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Hormonal Contraceptives: Precautions

Anticonceptivos hormonales; Contraceptifs Hormonaux; Hormonale Kontrazeptiva

Before hormonal contraceptives are given, the woman should undergo an appropriate medical examination and her medical history should be carefully evaluated. Regular examination is recommended during use. The contraceptive effectiveness of combined and progestogen-only preparations may be reduced during episodes of vomiting or diarrhoea and extra contraceptive measures may be necessary during and for 7 days after recovery. For precautions to be taken if a ‘pill’ is missed, see Uses and Administration, below.

Combined oral contraceptives are contra-indicated in women with markedly impaired liver function or cholestasis, the Dubin-Johnson or Rotor syndromes, hepatic adenoma, oestrogen-dependent neoplasms such as breast or endometrial cancer, cardiovascular disease (see also below) including previous or current thromboembolic disorders or high risk of them, and arterial disease or multiple risk factors for it, disorders of lipid metabolism, undiagnosed vaginal bleeding, possible pregnancy, or a history during pregnancy of pruritus or cholestatic jaundice, chorea, herpes gestationis, pemphigoid gestationis, or deteriorating otosclerosis. They are also contra-indicated in severe or focal migraine (or where there are other risk factors for cardiovascular disease) and should be used with caution in other forms of migraine (for further details, see below). They should be given with caution to women with a history of clinical depression, gallbladder disease, sickle-cell disease, or conditions influenced by fluid retention. Oral contraceptive absorption, and hence efficacy, may be reduced in women with inflammatory bowel disease when there is small bowel involvement or malabsorption. They should also be used with caution in those with varicose veins (and should be avoided where the restrictions outlined under Venous Thromboembolism apply, see Cardiovascular Disease, below). Where not actually contra-indicated, they should also be used with caution in those with a risk factor for cardiovascular disease such as diabetes mellitus, smoking, obesity, hypertension, or a family history of cardiovascular disorders (see also below). Current opinion is that low-dose combined oral contraceptives may be used in women over the age of 3 5 years provided they do not smoke and have no other risk factors for cardiovascular disease, but that they should be avoided over the age of 50 years. Use by those undergoing surgery or prolonged bed rest may increase the risk of thromboembolic episodes and it is generally recommended that combined oral contraceptives should be stopped 4 weeks before major elective surgery (but see also below). Combined oral contraceptives should not be used after recent evacuation of a hydatidiform mole until urine and plasma gonadotrophin concentrations have returned to normal. Contact lenses may irritate. The use of combined oral contraceptives may influence the results of certain laboratory tests including liver, thyroid, adrenal, and renal-function tests, plasma concentrations of binding proteins and lipid/lipoprotein fractions, and fibrinolysis and coagulation parameters.

Combined oral contraceptives should be stopped immediately, and appropriate investigations and treatment carried out, if any of the following occur:

• sudden severe chest pain, sudden breathlessness, or severe pain/swelling in calf of one leg (possibly indicative of thromboembolic complications)

• unusual, severe, prolonged headache, sudden disturbances of vision or hearing or other perceptual disorders, collapse, marked numbness or weakness affecting one side of the body, or other signs or symptoms suggestive of cerebrovascular accident

• a first unexplained epileptic seizure

• hepatitis, jaundice, generalised itching, liver enlargement, severe upper abdominal pain

• significant rise in blood pressure (above 160 mmHg systolic or 100 mmHg diastolic)

• clear exacerbation of other conditions known to be capable of deteriorating during oral contraception or pregnancy.

Progestogen-only contraceptives, whether oral or injectable, may be used when oestrogen-containing preparations are contra-indicated but certain contra-indications and precautions must still be observed. They are contra-indicated in women with undiagnosed vaginal bleeding, possible pregnancy, severe arterial disease, hormone-dependent neoplasms, and severe liver disease such as hepatic adenoma.

Like combined oral contraceptives they should not be used after recent evacuation of a hydatidiform mole. Progestogen-only contraceptives should be used with caution in women with heart disease, malabsorption syndromes, liver dysfunction including recurrent cholestatic jaundice, or a history of jaundice in pregnancy. Oral progestogen-only contraceptives should also be used with caution in past ectopic pregnancy (see above) or functional ovarian cysts. Despite unsatisfactory evidence of hazard, other suggested cautions for progestogen-only contraceptives include diabetes mellitus, hypertension, migraine, and thromboembolic disorders.

