Contraception Update August 2008

Contraceptive efficacy Pearl Index Life Table Analysis Perfect use Typical use

Current use of contraception by age, 2005/6 ONS, 2007

www.ffprhc.org.uk www.fsrh.org.uk

LARC – NICE Guidelines Contraceptive service providers should be aware that: all currently available LARC methods (intrauterine devices [IUDs], the intrauterine system [IUS], injectable contraceptives and implants) are more cost effective than the combined oral contraceptive pill even at 1 year of use – IUDs, the IUS and implants are more cost effective than the injectable contraceptives – increasing the uptake of LARC methods will reduce the numbers of unintended pregnancies

LARC includes: Copper IUD Progestogen-only IUS Progestogen-only injectable Progestogen-only subdermal implant Combined vaginal rings

However Current LARC Usage is Low7 % 7. Schering Data on File, 2006, WOMEN AGED 16 TO 44

Accidental Pregnancy in First Year of Typical Use8 % of accidental pregnancy * Norplant and Norplant 2: Data is from USA where Implanon is not available 8 Trussell J. Contraceptive efficacy. In: Hatcher RA, Trussell J, Stewart R. Contraceptive Technology, ed 18. NY: Ardent Media, 2004

Discontinuation Rates of Contraceptive Methods1

UK Medical Eligibility Criteria UKMEC1 No contraindication UKMEC2 Benefits usually outweigh risks UKMEC3 Risks usually outweigh benefits UKMEC4 Contraindicated

Sterilisation ‘Permanent’ but no longer the most effective Can be reversed but no guarantee Lifelong failure rate 5/1000 (i.e.10 times failure of vasectomy) Requires invasive procedure

Types of Combined Contraception 20, 30 or 35 micrograms of ethinyloestradiol Different progestogens 21 day and every day formulations Fixed dose or phasic Combined patch – Evra 4 or 12 week withdrawal - Seasonale Continuous pill Combined Ring – Nuvaring

Hormonal contraception Combined oestrogen and progestogen Combined pill (COC) Evra transdermal patch Nuva-Ring vaginal ring

Combined methods Advantages Disadvantages Suppress ovulation High efficacy Give predictable ‘periods’ Disadvantages Increased risk of thrombosis ?? Increased risk of breast cancer (Increased risk of hepatocellular cancer)

Constituents of COCs Oestrogens Ethinyloestradiol Mestranol Progestogens Norethisterone Levonorgestrel Desogestrel Gestodene Norgestimate Drospirenone Cyproterone The Combined Pill contains two hormones, oestrogen and progestogen. In practice, the type of oestrogen is now always ethinyloestradiol, but the type of progestogen may vary. The most commonly used progestogens nowadays are norethisterone, levonorgestrel and, more recently, desogestrel, gestodene, norgestimate and drospirenone.

Limitations on Dose Reduction Loss of efficacy Loss of cycle control (depends on both oestrogen and progestin) Wide range of blood levels via oral route

Revised information from MCA May 99 Third generation pills can be prescribed first-line VTE risk in data sheets: 15 per 100,000 - second generation 25 per 100,000 - third generation In 1998, following an appeal to the Medicines Commisson, the Department of Health announced an end to the 1995 restrictions on prescribing third generation pills, stating that ‘The absolute risk of VTE in women taking third generation COCs is very small and is much less than the risk in pregnancy’ and ‘provided women are fully informed of these very small risks and do not have medical contraindications, it should be a matter of clinical judgement and personal choice which type of oral contraceptive should be prescribed.’ (MCA 1999). Since 1998, the data sheets of gestodene and desogestrel-containing pills in the UK carry a new wording, stating that these types of pill carry a risk of VTE of ‘about 25 per 100,000 women per year’, while for second generation pills, the risk is ‘about 15 per 100,000 women per year.’. This low risk for second generation pills seems unlikely: there has, after all, not been any change in their formulation. It seems more likely that the risk of VTE with all combined pills is around 30 to 40 per 100,000 women per year (i.e. the figure which has been quoted since the studies of low dose pills in the 1980s, the higher figure from the 1995 studies and consistent with the latest data).

Breast cancer re-analysis 1996 - results No effect of duration of use No dose response Cancers in pill users less advanced Causal association unlikely ? acceleration of tumour growth ? surveillance bias This excess risk declines progressively after cessation of use, disappearing altogether after 10 years. There was no effect of duration of use, nor was there any effect of pill dose. Breast cancers diagnosed in pill users were clinically less advanced than those in never-users, and were less likely to have spread beyond the breast. This would suggest that mortality from breast cancer might actually be reduced in pill users. The authors state that the lack of both a duration of use and a dose-response effect makes a causal association unlikely. There are two plausible explanations for these results, either or both of which may play a part. Firstly, it is possible that the pill accelerates the growth of tumours which were already present, thus making them clinically obvious earlier. A second possibility is that of surveillance bias i.e. that women who take the pill are more 'breast aware' and are also more likely to be seeing doctors and nurses regularly, allowing the opportunity for advice and examinations. This would explain the earlier diagnosis in pill users compared with never-users, who may be less exposed to medical contact.

