Benefits and risks of oral contraception

Benefits and risks of oral contraception - technical

Topics covered:

  • Essentials
  • Introduction
  • Benefits of COC use
  • Disadvantages of COC use
  • Prescribing oral contraceptives

Essentials

Efficacy of the ‘pill’ as an oral contraceptive—users of combined oral contraceptives (COC) must understand the importance of not lengthening the pill-free (contraception-deficient) time, and be appropriately advised if prescribed enzyme-inducing drugs.

Noncontraceptive benefits of COC use—these include fewer disorders of the menstrual cycle and less risk of colorectal cancer and cancers of the ovary and endometrium, which may sometimes provide the principal indication for prescription.

Risks of COC use—these include (1) cancer of the breast (possible cofactor) and of the cervix (probable cofactor, with impact reducible through cervical screening); (2) venous thromboembolism—the attributable risk with any formulation of COC is very small without a hereditary or acquired predisposition, including obesity and immobility; (3) vascular diseases—the attributable risk of both acute myocardial infarction and haemorrhagic stroke is negligible without an added arterial risk factor; migraine with aura is a specific thrombotic stroke risk factor and contraindicates use of any oestrogen-containing method of contraception. By 10 years all-cause mortality in past-users is indistinguishable from that in never-users of the COC.

Progestogen-only pills—these have fewer contraindications than COC. Desogestrel 75 μg (Cerazette) blocks ovulation in 97% of cycles, hence it relies less than other progestogen-only pills on the cervical mucus effect and is a more effective option if COC is contraindicated.

Introduction

Combined oral contraceptives (COCs) contain an oestrogen (ethinylestradiol 20–35 µg in the majority of products in the United Kingdom) combined with one of eight progestogens. Progestogen-only pills (POP) have far fewer contraindications than COCs, since these are mainly oestrogen-related. Desogestrel 75 μg (Cerazette) is a useful new POP since it blocks ovulation in 97% of cycles, whereas other POPs do this only half the time, hence Cerazette relies less on the (weaker) contraceptive effect on the cervical mucus. This makes Cerazette, like all the COCs, highly effective in ‘perfect’ use (see Box 8.6.2 on p. 1263).

The COC replaces normal cycling with a 21-day cycle that is user-produced and caused directly at the end organ, i.e. the endometrium, during the (usually) 7 days of taking placebo or no pill. The withdrawal bleeding has minimal medical significance, can be deliberately postponed or made infrequent, and if it fails to occur poses no problem—once pregnancy is excluded. However, users must be advised never to lengthen the pill-free (contraception-deficient) time (Figure 1 below), and to act appropriately if tablets are missed (Bullet list 1).

Horseshoe' analogy to explain the 21-day cycle in women taking oral contraceptive pill. Omission of tablets either side of the gap in the horseshoe lengthens the 'contraception-losing interval

 

Figure 1 'Horseshoe' analogy to explain the 21-day cycle. Omission of tablets either side of the gap in the horseshoe lengthens the 'contraception-losing interval'

All medical treatments are a matter of balancing benefits and risks. In relation to the COC there are numerous reviews, chapters, systematic reviews, and guidance documents based on a vast literature since it was first marketed in 1960, comprising three main prospective studies (the Royal College of General Practitioners and Oxford/Family Planning Association in the United Kingdom and the Nurses Study in the United States of America) supplemented by numerous case–control studies and a few randomized controlled trials conducted by the World Health Organization (WHO) and other bodies.

Bullet list 1 Appropriate action if tablets are missed

  • In the final active-pill week, omit the oncoming placebo week
  • In the first week, take emergency contraception if any more than two of pills 1 to 7 are missed and unprotected intercourse has occurred since the last active tablet
  • 7 days of condom use whenever any pill is more than 24 hours late (though this is less important in contraceptive terms)

Benefits of COC use

Contraceptive

The COC is extremely effective: failures are less than 1 per 100 woman-years with ‘perfect use’, but this is rare and in the real world failure rates of 8 per 100 woman-years are common (see Box 8.6.2, p. 1263). Furthermore, the COC is convenient to use, not being related to intercourse, and its effects are reversible.

Noncontraceptive

There are often times when the COC pill is principally indicated for noncontraceptive purposes, e.g. in the treatment of dysmenorrhoea in a teenager who is not yet sexually active, or of menorrhagia in nulliparae unwilling to use an intrauterine system such as Mirena.

