thromboembolism could be expected in that population. Although the case fatality associated with venous thromboembolism is low (approx. 1-2%), the occurrence of deep vein thrombosis or pulmonary thromboembolism has a significant impact on many aspects of the lives of these otherwise healthy women.

Prior to publication of these studies, the risk of venous thromboembolism with any combined oral contraceptive was estimated at approximately 2 per 10,000 woman-years. As a result of the recent studies the estimated risk of venous thromboembolism with the contraceptives containing desogestrel or gestodene remains approximately 2 per 10,000 woman-years, but the estimated rate for the low dose contraceptives containing levonorgestrel has now fallen to approximately 1 per 10,000 woman-years. It is the opinion of the Ministry of Health and the MARC that, despite the absolute risk of venous thromboembolism being small, the evidence from the published studies of the differential risk between these products is enough to warrant provision of prescribing advice.

The advice from the MARC, which was confirmed at the Committee's June meeting and is outlined below, recommends careful consideration of the need for initiating prescription of oral contraceptives containing desogestrel or gestodene, and for those already taking these contraceptives it advises a change to the prescription in the presence of thromboembolic risk factors.

The conclusions of the MARC:

• the finding of a higher relative risk of venous thromboembolism in users of desogestrel or gestodene containing oral contraceptives appears to be real and cannot adequately be explained by selection bias or confounding factors;
• contraceptives containing desogestrel or gestodene do not appear to possess significant additional health benefits (for example, reliability of contraception, reduction in the risk of cardiovascular or cerebrovascular disease) above the second generation oral contraceptives, other than improvement in tolerability and quality of life in some patients;
• combined oral contraceptives containing gestodene or desogestrel may offer additional quality of life benefits and may be prescribed for women who have adverse effects such as breakhrough bleeding or androgenic side effects with other combined oral contraceptives; and
• women currently taking contraceptives containing desogestrel or gestodene should have their medication reviewed when their prescription is due for renewal.

In keeping with these conclusions the Committee advises medical practitioners and midwives to consider the following recommendations when prescribing low dose oral contraceptives.⁶

When initiating contraceptive therapy the prescriber should:

• take a comprehensive personal and family history to exclude contraindications to the use of combined oral contraceptives. If there is a family history of thromboembolism, screening for thrombophilia should be conducted in consultation with a haematologist. Hereditary thrombophilia and personal history of venous thromboembolism are contraindications;
• counsel women about the risks and benefits associated with the use of all forms of contraception, taking into account the recent studies on oral contraceptives as outlined in the table below.

Risks of venous thromboembolism

Absolute risk of venous thromboembolism	Risk per 100,000 woman-years*
	WHO Study	GPRD study#	Transnational studyƒ
Never or past use of oral contraceptives	3.9	3.8	-
Current use of low dose contraceptives containing levonorgestrel	10.3	16	-
Current use of low dose contraceptives containing desogestrel or gestodene	21	28	-
Adjusted risk ratio (95% CI‡) Desogestrel or gestodene: levonorgestrel	2.6 (1.4-4.8)	2.2 (1.0-4.7)	1.5 (1.1-2.1)

*	The risk of venous thromboembolism in pregnancy and immediately post-partum is approximately 60 per 100,000 woman-years.
#	United Kingdom General Practice Research Database study, ref 3.
ƒ	Ref 5.
‡	Confidence interval.

• consider prescribing a low dose combined oral contraceptive, containing no more than 35mcg, ethinyloestradiol and a progestogen other than desogestrel or gestodene, where the woman has no contraindications to the use of a combined low dose oral contraceptive and has indicated that she wishes to take a combined oral contraceptive. Prescribe a pill containing a higher dose of oestrogen only if it is specifically indicated.

When reviewing combined oral contraceptive therapy the prescriber should:

• review the personal and family history to identify contraindications for the use of combined oral contraceptives and risk factors for venous thromboembolism as for initiation of therapy;
• counsel about the risks and benefits associated with the use of the contraceptive the woman is currently taking compared to the risks and benefits of other forms of contraception;
• if contraindications to the use of combined low dose oral contraceptives are present, another form of contraception should be agreed upon.

For women taking oral contraceptives containing desogestrel or gestodene:

• in the presence of thromboembolic risk factors the woman should be advised to change to a preparation that does not contain gestodene or desogestrel, or to another contraceptive method, as appropriate;
• offer prescription of other hormonal or non-hormonal contraception if, after counselling, the woman finds the relative risk of venous thromboembolism with combined oral contraceptives containing gestodene or desogestrel unacceptable;
• respect the woman's informed choice if she chooses to continue to take her current contraceptive.

Risk factors for venous thromboembolism (VTE)

Historical	family history of VTE personal history of VTE*
Genetic	hereditary thrombophilia* (Leiden Factor V mutation)
Acquired predisposition	extensive varicose veins obesity (body mass index of ≥30 kg/m² lupus anticoagulant malignancy
Mechanical	immobility trauma surgery
Physiological	dehydration

*Contraindications for combined oral contraceptives.

Note: To assist women become better informed we included with this issue of Prescriber Update copies of a leaflet entitled "Advice for Women About Oral Contraceptives". Copies were included for medical practitioners, midwives and pharmacists.

The leaflet has since been update.  The new leaflet, entitled Oral Contraceptives and Blood Clots is available on this Website.

References

1. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Venous thromboembolism and combined oral contraceptives: results of international multicentre case-control study. Lancet 1995;346:1575-82.
2. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995;346:1582-88.
3. Jick H, Jick SS, et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995;.346:1589-93.
4. Bloemenkamp KWM, Rosendaal FR, et al, Enhancement by. factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestogen. Lancet 1995.346:1593-6.
5. Spitzer WO, Lewis MA, et al. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. Brit Med J 1.996;312:83-8.
6. These recommendations are based on those of the Faculty of Family Planning and Reproductive Health Care, Royal College of Obstetricians and Gynaecologists, London. See Mills AM Wilkinson CL Bromham DR, et al. Guidelines for prescribing combined oral contraceptives. Brit Med J 1996;312:121-2.