Combined oral contraceptives (COCs)

Combination pills (combined oral contraceptives - COCs) are the most widely used form of hormonal contraception.

According to the content of the estrogen component in the tablet in the form of ethinyl estradiol (EE), these drugs are divided into high-dose, containing more than 40 meg EE, and low-dose - 35 meg or less EE. In monophasic drugs, the content of the estrogen and gestagen components in the tablet remains unchanged throughout the menstrual cycle. In two-phase tablets, the content of the gestagen component increases in the second phase of the cycle. In three-phase COCs, the increase in the dose of gestagen occurs stepwise in three stages, and the dose of EE increases in the middle of the cycle and remains unchanged at the beginning and end of the intake. The variable content of sex steroids in two- and three-phase drugs throughout the cycle made it possible to reduce the total course dose of hormones.

Combined oral contraceptives are highly effective reversible means of contraception. The Pearl Index (IP) of modern COCs is 0.05-1.0 and depends mainly on compliance with the rules for taking the drug.

Each tablet of a combined oral contraceptive (COC) contains an estrogen and a progestogen. The estrogen component of COCs is a synthetic estrogen - ethinyl estradiol (EE), and the progestogen component is various synthetic progestogens (synonym - progestins).

Progestogen contraceptives contain only one sex steroid - progestogen, which provides the contraceptive effect.

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Benefits of combined oral contraceptives

Contraceptives

• High efficiency with daily intake IP = 0.05-1.0
• Fast effect
• No connection with sexual intercourse
• Few side effects
• The method is easy to use.
• The patient can stop taking the medication herself.

Non-contraceptive

• Reduces menstrual-like bleeding
• Reduces menstrual pain
• May reduce the severity of anemia
• May help establish a regular cycle
• Prevention of ovarian and endometrial cancer development
• Reduces the risk of developing benign breast tumors and ovarian cysts
• Protect against ectopic pregnancy
• Provides some protection against pelvic inflammatory disease
• Provides prevention of osteoporosis

Nowadays, COCs are very popular all over the world due to the benefits listed below.

• High contraceptive reliability.
• Good tolerance.
• Availability and ease of use.
• No connection with sexual intercourse.
• Adequate control of the menstrual cycle.
• Reversibility (complete restoration of fertility within 1–12 months after discontinuation of treatment).
• Safe for most physically healthy women.
• Therapeutic effects:
  • regulation of the menstrual cycle;
  • elimination or reduction of dysmenorrhea;
  • reduction of menstrual blood loss and, as a result, treatment and prevention of iron deficiency anemia;
  • elimination of ovulatory pain;
  • reduction in the incidence of inflammatory diseases of the pelvic organs;
  • therapeutic effect in premenstrual syndrome;
  • therapeutic effect in hyperandrogenic conditions.
• Preventive effects:
  • reducing the risk of developing endometrial and ovarian cancer, colorectal cancer;
  • reducing the risk of developing benign breast tumors;
  • reducing the risk of developing iron deficiency anemia;
  • reducing the risk of ectopic pregnancy.
• Removing the “fear of unwanted pregnancy”.
• The ability to “delay” the next menstruation, for example, during exams, competitions, or vacations.
• Emergency contraception.

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Types and composition of modern combined oral contraceptives

Based on the daily dose of the estrogen component, COCs are divided into high-dose, low-dose and micro-dose:

• high-dose - 50 mcg EE/day;
• low-dose - no more than 30–35 mcg EE/day;
• microdosed, containing microdoses of EE, 15–20 mcg/day.

Depending on the scheme of the combination of estrogen and gestagen, COCs are divided into:

• monophasic - 21 tablets with an unchanged dose of estrogen and progestogen per 1 cycle of administration;
• biphasic - two types of tablets with different ratios of estrogen and progestogen;
• three-phase - three types of tablets with different ratios of estrogen and progestogen. The main idea of three-phase is to reduce the total (cyclic) dose of progestogen by increasing its dose in three stages during the cycle. In the first group of tablets, the dose of progestogen is very low - approximately the same as in a monophasic COC; in the middle of the cycle, the dose increases slightly and only in the last group of tablets does it correspond to the dose in a monophasic drug. Reliability of ovulation suppression is achieved by increasing the dose of estrogen at the beginning or middle of the cycle. The number of tablets of different phases varies in different drugs;
• multiphase - 21 tablets with a variable ratio of estrogen and progestogen in tablets of one cycle (one package).

