BRIEF UPDATE ON CONTRACEPTION, by John Guillebaud (JG)

WHO CLASSIFICATION OF CONTRAINDICATIONS (for any method) - 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]

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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; any 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 aura]

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

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

This is now paired with: Selected Practice Recommendations (SPR) 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 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 they used COC till 35 [2].

Cervical cancer: Once the HPV oncogen virus is acquired, a good 2002 study [3] supports the COC being a co-factor for CIN progressing to more advanced stages (the rel. risk of invasive Ca up 4-fold after 10 years’ COC use). Yet invasive Ca cervix remains a minimal risk for COC-users (even if also smokers), so long as there is 3-yearly cervical cytology, plus colposcopy as indicated. Risk of VTE: Term "Generations" unhelpful, main thing is that LNG/NET progestogens may 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: Thrombotic stroke risk of COCs should be reducible by improved prescribing in migraine - for tips on diagnosing aura and chart for COC eligibility with migraine, see pp 42-44 in ref [2] or pp 214, 216 in [8] 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, with the NET option (Loestrin 20) an alternative. NB: the primary reason for using, or changing to, a DSG/GSD or other estrogen-dominant product at any age 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]- 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, do them only if clinically indicated.

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 relevant 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. NB: Beware the dis-ease of OBESITY: see page 2 below.

Counselling should be backed by the FPA leaflet "Your guide to the combined pill". NB: New edition (April 2005) has, as always, very good text, now based on WHO MEC and SPR (ref above). But its Flow Diagram re "missed pills" on pp 12-13 is disappointing. Most UK providers consider it should simply advise "more than 1 of any COC missed" as the action trigger for added condom use and, in last pill-week, for running on to the next pack; and that EC is only indicated if >2 pills are missed in first week + sexual exposure since last pack. JG’s practice until much-needed revision of this Flow dia is to delete pp 12-13 of FPA leaflet and give a separate instruction card!

YASMINtm containing DrospirenoneYasmintm 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. This may help to oppose the salt and fluid-retaining effects of EE and so reduce fluid retention symptoms.

Drospirenone is also an anti-androgen, so Yasmin is an alternative to Dianettetm (or the cheaper Marvelon, which is often effective) 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:

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 is overweight, the usual BMI advice should apply ie BMI > 30 is WHO 3 (= a LNG/NET product is preferred) and BMI > 39 remains WHO 4 for all EE-containing products (COCs, EVRA, NuvaRing).

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 plus most practical management advice about that relatively estrogen-dominant COC apply here. 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 was 1.8 % (complete) and 2.9 % (partial). The hormones are in the adhesive, so a dried-out fallen off patch should NOT be re-used! 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, plus still has the mucus effect: hence showed higher efficacy than in any previous POP study, Pearl Index 0.17 (CI 0-0.9). So this is a realistic 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 is 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. It is also an option with past history/ high risk of thrombosis and (unlike other POPs) a past ectopic. Often, but not very predictably, it benefits menstrual symptoms: eg dysmenorrhoea, menorrhagia, PMS, Mittelschmerz. There are no concerns about having to increase dose in women of high body mass. BUT should warn that unacceptable irregular bleeding may occur in early months, usually improving to offer 50% oligo-amenorrhoea at one year.

Missed Cerazette pills: 12 hour leeway in pill-taking is now approved, before extra precautions advised – but, for ALL POPs, Cerazette included: in the new WHO Practice Recommendations these need only be for 48 hours (+ EC if sex while the mucus block lost).

[NB Organon's own advice cannot deviate from their SPC, with the stricter requirement for 7 days’ added contraception if a tablet is taken > 12 hours late].

INJECTIONS/IMPLANTS

ImplanONtm is a single 40mm x 2mm subdermal rod releasing etonogestrel (the biologically active metabolite of desogestrel) over 3 years[9]. To date its effectiveness when actually inserted - assuming insertion is not too late in a conception cycle, indeed best to avoid that by an anovulant method pre-insertion - is unmatched: aside from abstinence and vasectomy. In studies, mean insertion and removal times were well under 5 minutes. NB special insertion training is vital: if put in too deep removal can be complex, under u/sound control. Should contact Organon for advice re such cases, using u/sound guidance. Frequent or prolonged bleeds affect around a fifth of users at one year. But there are no current worries here re low estradiol levels (cf DMPA below), so the high amenorrhoea rate is a bonus!

Irregular bleeding: With both DMPA and Implanon, if irregular bleeding is unacceptable – consider trial of a suitable 20-30 m g COC (if not contraindicated), for around 3 cycles. Mercilon contains the same progestogen as Implanon and usually controls the woman’s bleeding while the tablets are being taken, with shedding of her spotting–prone endometrium between packs. Thereafter she may (or may not!) achieve what she finds an acceptable bleeding pattern - though she should be pre-warned that it is unlikely to be as good as on the short-term 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, preferably by transdermal patches since this route causes least alteration in clotting factors.