Cervical cancer risk factors Human Papillomavirus Smoking Oral contraceptives ? There has, for many years, been a suggestion of an association between the COC and an increased risk of cervical cancer. However, because the most important risk factor is known to be sexually acquired infection with high risk human papillomavirus (HPV) types, it has always been difficult to separate the possible effects of the COC from those of sexual behaviour.

Benefits of the COC (1) Very effective, non-intercourse related contraception Reduction in menstrual disorders ¯ functional ovarian cysts x 92% ¯ menorrhagia, irregular bleeding x 50% ¯ dysmenorrhoea x 40% ¯ PMS ¯ Iron deficiency anaemia x 50% ¯ PID x 50% ¯ Ectopic pregnancy x 90% The Pill has many health benefits. Firstly, it is an extremely effective reversible method of contraception. The Pill has a major impact on almost all menstrual disorders. It has been estimated that at least 8% of women on the Pill are taking it for no other reason apart from relief from menstrual problems like dysmenorrhoea and PMS. The reduction in iron deficiency anaemia seen with the Pill is due mainly to the decrease in menorrhagia. Several large studies have shown that the Pill gives a ten fold reduction in the incidence of symptomatic functional ovarian cysts requiring hospitalisation. Similarly, the need for surgery for benign breast disease is reduced by 50-75% in Pill users. The Pill has been shown to reduce the incidence of PID by 50% overall, and by 70% in women who have used it for more than a year.

Benefits of the COC (2) ¯ Fibroids x 30% ¯ Benign breast disease x 50 - 75% Symptomatic relief / treatment of endometriosis ? ¯ Duodenal ulcer ¯ Rheumatoid arthritis x 50% ¯ Endometrial cancer x 50% ¯ Ovarian cancer x 40% ¯ Colorectal cancer x 20% The Oxford / FPA study has shown that the risk of fibroids decreases by about 17% with every five years of Pill use, so by ten years, the risk is reduced by 30%. Endometriosis can be a very distressing condition, and not all women tolerate the side effects of Danazol. The Pill is not as effective, but it can certainly reduce the symptoms quite considerably. The RCGP study showed a 50% reduction in the incidence of rheumatoid arthritis in Pill users, and also a reduction in the incidence of duodenal ulcers. The rheumatoid arthritis benefit has in fact now been confirmed by other studies. Pill users have a 50% reduction in the risk of developing endometrial cancer. There is a reduced risk even after only one year of use, by a factor of 20%. At least four years of use are necessary to achieve the 50% reduction, and this appears to persist for 15 years after stopping the pill. This is an important factor, since endometrial cancer is a disease of older women, who are very unlikely to be current or very recent pill users. Similarly, studies have shown a 40% reduction in the risk of developing ovarian cancer after three years of pill taking and about 60% after seven years. As for endometrial cancer, the effect appears to persist for 15 years after cessation of pill. A meta-analysis in 2001 has also shown a 20% reduction in the risk of colorectal cancer in ever users of the pill, with a 50% reduction in recent users.

Conception due to missed COCs 'only' occurs if this leads to lengthening of the pill - free interval NB - at either end Prolonging the pill -free week is actually the most likely way a woman can become pregnant while taking the pill. Oestrodiol levels rise appreciably during the seven days off the pill. If, for any reason, the woman has a break of more than seven days, ovulation might occur. It is important to remember that this can mean missed pills at the end of a packet as well as being late in starting the new one. Women may not mention this as they will have been falsely reassured by a withdrawal bleed. However, it has also been shown that after 7 days of pill taking, ovarian activity is suppressed. Therefore missing pills in the middle of a packet is unlikely to place the woman at risk.