In the treatment of menstrual cycle disorders the COC pill can offer the following advantages:

  • less heavy bleeding, and hence less anaemia
  • less dysmenorrhoea; regular bleeding, the timing of which can be controlled—no COC-taker need ever have ‘periods’ at weekends, indeed continuous pill-taking with or without infrequent breaks reduces the number of days of (inconvenient) bleeding per year, increases efficacy, e.g. during enzyme-inducing drug therapy, avoids hormone-withdrawal headaches, and has become an option marketed in some countries
  • less premenstrual tension
  • usually no ovulation pain and fewer functional ovarian cysts

Other advantages of the COC include:

  • reduced risk of cancers of ovary and endometrium, and very probably also colorectal cancer
  • fewer extrauterine pregnancies because ovulation is inhibited
  • reduction in pelvic inflammatory disease
  • fewer sebaceous disorders, especially acne and mild hirsutism (with oestrogen-dominant COCs such as Marvelon and Yasmin)—with or without the diagnosis of polycystic ovarian syndrome (PCOS)
  • beneficial social effects (facilitating women’s higher education and careers).

Disadvantages of COC use

Tumours

The COC is a possible cofactor for cancer of the breast, but risk relates to recency, i.e. it occurs during use but diminishes to nil thereafter over 10 years. COC use for any duration ceasing at age 35 years appears to add one case to the background 10 per 1000 by age 45 years, with no subsequent added risk.

COC is a probable cofactor for cancer of the cervix, weaker than cigarette smoking, but with both increasing the rate of progression of (human papilloma virus-induced) cervical intraepithelial neoplasia. However, invasive cervical cancer should be an avoidable risk for COC users (with/without smoking), so long as there is 3-yearly cervical cytology from age 25 years, plus colposcopy as indicated, and eventually through earlier vaccination against causative human papilloma virus.

Malignant and benign tumours of liver have been said to be associated with the COC, but their rarity has led to imprecise but always very small relative risk estimations. However, the attributable death rate of this rapidly fatal cancer has not changed detectably in the United States or in Sweden, where the COC has been very widely used since the 1960s, moreover, there is no evidence of synergism with either cirrhosis or hepatitis B infection.

No other cancers have beneficial or adverse associations in the causation of with COCs or POPs.

Circulatory disease

Venous thromboembolism (VTE)

The main outcome of the 1995 ‘pill scare’ was an understanding that ethinylestradiol is the prothrombotic hormone, but for a given ethinylestradiol dose second-generation levonorgestrel (LNG) and norethisterone (NET) progestogens reduce VTE risk. Using absolute rates from the Committee on Safety of Medicines in 1999, the risk amounts to 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 third-generation desogestrel (DSG)/gestodene (GSD) products and second-generation LNG/NET products.

To put this into context 1 h of driving gives a 1 per million mortality risk, hence if a pill-taker chooses to control any minor side effect by switching—as she sensibly may—from Microgynon 30 (the usual first-line COC) to (say) Marvelon or Femodene, then if she avoids one 2-h 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. It is important to recognize that the risk factors for VTE (Table 1), obesity and immobility above all, affect risk far more than the differences between formulations of contraceptive pill.

Table 1 Risk factors for venous thromboembolism and their relation to use of oral contraceptives
Risk factor Absolute contraindication Relative contraindication Remarks
WHO 4 WHO 3 WHO 2
Personal or FH of thrombophilias, or of venous thrombosis in sibling or parent
  • Past VTE event; or identified clotting abnormality whether hereditary or acquired
  • FH of a defined thrombophilia or idiopathic thrombotic event in parent or sibling <45 and thrombophilia screen not (yet) available
FH of thrombosis in parent or sibling <45 with recognized precipitating factor (e.g. major surgery, postpartum) and thrombophilia screen not available FH of thrombotic event in parent or sibling <45 with or without a recognized precipitating factor and normal thrombophilia screen FH in parent or sibling ≥45 or FH in second-degree relative (classified WHO 2 but tests not indicated)
  • Idiopathic VTE in a parent or sibling <45 is an indication for a thrombophilia screen if available. The decision to undertake screening in other situations (including where there was a recognized precipitating factor), will be unusual because very cost-ineffective—might be done on clinical grounds, in discussion with the woman.
  • Even a normal thrombophilia screen cannot be entirely reassuring, as some predispositions not yet known
Overweight—high BMI BMI ≥40 BMI 30–39 BMI 25–29  
Immobility Bed-bound, with or without major surgery; or leg fractured and immobilized Wheelchair life, debilitating illness Reduced mobility for other reason Minor surgery such as laparoscopic sterilization is WHO 1
VVs
  • Current superficial vein thrombosis in the upper thigh
  • Current sclerotherapy for VVs (or imminent VV surgery)
  History of superficial vein thrombosis (SVT) in the lower limbs, no deep vein thrombosis
  • SVT does not result in pulmonary embolism, although this past history means some caution (WHO 2) in case it might be a marker of future VTE risk
  • Uncomplicated VVs are irrelevant to VTE risk (WHO 1)
Cigarette smoking   ≥15 cigarettes/day <15 cigarettes/day On balance the literature suggests a VTE risk from smoking, though less than the arterial disease risk
Age >35 >51   35–51 if age is sole risk factor VTE risk like arterial diseases risk goes up with increasing age

