A BRIEF UPDATE ON CONTRACEPTION, by John Guillebaud (JG)

WHO CLASSIFICATION OF CONTRAINDICATIONS - with some amplifications by JG

WHO 1: A condition for which there is no restriction for the use of the contraceptive method

"A" is for ALWAYS USABLE [eg COC with history of Candidiasis; uncomplicated varicose veins]

WHO 2: A condition where the advantages of the method generally outweigh the theoretical or proven risks

"B" is for BROADLY USABLE [eg COC in smoker age 20; history of hypertension in pregnancy only]

WHO 3: A condition where the theoretical or proven risks usually outweigh the advantages (suggest alternative). Yet respecting the patient/client's autonomy - if she accepts risks and relevant alternatives are contra-indicated or rejected, given the risks of pregnancy the method can be used with care/monitoring

"C" is for CAUTION/COUNSELLING, if used [eg COC in diabetes; enzyme inducer treatment]

WHO 4: A condition which represents an unacceptable health risk

"D" is for DO NOT USE, at all [eg COC with personal history of VTE; or migraine with focal aura]

Note: Clinical judgement is required, always in consultation with the contraceptive user, especially:

[Reference: WHO/RHR/00.02. Medical Eligibility Criteria for contraceptive use (2nd Ed). Geneva: WHO, 2001.

This is now paired with: Selected Practice Recommendations for contraceptive use. Geneva: WHO, 2002]

COMBINED ORAL CONTRACEPTIVES (COCs – full glossary at end)

Breast Cancer risk: Good news! A major US study [1] of 4575 women aged 35-64 with breast cancer and matched controls shows no increased risk – OR 1 or less - whether for current users, past users, long-term users, users starting at a young age or before full-term pregnancy (thus good reassurance about the so-called "time-bomb") or users with a family history! Reassuring, given volunteers’ Pill exposure >75 %, though not the "last word". Study also did not recruit COC-continuers right up to menopause, nor EARLY Ca’s developing pre-age 35. For the latter we still use the 1996 model, equating to 1:1000 extra cases by age 45 if used COC till 35 [2].

Cervical cancer: Once the HPV oncogen is acquired, a good 2002 study [3] supports the COC being a co-factor in the progression of CIN through to more advanced stages (the OR of invasive Ca up fourfold after 10 years’ COC use). Yet invasive Ca cervix still minimal risk with max 3-yearly intervals for cervical cytology plus colposcopy for COC-users (even if also smokers). Risk of VTE: Term "Generations" unhelpful, main thing is that LNG/NET progestogens reduce VTE risk, for given EE dose. Using the absolute rates given by the CSM in 1999 (other estimates exist), with around 100 extra cases per million users per year, and assuming 2% mortality for VTE gives 2 per million difference in annual VTE mortality between 3rd gen DSG/GSD products and 2nd gen LNG/NET products. One hour of driving gives a 1 per million mortality risk. So if a pill-taker chooses to switch from Microgynontm to say Marvelontm/Femodenetm, as she sensibly may to control any minor side effect: if she avoids one 2-hour drive in a whole year, she will have the same overall VTE risk next year as she would otherwise have if she did not change brands! [2].

Risk of arterial disease: Latest and probably better study [4] contradicts ‘MICA’ [5] and suggests that pills with 3rd gen progestogens may actually be better than LNG ones for risk of myocardial infarction. So, pending more data, I advise that we (continue to) use 20 m g DSG or GSD products for risk-factor and migraine-free COC-users above age 35 through as may be requested to age 51, but sometimes the NET option (Loestrin 20). NB: the primary reason for using, or changing to, a DSG/GSD product remains for the control of side effects [2,8].

Reassuringly, COCs have their main (small) effect on every known cause of mortality during current use and for some varying time thereafter: 10 years after use ceases, mortality in past users is indistinguishable from that in never users [6].

Prescribing: Current scientific evidence suggests only two pre-requisites for the safe provision of COCs: a careful personal and family history with particular attention to cardiovascular risk factors including migraine [2,8] - for tips on diagnosing aura, see p 42 in ref [2] - and a well-taken blood pressure [7]. Routine screening by any blood test, and breast/bimanual examinations are not relevant to the COC per se.

Intercurrent diseases [8]: It is impossible to list every known disease which might have a bearing (ie WHO 4, 3 or 2) on COC prescription, and for many the usage data do not exist. A working rule therefore is to ascertain whether or not the condition might lead to summation with known major adverse effects of COCs, particularly with the risk of any circulatory disease. This usually means WHO 4, sometimes 3. If not, COCs are WHO 2, though used with alertness for the onset of new risk factors. Reliable protection from pregnancy is often particularly important in these cases.