Missed pills – WHO Advice for COCS Just keep going Also if pill missed is in week 3 omit pill-free interval Also backup or abstinence for 7 days if following number of pills missed - Two for twenty - Three for thirty It is important to teach each woman the basics of how to take COCs and to reinforce this information at check visits. The actions necessary in the case of missed tablets and the other factors that may reduce contraceptive effectiveness also need careful explanation. This verbal information should be backed up with appropriate written information

Lamotrigine (Lamictal) and the pill Not an enzyme inducer Interaction reduces levels of both agents No evidence of reduced efficacy for COC No evidence on POP

Why take a break ? History Tricycling 25/3 may give better ovarian suppression Continuous

EVRA: Simple administration schedule 20 mcg ethinyloestradiol and 150 mcg norelgestromin Apply weekly for 3 weeks Apply same day-of-the-week 1 week patch-free Sunday Sunday Sunday Sunday Sunday Patch # 1 Patch # 2 Patch # 3 Patch-free Start next cycle 28-day cycle 28-day cycle Ref: Evra SmPC

EVRA Continuously Delivers EE Within Reference Ranges 150 Evra 125 Cilest 100 EE serum concentration (pg/mL) 75 Patch removed 50 25 1 2 3 4 5 6 7 8 9 10 11 12 Days Adapted from Abrams Fertility and Sterility 2002

Dosing Reserve Results for ethinyl estradiol 100 80 Patch changed on schedule Patch removal delayed 60 EE serum concentration (pg/mL) Patch removed 3 days late 40 20 2 4 6 8 10 12 14 16 18 Days Ref: Abrams et al Fertility and Sterility 2002,

Evra – is a patch really better ? Less variability in levels, but not a lower dose Effects on SHBG similar or greater ? Relevance of enzyme-inducers, antibiotics, etc ? Thrombosis risk

New Delivery System: Vaginal Ring Progestin: Etonogestrel: 120 µg/day Estrogen: Ethinyl estradiol: 15 µg/day Worn for three out of four weeks Self insertion & removal Pregnancy rate 0.65 per 100 woman–years This ring releases 120 µg of the progestin etonogestrel, formerly 3-keto-desogestrel, and 15 µg of the estrogen ethinyl estradiol per day It can be easily inserted and removed by the woman herself, and is intended to be used for one cycle consisting of 3 weeks of continuous ring use and a 1 week ring-free period A total of six pregnancies were reported during treatment, giving it a Pearl Index of 0.65 Roumen FJ, et al. Hum Reprod. 2001;16(3):469-475. Suggested Core Slide

Progestogen-only methods Advantages Greater safety Variable efficacy (from extremely low to better than COC) Some measure of loss of cycle control (varies with route, type and dose)

Routes available Progestogen-only pill (POP) Emergency contraception (Levonelle) Injectable (Depo-Provera) Intrauterine (Mirena) Implant (Implanon)

Desogestrel POP (Cerazette) 75 micrograms Desogestrel Suppresses ovulation Lower failure rate Different rules for missed pills

Emergency Contraception Products Levonelle One Step Any copper IUD, including GyneFix Indications Unprotected sex Potential barrier failures Potential pill failure 2 missed pills in first week 4 missed pills in mid-packet Potential IUD failure Increased risk of ectopic in failures Awareness of risk may not translate into action

Levonelle One Step 1500 micrograms levonorgestrel Within 72 hours Efficacy < 24 hours 95 % 24-48 hours 85 % 49-72 hours 58 %

Emergency Hormonal Contraception (EHC) Side effects 23 % nausea 6 % vomiting Contraindications Established pregnancy

Depo-Provera 150 mg medroxyprogesterone acetate IM Every 12 weeks Failure rate approx 0.5% High incidence of amenorrhoea Long-term use associated with reduced bone density which recovers with addback or discontinuation

Fertility awareness Depends on abstinence Requires high degree of motivation Failure rates high especially in new users Based on a number of false premises about fertility, therefore relatively high method failure rate as well as high user failure

IUD (Copper devices) Gold standard Copper T 380 Not user-dependant Good efficacy (failure rate 1% or less p.a.) Requires insertion and removal Some increased risk of infection in first 60 days especially when cervix colonised Periods may be heavier, longer, more painful

Intrauterine Mirena releases 20 mcg levonorgestrel daily for 5 years Failure rate equal to or less than female sterilisation Reduction in menstrual loss a beneficial side-effect

Mirena Good contraception Control of menorrhagia May help dysmenorrhoea Effective endometrial protection Some systemic absorption Irregular bleeding may persist Insertion not always easy

Implanon Subdermal Etonogestrel Menstrual irregularity common Failure rate far below that of sterilisation

The design of Implanon® Progestogen only contraceptive Core Rate-controlling membrane (0.06 mm) 2 mm 40 mm Core: 40% EVA 60% etonogestrel Membrane: 100% EVA

Implanon® Mode of action Ovulation inhibition : primary effect Effect on cervical mucus: secondary effect Core message - Mechanisms of action of Implanon®. It primarily acts by inhibiting ovulation but in the third year the effect on the cervical mucous is an important secondary effect. For further information refer to pages 91-97 of the Contraception supplement published in December 1998.

Contraception 1998;58: 99S-107S