BMI, body mass index; FH, family history; VTE, venous thromboembolism; VV, varicose veins(s).

Notes

1. A single risk factor in the relative contraindication columns indicates use of LNG/NET pill if any COC used (as in BNF).

2. Beware of synergism: more than one factor in either of relative contraindication columns. As a working rule, two WHO 2 conditions makes WHO 3; and if WHO 3 applies (eg BMI 30–39) addition of either a WHO 3 or WHO 2 (eg reduced mobility) condition normally means WHO 4 (do not use).

3. Nonhereditary predispositions include antiphospholipid syndrome

4. There are also important acute VTE risk factors, which need to be considered in individual cases, notably major surgery, all leg surgery, long-haul flights, and dehydration through any cause.

5. There are minor differences in above table from the Faculty of Family Planning and Reproductive Health Care UK Medical Eligibility Criteria (see ‘Further reading’), notably the author’s more cautious categorization of BMI above 25.

Arterial disease Although the relative risk is increased, the attributable risk of acute myocardial infarction and of haemorrhagic stroke from the COC is negligible unless there is an added risk factor such as those listed in Table 2, the commonest of these being smoking. Thrombotic stroke risk can be minimized by using an ethinylestradiol-free method (e.g. a POP such as Cerazette) for all women with the specific risk factor of migraine with aura, but migraine without aura adds minimal extra risk.

Table 2 Risk factors for arterial disease and their relation to use of oral contraceptives
Risk factor Absolute contraindication Relative contraindication Remarks
WHO 4 WHO 3 WHO 2
FH of atherogenic lipid disorder or of arterial CVS event in sibling or parent Identified familial hyperlipidaemia, persisting despite treatment FH of known familial lipid disorder or idiopathic arterial event in parent or sibling <45 and client’s lipid screening result not available or confirmed and responding to treatment
  • Client has the less problematic common hyper-lipidaemia and well treated
  • FH of arterial event with risk factor (e.g. smoking), in parent or sibling < 45, and lipid screen not available
  • FH of premature arterial CVS disease without other risk factors, or a known atherogenic lipid disorder in a parent or sibling <45 indicate fasting lipid screen, if available.
  • Despite any FH, normal lipid screen in client is reassuring, means WHO 1 (in contrast to thrombophilia screening)
Cigarette smoking ≥40 cigarettes/day 15–39 cigarettes/day <15 cigarettes/day Cut-offs here are somewhat arbitrary
DM Severe, longstanding or diabetic complications present (e.g. retinopathy, renal damage) Not severe/labile and no complications, young patient with short duration of DM   DM is always at least WHO 3 (safer options available)
Hypertension (consistently elevated BP, with properly taken measurements)
  • Systolic BP ≥160 mmHg
  • Diastolic BP > 95 mmHg
  • Systolic BP ≥140–159 mmHg
  • Diastolic BP > 95 mmHg or:
  • On treatment for essential hypertension, with good control
Past history of pre-eclampsia (WHO 3 if also a smoker) Levels for WHO 4 and WHO 3 consistent with UKMEC
Overweight, high BMI BMI >40 BMI 30–39 BMI 25–29 High BMI increases arterial as well as VTE risk
Migraine
  • Migraine with aura
  • Migraine without aura if severe + prolonged attacks (>72 h)
Migraine without aura plus a strong added arterial risk factor Migraine without aura
  • Relates to thrombotic stroke risk
  • Triptan treatment does not affect the category
Age > 35 Age >51 (safer options available)   Age 35–51 if no other risk factors
  • In persistent smokers, age >35 remains best classified as WHO 4
  • In ex-smokers, UKMEC permits WHO 2 category after one year of not smoking

BMI, body mass index; BP, blood pressure; CVS, cardiovascular system; DM, diabetes mellitus; FH, family history; VTE, venous thromboembolism.