Counselling should be backed by useful FPA leaflet "Choosing and Using COCs", which explains (eg) those symptoms which should trigger taking urgent medical advice, recording the publication date in the case-notes. NB: FPA leaflets will be updated before UK activation of the new WHO Practice Recommendations (ref above), affecting ‘missed pills’ advice etc.

YASMINtm containing Drospirenone

Yasmintm contains 3.0 mg drospirenone and 30 m g of ethinylestradiol (EE). Drospirenone differs from other progestogens in COCs: it has diuretic properties due to anti-mineralocorticoid activity "comparable to a 25 mg dose of spironolactone", according to the SPC. This may help to oppose the salt and fluid-retaining effects of EE and so reduce fluid retention symptoms. It has also been associated in a small trial comparing it with Microgynon with a very small mean lowering of blood pressure (a unique finding, needs much more study, statistically but not yet proven to be clinically significant – though it might be in a sub-group, see below).

Drospirenone is also an anti-androgen, so Yasmin may be an alternative to Dianettetm (or the cheaper Marvelon) for conditions like PCOS. The combination with EE is estrogen-dominant, and so cannot be expected a priori to have the lower risk of VTE associated with the functionally anti-estrogenic levonorgestrel in, for example Microgynon.

ELIGIBILITY. Yasmin adds some new WHO 4 conditions: this particular brand should not be used – if COCs usable at all – in anyone at risk of high potassium levels (i.e. severe renal insufficiency, hepatic dysfunction, and adrenal insufficiency).

Q: On what criteria will you consider Yasmin?

A: The need for contraception, PLUS:

usually the best for maintenance treatment after Dianette - is judged unsatis.

What about weight? Not usually an indication, given the lack of evidence of a true (ie non-fluid-related) weight benefit of the product and its extra cost: moreover if a woman already has a high BMI, the usual eligibility levels should apply ie BMI 30 + is WHO 3 (LNG/NET product preferred) and BMI 39 + remains WHO 4 for all COCs.

EVRAtm transdermal combined hormonal contraception

This is an innovative transdermal patch delivering ethinylestradiol (EE) with norelgestromin, the active metabolite of norgestimate. The daily skin dose of 150 µg norelgestromin and 20 µg EE produces blood levels in the range of those after a tablet of Cilest. All the absolute and relative contraindications and indeed most practical management advice about that COC applies. It appears to be relatively oestrogen-dominant, plus about 2 percent of women in the trials had local skin reactions which led to discontinuation.

The patch has excellent adhesion, the incidence of detachment of patches was 1.8 % (complete) and 2.9 % (partial). Failure rate for consistent users of EVRA was similar to the oral pills - and less than 1 per 100 woman-years.

PROGESTOGEN-ONLY PILLS (POPs)

Cerazettetm: the first POP to be primarily an anovulant. This contains desogestrel 75 m g, blocks ovulation in c 97% of cycles, hence higher efficacy than in any previous POP study, Pearl Index 0.17 (CI 0-0.9). So this is a real alternative if the COC is WHO 4 in a young woman: though cheaper old-type POPs suffice in low fertility states like lactation or above age 40 where POP already so effective. Useful for trial sometimes before inserting Implanon, though this only helps to predict hormonal side effects - and risks Cerazette’s usual early bleeding problems. Also option with past history/ high risk of thrombosis and (unlike other POPs) a past ectopic. May benefit menstrual symptoms: eg dysmenorrhoea, menorrhagia, PMS, Mittelschmerz. No requirement to increase dose in women of high body mass. BUT warn that unacceptable irregular bleeding may occur in early months, usually improving to offer 50% oligo-amenorrhoea at one year. SPC still advises no more than 3 hour pill-taking delay before extra precautions – but in new WHO Practice Recommendations these need only be for 48 hours, for Cerazette like ALL POPs.

INJECTIONS/IMPLANTS

ImplanONtm is a single 40mm x 2mm sub-dermal rod releasing etonogestrel (the biologically active metabolite of desogestrel) over 3 years. To date its effectiveness when actually inserted (and assuming the insertion is not too late in a conception cycle) is unmatched by any other method, aside from abstinence. In studies, mean insertion and removal times were only 1.1 and 2.7 minutes respectively. NB special insertion training vital, removal if put in too deep can be complex, under u/sound control. Frequent or prolonged bleeds are a problem, affecting c17 % of users at one year. But despite anovulation (see below), the 20 percent amenorrhoea rate is a bonus!