Currently, low- and micro-dose preparations should be used for contraception. High-dose COCs can be used for planned contraception only for a short time (if it is necessary to increase the estrogen dose). In addition, they are used for therapeutic purposes and for emergency contraception.

Mechanism of contraceptive action of combined oral contraceptives

• Suppression of ovulation.
• Thickening of cervical mucus.
• Endometrial changes that prevent implantation. The mechanism of action of COCs is generally the same for all drugs, it does not depend on the composition of the drug, the dose of the components and the phase. The contraceptive effect of COCs is provided mainly by the progestogen component. EE in COCs supports proliferation of the endometrium and thus ensures cycle control (no intermediate bleeding when taking COCs). In addition, EE is necessary to replace endogenous estradiol, since when taking COCs there is no follicle growth and, therefore, estradiol is not secreted in the ovaries.

Classification and pharmacological effects

Chemical synthetic progestogens are steroids and are classified by origin. The table shows only progestogens included in hormonal contraceptives registered in Russia.

Classification of progestogens

Testosterone derivatives	Progesterone derivatives	Spironolactone derivatives
Containing an ethynyl group at C-17: Norethisterone Norgestrel Levonorgestrel Gestodene Desogestrel Norgestimate Not containing ethynyl group: Dienogest	Cyproterone acetate Chlormadinone acetate Medroxyprogesterone acetate	Drospirenone

Like natural progesterone, synthetic progestogens cause secretory transformation of the estrogen-stimulated (proliferative) endometrium. This effect is due to the interaction of synthetic progestogens with the progesterone receptors of the endometrium. In addition to the effect on the endometrium, synthetic progestogens also act on other target organs of progesterone. The differences between synthetic progestogens and natural progesterone are as follows.

• Higher affinity for progesterone receptors and, as a consequence, a more pronounced progestogenic effect. Due to the high affinity for progesterone receptors of the hypothalamic-pituitary region, synthetic progestogens in low doses cause a negative feedback effect and block the release of gonadotropins and ovulation. This is the basis for their use for oral contraception.
• Interaction with receptors of some other steroid hormones: androgens, gluco- and mineralocorticoids - and the presence of corresponding hormonal effects. These effects are expressed relatively weakly and are therefore called residual (partial or partial). Synthetic progestogens differ in the spectrum (set) of these effects; some progestogens block receptors and have a corresponding antihormonal effect. For oral contraception, the antiandrogenic and antimineralocorticoid effects of progestogens are favorable, the androgenic effect is undesirable.

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Clinical significance of individual pharmacological effects of progestogens

A pronounced residual androgenic effect is undesirable, as it can cause:

• androgen-dependent symptoms - acne, seborrhea;
• a change in the lipoprotein spectrum towards the predominance of low-density fractions: low-density lipoproteins (LDL) and very low-density lipoproteins, since the synthesis of apolipoproteins and the destruction of LDL are inhibited in the liver (an effect opposite to the influence of estrogens);
• decreased carbohydrate tolerance;
• increase in body weight due to anabolic action.

Based on the severity of their androgenic properties, progestogens can be divided into the following groups.

• Highly androgenic progestogens (norethisterone, lynestrenol, ethynodiol diacetate).
• Progestogens with moderate androgenic activity (norgestrel, levonorgestrel in high doses - 150–250 mcg/day).
• Progestogens with minimal androgenicity (levonorgestrel at a dose of no more than 125 mcg/day, gestodene, desogestrel, norgestimate, medroxyprogesterone). The androgenic properties of these progestogens are detected only in pharmacological tests and have no clinical significance in most cases. WHO recommends using mainly oral contraceptives with low-androgenic progestogens.

The antiandrogenic effect of cyproterone, dienogest and drospirenone, as well as chlormadinone, is of clinical significance. Clinically, the antiandrogenic effect is manifested in the reduction of androgen-dependent symptoms - acne, seborrhea, hirsutism. Therefore, COCs with antiandrogenic progestogens are used not only for contraception, but also for the treatment of androgenization in women, for example, in polycystic ovary syndrome (PCOS), idiopathic androgenization and some other conditions.