Breast feeding. Progestogen-only contraceptives are the hormonal contraceptives of choice for breast-feeding women because they do not affect lactation, but recommendations vary about when they can or should be started, and may not match licensed product information. Some guidelines recommend that all progestogen-only methods can be started 6 weeks after birth. Others suggest that oral preparations can be started any time in breast-feeding women, although they are not needed before 3 weeks postpartum the BNF also warns that there is an increased risk of breakthrough bleeding if progestogen-only oral contraceptives are started before 3 weeks postpartum. Progestogen-only parenteral contraceptives, such as medroxyprogesterone acetate, are usually not given until 6 weeks postpartum troublesome bleeding can occur before this time. The etonogestrel implant may be used 3 weeks postpartum and the levonorgestrel IUD may be inserted 4 weeks postpartum.

Combined oral contraceptives can reduce the volume of breast milk and are therefore avoided in breast-feeding women for the first 6 weeks after birth. In general, they are not recommended for 6 months or until weaning, but some suggest that they may be considered between 6 weeks and 6 months postpartum if breast feeding is established and other contraceptive methods are unacceptable.

Very small amounts of oestrogens and progestogens from hormonal contraceptives are distributed into breast milk, but there is no indication that this adversely affects development of the breast-fed infant. The American Academy of Pediatrics has also reviewed the use of hormonal contraceptives during lactation, commenting that early information was based on the use of high-dose contraceptives. It was noted that there might be a decrease in milk production, but that there was insufficient information to confirm that there was any alteration in the composition of breast milk, and that although there had been rare cases of gynaecomastia in breast-fed infants of mothers who received high-dose contraceptives, there was no consistent evidence of long-term adverse effects on the infant. A later study of 48 children whose mothers had received high-dose combined oral contraceptives during breast feeding found no effect on these children compared with controls, up to 8 years of age. The Academy therefore considers that combined oral contraceptives are usually compatible with breast feeding.

Breast feeding itself suppresses ovulation and can be used, if started immediately postpartum, as the lactational amenorrhoea method of contraception for further details, see Contraception.

Cardiovascular disease. Combined oral contraceptives are associated with a number of arterial and venous risks. Progestogen-only contraceptives are associated with fewer risks, although they still need to be avoided when arterial disease is severe.

Arterial disease. In the UK the BNF has, recommended that combined oral contraceptives may be used with caution if any one of the following factors are present, but should be avoided if two or more factors are present:

family history of arterial disease in first-degree relative aged under 45 years (avoid if there is also an atherogenic lipid profile)

diabetes mellitus (avoid if diabetic complications are present)

hypertension (avoid if blood pressure is above 160/100 mmHg)

smoking (avoid if 40 or more cigarettes are smoked daily)

age over 35years (avoid if over 50 years)

obesity — body-mass index above 30 kg/m (avoid if body-mass index exceeds 39 kg/m)

migraine, see under Migraine, below.

Venous thromboembolism. Combined oral contraceptives increase the risk of venous thromboembolism and should not be used in women with a personal history of venous or arterial thrombosis. In addition they should be used with caution if any one of the following risk factors are present, but should be avoided if two or more factors are present:

family history of venous thromboembolism in first-degree relative aged under 45 years (avoid if there is a known prothrombotic coagulation abnormality such as antiphospholipid antibodies, which may occur in patients with SLE, or factor V Leiden)

long-term immobilisation such as wheelchair use (avoid if confined to bed or with a leg in plaster)

varicose veins (avoid during sclerosing treatment)

obesity — body-mass index above 30 kg/m (avoid if body-mass index greater than 39 kg/m).

The BNF also advises that women taking combined oral contraceptives may be at an increased risk of deep-vein thrombosis during travel involving prolonged periods of immobility (over 5 hours). The risk may be reduced by appropriate exercise during the journey, and possibly by wearing graduated compression hosiery.