Irregular bleeding: With both DMPA and Implanon, if irregular bleeding is unacceptable – consider a trial of a suitable 20 m g COC (if not contraindicated) for 2-3 cycles. Mercilon contains same progestogen as Implanon and usually controls the bleeding while the tablets are being taken, with withdrawal bleeds. Thereafter the woman may (or may not!) achieve an acceptable bleeding pattern - though she should be warned that it always goes back to being less regular than on the COC. If the combined pill is contraindicated, in selected cases it is acceptably safe (i.e. WHO 3) to use a similar cyclical course of a natural estrogen, eg by transdermal patches.

Implanon and body weight: The blood levels of etonogestrel were lower in obese women and it has been suggested that in those with the very greatest body mass (say over 100 kg) it may be appropriate to discuss replacing their Implanon early. Unlike the old-type POPs, this product is primarily an anovulant and there were no failures at all in the pre-marketing trials. Hence there must be some ‘margin’. If after discussion the >100 kg woman wishes to do so, and particularly if she is amenorrhoeic - which suggests continuing anovulation – she may continue with implant to the end of the third year. (And if she weighed less than 100 kg I would not even discuss the point, unless raised by herself).

Implanon and enzyme inducers: The SPC does point out that enzyme inducers lower the blood levels of etonogestrel. Organon therefore recommends that "an additional contraceptive" be used. They do not recommend inserting two Implanons, but otherwise leave the choice open. Patients in monogamous relationships may be uncomfortable about using, long term, additional condoms or the more user-friendly option of say Delfentm foam. So the "added contraceptive" might instead (JG’s opinion) be a daily Cerazette, the obvious progestogen-only pill here, in addition: unlicensed, so on a "named patient" basis [2]. If the woman is to be on an enzyme inducer long term, she could continue the combination indefinitely. But as users of enzyme-inducers do so well with Mirenatm (see below), this might be a better as well as a cheaper choice.

DMPA 150 mg every 12 weeks – NB the same frequency is now advised even if woman is on an enzyme-inducer

Late injections (JG’s advice):

How long to use DMPA? given ongoing concern about anovulation with low estradiol levels. Much uncertainty persists. My own protocol is cautious: WHO 3 or even 4 from the start IF very strong risk factors for osteoporosis or arterial disease are present. WHO classifies DMPA as WHO 2 under age 18 (concern that it may prevent achievement of peak bone mass) and above age 45 (ie peri-menopausal with ovarian failure). Otherwise I now consider DMPA as ordinarily (but not only) a very useful method for 5 years’ use. If she wishes to use it for longer, even much longer, it is as always the woman’s right to decide, after counselling about the uncertainty (remembering it is overall even safer than any COC) and all the new alternatives. For fuller protocol, see p 86 in ref [2].

Same problem with long term Implanon? No, the data are reassuring so far, re both estradiol and bone density: in a comparative 2-yr. study both remained similar to those in copper IUD-users. No worries yet on this account with Cerazette, by analogy, either - or with the IUS (below) whose amenorrhoeic action is primarily at the end-organ level, the endometrium.

MORE ABOUT INTRAUTERINE DEVICES (IUDs)

The banded T-Safe Cu 380Atm is the ‘gold standard’, the first choice device unless an alternative is specifically indicated

The Multiloadstm are without any established advantages. Schering no longer market the ineffective Nova-T 200.

Some tips about the T-Safe Cu 380A (FP Sales Ltd): Yes, it is a fiddle to load! If the little plastic loading capsule is used, once the device is in the inserter tube it is essential to grasp the threads firmly at the other end of the tube. Otherwise the capsule simply takes the device out again when removed! Alternatively, use sterile gloves. Once loaded, although the side arms of the device appear to present a rather large object to get through the cervix, the loaded assembly is actually quite nicely rounded and also narrow in one diameter. It usually passes through the cervical canal surprisingly easily in all parous women. Nulliparity in a truly monogamous relationship is WHO 2 for IUDs and for them also the T-safe Cu 380A is the first-choice IUD, though it may be necessary to dilate to Hegar 5 (consider LA). It costs < £10 and is on the Drug Tariff.

¨ It really is worth the effort to make this IUD one’s first choice, since it is licensed for 8 years, and 10 years in other countries so usable in practice till then - and research in the past 50 years has so clearly shown that most IUD complications are insertion-related and diminish with duration of use.