Notes

1. Beware of synergism: more than one factor in either of relative contraindication columns. As a working rule, two WHO 2 conditions makes WHO 3; and if WHO 3 applies, (e.g. smoking >15 cigarettes/day) addition of either a WHO 3 or WHO 2 (eg. age >35) condition normally means WHO 4 (as in table).

2. The pill seems to have negligible adverse effect in arterial disease unless there is a risk factor. In continuing smokers the COC is generally stopped at age 35 years in the UK.

3. WHO numbers also relate to use for contraception: use of COCs for medical indications such as PCOS often entails a different risk/benefit analysis, i.e. the extra therapeutic benefits might outweigh expected extra risks, such as a high BMI-common in PCOS.

4. There are minor differences in above Table from UK Medical Eligibility Criteria of Faculty Family Planning and Reproductive Health Care (see references), notably the author’s more cautious categorization with respect to smoking, hyperlipidaemia and DM.

Reassuringly, COCs have their main (small) effect on every known associated cause of mortality during current use and the excess thrombotic risk has vanished by 4 weeks. By 10 years all-cause mortality in past users is indistinguishable from that in never-users.

Prescribing oral contraceptives

Current scientific evidence suggests only two prerequisites for the safe provision of COCs: a careful personal and family history with particular attention to cardiovascular risk factors, and a well-taken blood pressure at baseline and follow-up. The WHO has introduced an invaluable 1 to 4 scale for risks and many, though not all, relevant conditions are now usefully categorized on this scale by the United Kingdom Medical Eligibility Criteria of Faculty Family Planning and Reproductive Health Care (see Tables 1 and 2 above).

Principles for establishing contraindications

A careful personal and family history excludes absolute (WHO 4) and relative (WHO 3 or 2) contraindications to COC use (Tables 14.19.1 and 14.19.2). It is impossible to list them all here; indeed. for many diseases the relevant data do not exist. The working rules therefore require prescribers to ascertain whether or not any condition might lead to summation with a known major adverse effect of COCs, particularly relating to arterial or venous circulatory disease (see Bullet list 2), or a current hormone-sensitive tumour (breast, liver, or trophoblastic), or might affect COC metabolism in the liver, e.g. severe hepatocellular disease or enzyme-inducing drug use.

All these usually mean WHO 4 (Do Not Use), or sometimes—as with enzyme-inducing drug use—WHO 3. The use of enzyme-inducing drugs always means that another method (specifically an injectable or intrauterine method) would be preferable, but if these are not acceptable oral contraceptive use requires special conditions (i.e. double dose with elimination and/or shortening of the contraception-deficient intervals).

Bullet list 2 Important examples of circulatory conditions to be considered with respect to COC use

  • A personal history of definite VTE, acute myocardial infarction, any kind of stroke or transient ischaemic attack, or of migraine with aura are all WHO 4 contraindications.
  • Structural (uncorrected) heart disease such as valvular heart disease or shunts/septal defects are WHO 4, but if there is little or no direct or indirect risk of thrombo-embolism—this being the crucial point to check with the cardiologist—the COC is usable (WHO 3 or even 2), especially if patient is on lifetime warfarin.
  • Important WHO 4 heart conditions are pulmonary hypertension, cyanotic heart disease, atrial fibrillation or flutter whether sustained or paroxysmal—or not current but high risk (e.g. mitral stenosis), dilated left atrium (>4 cm), any dilated cardiomyopathy (but this is classified only as WHO 2 with a past history of any type in full remission, including pregnancy cardiomyopathy).

It is important to emphasize that WHO 4 means ‘do not use’ any hormonal method containing ethinylestradiol (including the patch Evra or vaginal ring NuvaRing) combined with any progestogen, but all progestogen-only methods are usable. Indeed, Cerazette and Mirena are most valuable options, the former especially in adolescents with treated congenital heart disease. More generally, Cerazette is a realistic alternative if the COC is WHO 4 or 3 in any young woman, although the cheaper old-type POPs suffice in low-fertility states such as lactation or above age 40 years.

In all other medical conditions the use of COCs is generally graded as WHO 2, though always with alertness for the onset of new risk factors. Reliable protection from pregnancy is often particularly important in chronic disease states.

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