In the light of evidence indicating an increased risk of venous thromboembolism with combined oral contraceptives containing desogestrel or gestodene (see Venous Thromboembolism, under Effects on the Cardiovascular System, above), the UK CSM advised additional precautions for these products. As well as the usual precautions, it was initially advised they should not be used by obese women (body-mass index greater than 30 kg/m), those with varicose veins, or those with a history of thrombosis of any cause. Moreover, it was also recommended that they should be used only by women who were intolerant of other combined oral contraceptives and who were prepared to accept an increased risk of venous thromboembolism. Subsequently the CSM modified its advice as follows: they recommended that these products should be avoided in women with known risk factors for venous thromboembolism. However, in women without contra-indications, the type of combined contraceptive was considered a matter of clinical judgement and personal choice, as long as the woman was fully informed of the small excess risk associated with desogestrel- and gestodene-containing products.

Lupus erythematosus. SLE is an auto-immune disease that is far more common in women than in men, and usually has a peak onset for women in their 20s and 30s. There is some evidence to suggest that oral contraceptive use may be associated with a slightly increased risk in the onset of SLE. There are also reports and studies of the effect of contraceptives on disease exacerbation, although there has been an apparent reduction in reports which has coincided with the lowering of oestrogen content in contraceptive preparations. More recently, controlled studies’ have found that disease activity and flares over 12 months in women with stable SLE were similar whether they were given a combined oral contraceptive (containing ethinylestradiol 30 or 35 micrograms), a progestogen-only oral preparation, placebo, or copper IUD. However, patients with major disease, such as lupus nephritis, could be at greater risk of exacerbation. It is also generally advised that combined oral contraceptives should be avoided in women with antiphospholipid antibodies (which includes about a third of all patients with SLE) because they are at increased risk of venous thromboembolism.

Migraine. Both migraine and the use of combined oral contraceptives have been identified as risk factors for ischaemic stroke. A systematic review concluded that in women with a history of migraine, users of combined oral contraceptives were 2 to 4 times more likely to have an ischaemic stroke than non-users. It was unclear, however, whether this increase in relative risk was due to independent effects of contraceptives and migraine, or whether contraceptive use had a greater effect in women with a history of migraine than in those without. In the UK the BNF has, recommended that combined oral contraceptives be contra-indicated in:

• migraine with typical focal aura

• severe migraine regularly lasting longer than 72 hours despite treatment

• migraine treated with an ergot derivative

It also recommends caution in migraine without focal aura and migraine controlled with a serotonin (5-HT1) agonist. A woman receiving a combined oral contraceptive should report any increase in headache frequency or the onset of focal symptoms. If focal neurological symptoms not typical of aura persist for longer than one hour the combined oral contraceptive should be discontinued and the woman referred urgently to a neurologist. Other risk factors for arterial disease should also be considered in women with a history of migraine (see Cardiovascular Disease, above).

Obesity. It has been suggested that higher body-weight or BMI might be associated with a greater risk of oral contraceptive failure. A number of cohort and case-control studies have evaluated this association, with mixed results that may have been confounded by recall bias, inaccuracy of reported body-weight, non-compliance, and change in oestrogen dose over time. Some studies have suggested that there is an increased risk of contraceptive failure, while others have found no association. In addition, some have found a weak association that was no longer statistically significant when results were adjusted for confounders such as education, income, and ethnicity. It is therefore unclear whether an association exists, but obesity is a risk factor for cardiovascular disease and combined oral contraceptives should be used with caution, or avoided, in these women (see Cardiovascular Disease, above).

Porphyria. Oral contraceptives have been associated with acute attacks of porphyria and are considered unsafe in porphyric patients. The progestogen content is considered more hazardous than the oestrogen content. A progestogen-only contraceptive may be used with extreme caution if non-hormonal contraception is inappropriate and potential benefit outweighs the risk. The risk of an acute attack is greatest in women who have had a previous attack or are under 30 years of age. Long-acting progestogen preparations should never be used in those at risk.

Pregnancy. In contrast to the numerous cases of congenital malformations reported after the use of high doses of sex hormones for hormonal pregnancy tests, there have been only a few suggestions that continued use of oral contraceptives during early pregnancy may result in congenital limb reduction deformities, and one case of neonatal choreoathetosis after prenatal exposure to oral contraceptives.