¨ UK practice since 1990 is that ANY copper IUD fitted above age 40 can be used for the rest of reproductive life.

¨ Pre-medication with a NSAID should be routine for all insertions, and LA, at least to 12 o’clock on cervix, always offered.

When to use the Nova T380? In my opinion this one might be appropriate for a nulliparous woman using it for emergency contraception (EC) and definitely planning to have the device removed once established on a new method, such as DMPA.(though the Flexi-T 300tm at only £8.65 would be cheaper and v easy to fit). But a recent randomised controlled trial [9] showed former to be significantly less effective than the T-Safe Cu 380A (cumulative failure rate at 3 years 3.6 versus 1.7 for the T-Safe). Therefore, adding in the benefit of fewer routine re-insertions, when long-term use by a young fertile woman is actually expected after EC, the Nova T 380 should normally only be used if the T-safe cannot be fitted, for some reason. Even then, on long-term efficacy grounds GyneFix, which is similar in having copper bands, might be preferred.

When to use the GyneFixtm [10]? – NB special insertion training needed. Special indications for this product are:-

the IUS is not acceptable – important to remember that Mirena can be brilliant for menstrual PAIN [10].

GyneFix is licensed for 5 years in situ but application is being made for 10 years – based on >250 users up to 10 years in 2 studies, one in China and the other WHO-linked (Wildemeersch, Personal Communication), with only one conception occurring between end of years 5 and 10. Long "life" is very believable because it is a banded IUD. But forewarn all about unrecognised expulsion: being able to feel the threads is particularly important with this product.

Mirenatm IUS [11,12]

This is a major advance in contraceptive technology, with added value in relief of PAIN [11] as well as menorrhagia: facts still not widely enough appreciated! But there are two more differences between Mirena and copper IUDs:

New inserter: This is a real advance and welcomed. But attention to detail is important, esp to be VERY sure that the green slider stays initially fully in the starting (forward) position, not only when loading the Mirena into the forward end and cleating the thread, but also when first passing the loaded inserter into the fundus: if the green slider is slightly back from max forward, friction at the internal os can make the outer tube slide back – ie the system tries to release the IUS in the cervix!

What about Mirena and enzyme-inducers? Walli Bounds of Margaret Pyke Centre collected data on about 50 UK users of this combination and only one definite pregnancy was reported. This good effectiveness is biologically plausible, since the LNG would be released locally in the normal high concentration and should therefore still have its normal effects, on the utero-cervical fluid and also in impairing implantation.

Pending more data, the use of Mirena by women with epilepsy and others on enzyme-inducers is a good choice, a WHO 2 situation. No added precautions need be taken, but the woman should be advised there is some residual uncertainty as to whether the amazing efficacy of Mirena might be slightly reduced in these circumstances.

PID risk? The essential thing, whether in IUD or IUS users, is selection: verbally, for mutual monogamy; PLUS the practice of inserting only through a "Chinese cervix" – as explained on pages 85-87 of ref [2], this means one established by screening (at least for Chlamydia) to be pathogen-free….

Past ectopic? Although anovulant methods would be even better, this is at most WHO 3 for the IUS or banded IUDs [13].

FEMALE STERILIZATION? - OR NEW-TYPE IUD OR IUS?

The Peterson et al study of 1996 [14] showed the mean female sterilization failure rate in the USA to be 18/1000 at 10 years! – very comparable to the T-Safe Cu 380A and the IUS (14/1000 and 11/1000 failures respectively by 7 years) [11]. In UK RCOG estimates the ‘lifetime’ failure rate of the Filshie clip as 5:1000, whereas it is 5:10,000 for vasectomy [15].

EMERGENCY CONTRACEPTION

The LNG-only method is more effective than the previous combined hormonal method, now superseded [16-17]. Every 12 hours’ delay increased the failure rate by 50 % [18]. Now a further WHO study [19] shows that the two 750 m g tablets may be given at once, working equally well with NO difference in side effects - and since Oct 2003 this is now licensed. The protocol allowed use up to 5 days and there were 8 failures among 314 women (2.5%), treated with 1500 m g LNG either stat or in divided doses, between 72 and 120 hours after a single coital exposure [19] WHO concludes that this is "prevention of a high proportion of pregnancies even up to 5 days after coitus" and thus Levonelletm may be so offered (unlicensed use, see therefore pp 114-5 of reference [2]) – though it should be stated to the client that insertion of a copper IUD would be even more effective [20], failure rate about 0.1%.