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. However 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 certainly continue with her 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 not wish to use additional condoms or even user-friendly options like the sponge or a spermicide. So the chosen "added contraceptive" might instead (JG’s opinion) be a daily Cerazette, the obvious progestogen-only pill here, in addition: though on a "named-patient"* basis [2,8] as this use is unlicensed. There is more re what NP use means in EC section below. If the woman is to be on an enzyme inducer long term, she could continue that 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 injection frequency is now advised even if the user is on an enzyme-inducer

Late injections (JG’s advice; WHO and the Faculty give more ‘leeway’):

How long to use DMPA? given ongoing concern about anovulation with low estradiol levels. Much uncertainty persists, not all eliminated by latest CSM circular (18/11/2004) which mainly recommends "careful re-evaluation of risks and benefits in all those who wish to continue use for more than 2 years". IF strong risk factors for osteoporosis are present, DMPA is WHO 3 or even 4 for all, at any time. Under age 19, due to concern that it may prevent achievement of peak bone mass, WHO classifies DMPA as WHO 2; and the UK advice of Nov 2004 is to use it first-line "but only after other methods have been discussed" and are unsuitable or unacceptable. DMPA is also WHO 2 above age 45 (since ?early ovarian failure). In sum, DMPA is very useful for relatively short term use, after which switching to another long-term method is usual. If the woman wishes to use it for longer, even much longer, it is as always her right to decide to do so, after counselling about the uncertainty. This should be with formal 2-yearly reassessment of alternatives but without imaging or blood tests unless clinically indicated for that woman. Remember it is clearly safer, overall, than the COC!

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

INTRAUTERINE DEVICES (IUDs) [NB see reference 10, which is excellent, for all long-acting methods]

Any banded Cu IUD is in the ‘gold standard’ category, first choice unless an alternative is indicated - all are on the Drug Tariff. They are: T-Safe Cu 380Atm (a), OR a new variant (b) with the same name but with its copper bands sunk into the plastic frame (available June 2005 from FP Sales) OR a third clone (c) available from Durbin plc and called the TT 380 Slimline (itself essentially identical to (b) but has simpler loading system than the fiddly little plastic "hat" of (a) or (b) – however NOTE slightly wider introducer).

¨ It really is worth the effort to make this banded IUD one’s first choice, since it is usable for 10 years (the newest clones of it are actually licensed for this long) and the data support its effectiveness till 12 years, even when fitted below age 40. The main reason is not its probable greater efficacy [10] – above all in its latest form, with the copper bands near each tip of the T – but rather, the fact that research in the past 50 years has so clearly shown that most IUD complications can be insertion-related and reduce in frequency with duration of use. It usually passes through the cervical canal surprisingly easily, in all parous women.

When to use the Nova T380tm? In my opinion, this one might be appropriate for a nulliparous woman using it for emergency contraception (EC) and planning to have the device removed once established on a new method, such as DMPA. But a randomised controlled trial [10] showed the Nova T380 (aren’t the names confusing?!) which has copper wire but no bands, 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, in my view either Nova T 380 or the UT 380 Short (from Durbin plc = Nova T style but on a short stem)

should usually be reserved for when the T-Safe Cu 380A or equivalent cannot be fitted, for some reason (including the tight cervix of some nulliparae). Another good EC option for nulliparae is the Flexi-T 300tm which is tiny and has an exceptionally easy push-in fitting technique with no separate plunger - and at only Ł8.80 would be cheaper. But it has been shown to have a highish expulsion rate. There is now also available the Flexi-T 380tm, on a slightly larger frame and with bands on its side arms but otherwise identical in shape. We need more data on this, sought but not so far forthcoming! It might be very effective and usable for longer than its 5 year licensed life; be as easily inserted as the Flexi-T 300; and have an acceptable expulsion rate. IF all that were true, being Cu-banded it might come to rival the T-Safe Cu 380A and its clones, above. At present we lack the data to be sure.

When to use the banded GyneFixtm [11]? – NB not widely available, specific insertion training needed. Useful in some cases.

Special indications include a distorted cavity on ultrasound scan (if IUD useable at all), or a small uterine cavity sounding <6 cm. [A rival option for the latter, however, is that new UT 380 Short or one of the Flexi-Ts].

All users should be forewarned about unrecognised expulsion: being able to feel the threads is particularly important with GyneFix.

[Note: the Multiloadstm are without any established advantages. Schering no longer market the ineffective Nova-T 200.]