Many studies, conversely, have shown no evidence that the use of oral contraceptives is associated with congenital malformations or teratogenic effects, whether past use (stopped before conception), use after the last menstrual period, or known use in early pregnancy. A meta-analysis confirmed this the relative risk for all malformations with use of oral contraceptives was estimated to be 0.99 (95% confidence intervals 0.83 to 1.19). The use of oral contraceptives in early pregnancy also appears unlikely to increase the risk of hypospadia in male fetuses’ (see also under Precautions of Estradiol).

Depot intramuscular medroxyprogesterone acetate is a highly effective contraceptive, but failures do occur rarely. A review of such failures had limited data on birth outcome in 100 women who continued the pregnancy, but no abnormalities or fetal anomalies were reported.

In 25 pregnancies that were continued after the failure of levonorgestrel-based emergency contraception, there was 1 case of gastro-oesophageal reflux requiring medical treatment and 1 case of nasolachrymal duct obstruction that was surgically drained, but compared with a control group and expected baseline risk there was no increased risk of congenital or genital abnormalities.

For a discussion of the ectopic pregnancy risk in users of hormonal contraceptives, see above.

Sickle-cell disease. Sickle-cell disease and oral contraceptive use are both associated with an increased risk of thrombosis but it is by no means certain that the two risks are additive. Study of a small number of women with sickle-cell disease found that combined and progestogen-only contraceptives had no effect on red cell deformability. Licensed product information for some preparations has specifically warned against the use of combined oral contraceptives in sickle-cell disease. However, there is a lack of strong clinical evidence to support such a contra-indication, and there is some suggestion that progestogen-only contraception may be associated with improvements in clinical symptoms and sickle-cell crises. WHO considers that in women with sickle-cell disease the benefits generally outweigh the risks for low-dose combined oral contraceptives (35 micrograms or less of ethinylestradiol) and other forms of combined hormonal contraceptives (injectable, transdermal patch, and vaginal ring), and that there is no restriction for the use of progestogen-only contraceptives (oral, depot injection, implant, and intra-uterine device).

For sickle-cell trait there is no increased risk of thrombosis and no contra-indication to the use of a combined or progestogen-only preparation. Many women with sickle-cell trait have, unnecessarily, been denied the use of oral contraceptives in the mistaken belief that advice for sickle-cell disease applies to the trait.

Surgery. Case reports and epidemiological studies showing an increased risk of idiopathic deep-vein thrombosis and pulmonary embolism in young women taking combined oral contraceptives (see above) led to the widespread belief that oral contraceptives may predispose to deep-vein thrombosis postoperatively. In consequence, the advice commonly given in the UK has been that, if possible, combined oral contraceptives should be stopped 4 weeks before major elective surgery and all surgery of the legs, and that prophylactic heparin should be considered where this was not possible. They can normally be started again at the first menses occurring at least 2 weeks after full mobilisation. However, estimates of the size of the risk are variable ” one report found that the incidence of deep-vein thrombosis postoperatively in young women taking combined oral contraceptives was about twice that of women not taking contraceptives but the difference was not statistically significant. Some have considered that the risk to young women of becoming pregnant after stopping oral contraceptives, or of developing adverse effects from heparin prophylaxis, may be greater than the risk of developing postoperative deep-vein thrombosis. This is in line with the views of the Thromboembolic Risk Factors (THRIFT) Consensus Group. They suggested that unless there were other risk factors there was insufficient evidence to support a policy of routinely stopping combined oral contraceptives before major surgery. Additionally, there was insufficient evidence to support routine specific thromboembolic prophylaxis in women without additional risk factors. A review has subsequently recommended that women for whom major elective surgery was planned should continue taking the combined oral contraceptive but should receive thromboprophylaxis in the perioperative period. It has also been pointed out’ that for patients awaiting surgery who require contraception, a progestogen-only oral contraceptive or an injection of medroxyprogesterone acetate may be suitable since neither preparation increases the risk of thrombosis.

Travel. For a warning that women taking oral contraceptives may be at increased risk of deep-vein thrombosis from travel involving prolonged immobility see Cardiovascular Disease, above.

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