The only known absolute contraindications (WHO 4) aside from current pregnancy to LNG-only EC are:

Caution also required if it is used in women on Warfarin – enhanced anti-coagulation reported [21], so check INR post-treatment.

Brief Glossary: COC combined oral contraceptive / OR odds ratio = relative risk / Ca cancer / VTE venous thrombo-embolism / EE ethinylestradiol/ DSG desogestrel / GSD gestodene / LNG levonorgestrel/ NET norethisterone/ SPC Summary of Product Characteristics / PCOS the polycystic ovarian syndrome / BMI body mass index / POP progestogen-only pill / PMS premenstrual syndrome / DMPA depot medroxyprogesterone acetate /EC emergency contraception/ IUD (IUS) intrauterine device (system) / NSAID non-steroidal anti-inflammatory drug / LA local anaesthesia / inr international normalized ratio (test for anti-coagulant action).

SELECTED REFERENCES AND FURTHER READING

  1. Marchbanks P, McDonald J, Wilson H et al. Oral contraceptives and the risk of breast cancer. New Engl J Med 2002; 346:2025-32.
  2. Guillebaud J. Contraception Today. A Pocketbook for General Practitioners (5th Ed) London: Martin Dunitz, 2004, pp 26-37, 42-5, 73-4, 86, 96-8, 102-5, 141.
  3. Moreno V, Bosch F, Munoz N et al. Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. Lancet 2002; 359:1085-92.
  4. Tanis, B, van den Bosch M, Kemmeren J.et al. Oral contraceptives and the risk of myocardial infarction. New Engl J Med 2002; 345:1787-1793
  5. Dunn N, Thorogood M, Faragher B et al. Oral contraceptives and myocardial infarction: the results of the MICA case-control study. BMJ 1999; 319:795-6
  6. Beral V, Hermon C, Kay C et al. Mortality associated with oral contraceptive use: 25 year follow up of cohort of 46 000 women from RCGP OC study. BMJ 1999;318:96-100.
  7. Hannaford P, Webb, A. Evidence-guided prescribing of combined oral contraceptives: consensus statement. Contraception 1996; 54:125-9.
  8. Guillebaud J. Contraception: Your Questions Answered (4th Ed) Oxford: OUP, 2004, pp 199-212, 213-218, and other pages expanding on those given at ref [2].
  9. Skjeldestad F, Rauramo I. An open randomised trial of two copper IUDs, Nova T380 versus Gyne T 380 Slimline: 3 year results. Abstract 38 presented at 29th British Congress of Obstetrics & Gynaecology, Birmingham, July 2001.
  10. Anon. Frameless intra-uterine contraceptive device (GyneFix). Drug and Ther Bulletin 2002;40(3):21-22
  11. Sivin I, Stern J. Health during prolonged use of levonorgestrel 20 m g/d and the TCu 380Ag intrauterine contraceptive devices: a multicenter study. Fertil Steril 1994;61:70-7.
  12. Sturridge F, Guillebaud J. Gynaecological aspects of the LNG-releasing intrauterine contraceptive device (Review). Br J Obstet Gynaecol 1997; 104: 285-9.
  13. Dennis J, Hampton, N. IUDs: which device? (Review). J Fam Planning & Reprod Health Care 2002; 28: 61-68.
  14. Peterson H B, Zhisen X, Hughes J M. et al. The risk of pregnancy after tubal sterilization: findings from the U.S. Collaborative Review of Sterilization. Am J of Obstet Gynecol 1996; 174: 1161-70.
  15. Male and female sterilization. Evidence-based Guidelines No 4. Royal College of Obstetricians and Gynaecologists (RCOG): London, 2003. See < www.rcog.org.uk >
  16. WHO. Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet 1998;352:428-33.
  17. Guillebaud J. Time for emergency contraception with levonorgestrel alone. Lancet 1998;352:416.
  18. Piaggio G, Von Hertzen H, Grimes D, van Look P. Timing of emergency contraception with levonorgestrel or the Yuzpe regimen. Lancet 1999; 353: 721.
  19. Von Hertzen H, Piaggio G, Ding J et al. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial. Lancet 2002; 360: 1803-10.
  20. CEU of Faculty of FPRHC Guidance: emergency contraception. J Fam Planning & Reprod Health Care 2003;29:9-15. Also at www.ffprhc..org.uk
  21. Ellison J, Thomson A, Greer I. Apparent interaction between warfarin and levonorgestrel used for emergency contraception. BMJ 2000;321:1382.

JOHN GUILLEBAUD, Professor Emeritus of Family Planning and Reproductive Health, UCL January 2004