Mirenatm IUS [12,13]

This is a major advance in contraceptive technology, with the added value in relief of PAIN [12] as well as menorrhagia: facts still not widely enough appreciated! But there are two more differences between Mirena and copper IUDs:

Insertion: 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 to-be-inserted 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 IUS plus enzyme-inducer-users and good effectiveness was maintained (one definite pregnancy reported) [10]. This is biologically plausible, since the LNG would be released in high local concentration locally and should therefore still have its normal effects, on the utero-cervical fluid and also in impairing implantation. Therefore, pending more data, the use of Mirena by women on enzyme-inducers is a good choice, a WHO 2 situation. No added precautions need be taken, but with advice that there might be a minimal reduction in its amazing efficacy.

PID risk? Neither IUDs nor IUSs, intrinsically, increase PID risk. The essential thing is selection so far as possible for mutual monogamy; PLUS secondly the practice of inserting only through a "Chinese cervix" – as explained on pp 85-87 of ref [2] & pp 390-5 in ref [8], this means one established, by screening - verbally always, and where appropriate also for Chlamydia - to be pathogen-free….

Past ectopic? Although anovulant methods would be even better, in my view this is at most WHO 3 for the IUS or banded IUDs [14].

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

The Peterson et al study of 1996 [15] showed the failure rate of female sterilization as performed 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) [12]. In UK the RCOG estimates the ‘lifetime’ failure rate of the Filshie clip as better, 3-4/1000, whereas it is 0.5/1000 for vasectomy with azoospermia [16]

EMERGENCY CONTRACEPTION

The LNG-only method is more effective than the previous combined hormonal method, now superseded [17-18]. Every 12 hours’ delay increased the failure rate by 50 % [19]. Now a further WHO study shows that the whole 1500m g dose (now a single tablet) may and indeed should be given at once, working equally well with NO difference in side effects. WHO’s 2002 protocol [20] 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 [20]. WHO concluded this is "prevention of a high proportion of pregnancies even up to 5 days after coitus". So use of Levonelletm up to 5 days is acceptable as an example of evidence-based but unlicensed use of a licensed product what is usually termed *‘Named patient’use [see p141 of [2] or p535 of [8]]. For medico-legal safety, there should be a record that the woman understands this and gave informed verbal consent, ideally backed by a written handout to explain the difference(s) from the PIL of Levonelle. In this example she should also understand that a copper IUD would definitely be a more effective method of EC [21], failure rate about 0.1%.

Aside from current pregnancy the only absolute contraindications (WHO 4) to hormonal LNG-only EC are:

Caution (WHO 3) also applies: {if used in women on Warfarin – enhanced anti-coagulation reported [22], so check INR post-treatment –

{OR if an enzyme-inducer is in use (eg St John’s Wort), indicating a second 1500m g dose after 12 hours.

SELECTED REFERENCES, FURTHER READING and GLOSSARY

  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, 535 and other pages expanding on those at ref [2].
  9. Implanon r , a new single rod contraceptive implant. Presentation of the clinical data. Contraception 1998; 58 (6-Supplement):75S-115S.
  10. The effective and appropriate use of long-acting reversible contraception. National Institute for Health and Clinical Excellence. London: RCOG, October 2005. < http://www.nice.org.uk/pdf/CG030fullguideline.pdf >[Re efficacy of banded IUDs see pp 39-41; re IUS and drug interactions see p 79].
  11. Anon. Frameless intra-uterine contraceptive device (GyneFix). Drug and Ther Bulletin 2002;40(3):21-22
  12. Sivin I, Stern J. Health during prolonged use of levonorgestrel 20 m g/d and the TCu 380Ag IUDs: a multicenter study. Fertil Steril 1994;61:70-7.
  13. Sturridge F, Guillebaud J. Gynaecological aspects of the LNG-releasing intrauterine contraceptive device (Review). Br J Obstet Gynaecol 1997; 104: 285-9.
  14. Dennis J, Hampton, N. IUDs: which device? (Review). J Fam Planning & Reprod Health Care 2002; 28: 61-68.
  15. 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.
  16. Male and female sterilization. Evidence-based Guidelines No 4. Royal College of Obs and Gynaecologists (RCOG): London, 2003. See < www.rcog.org.uk >
  17. WHO. Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet 1998;352:428-33.
  18. Guillebaud J. Time for emergency contraception with levonorgestrel alone. Lancet 1998;352:416.
  19. Piaggio G, Von Hertzen H, Grimes D, van Look P. Timing of emergency contraception with levonorgestrel or the Yuzpe regimen. Lancet 1999; 353: 721.
  20. 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.
  21. CEU of Faculty of FPRHC Guidance: emergency contraception. J Fam Planning & Reprod Health Care 2003;29:9-15. Also at www.ffprhc..org.uk
  22. Ellison J, Thomson A, Greer I. Apparent interaction between warfarin and levonorgestrel used for emergency contraception. BMJ 2000;321:1382.

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 /PIL Patient Information Leaflet / INR International normalized ratio (test for anti-coagulation).

JOHN GUILLEBAUD, Professor Emeritus of Family Planning and Reproductive Health, UCL January 2006