Severity of the antiandrogenic effect (according to pharmacological tests):

• cyproterone - 100%;
• dienogest - 40%;
• drospirenone - 30%;
• chlormadinone - 15%.

Thus, all progestogens included in COCs can be arranged in a row according to the severity of their residual androgenic and antiandrogenic effects.

Taking COCs should begin on the 1st day of the menstrual cycle, after taking 21 tablets, take a 7-day break or (with 28 tablets in a package) take 7 placebo tablets.

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Missed Pill Rules

The current rules for missed tablets are as follows. If less than 12 hours have passed, the tablet should be taken at the time the woman remembered to take it, and then the next tablet should be taken at the usual time. No additional precautions are required. If more than 12 hours have passed since the missed tablet, the same should be done, but additional contraception should be used for 7 days. If two or more tablets are missed in a row, two tablets should be taken daily until the usual schedule is reached, using additional contraception for 7 days. If bleeding begins after the missed tablets, it is better to stop taking the tablets and start a new pack 7 days later (counting from the start of the missed tablets). If even one of the last seven hormone-containing tablets is missed, the next pack should be started without a seven-day break.

Rules for changing medications

The transition from higher-dose drugs to low-dose drugs is carried out with the start of taking low-dose COCs without a seven-day break on the day following the end of the 21st day of taking high-dose contraceptives. The replacement of low-dose drugs with high-dose drugs occurs after a seven-day break.

Symptoms of possible complications when using COCs

• Severe chest pain or shortness of breath
• Severe headaches or blurred vision
• Severe pain in the lower limbs
• No bleeding or spotting during the pill-free week (21-day pack) or while taking the 7 inactive pills (28-day pack)

If any of the above symptoms occur, an urgent consultation with a doctor is required!

Restoring Fertility

After discontinuing COC use, normal functioning of the hypothalamic-pituitary-ovarian system is quickly restored. More than 85-90% of women are able to become pregnant within 1 year, which corresponds to the biological level of fertility. Taking COCs before the conception cycle does not have a negative effect on the fetus, the course and outcome of pregnancy. Accidental use of COCs in the early stages of pregnancy is not dangerous and is not a reason for abortion, but at the first suspicion of pregnancy, a woman should immediately stop taking COCs.

Short-term use of COCs (for 3 months) causes an increase in the sensitivity of the receptors of the hypothalamus-pituitary-ovarian system, therefore, when COCs are discontinued, tropic hormones are released and ovulation is stimulated. This mechanism is called the "rebound effect" and is used in some forms of anovulation.

In rare cases, amenorrhea is observed after discontinuation of COCs. It may be a consequence of atrophic changes in the endometrium that develop when taking COCs. Menstruation appears when the functional layer of the endometrium is restored independently or under the influence of estrogens therapy. In approximately 2% of women, especially in the early and late periods of fertility, amenorrhea lasting more than 6 months is observed after discontinuation of COCs (the so-called post-pill amenorrhoea - hyperinhibition syndrome). The nature and causes of amenorrhea, as well as the response to therapy in women who used COCs, do not increase the risk, but can mask the development of amenorrhea with regular menstrual-like bleeding.

Rules for individual selection of combined oral contraceptives

COCs are selected for a woman strictly individually, taking into account the characteristics of her somatic and gynecological status, and personal and family history. COCs are selected according to the following scheme.

• A targeted survey, assessment of somatic and gynecological status and determination of the acceptability category of the combined oral contraceptive method for a given woman in accordance with the WHO acceptability criteria.
• Selection of a specific drug taking into account its properties and, if necessary, therapeutic effects; counseling a woman on the method of combined oral contraception.
• Observation of the woman for 3–4 months, assessment of tolerability and acceptability of the drug; if necessary, a decision to change or discontinue COCs.
• Dispensary observation of the woman during the entire period of using COCs.

The woman's survey is aimed at identifying possible risk factors. It necessarily includes the following series of aspects.

• The nature of the menstrual cycle and gynecological history.
  • When was your last menstruation, was it normal (pregnancy should be ruled out at this time).
  • Is the menstrual cycle regular? Otherwise, a special examination is necessary to identify the causes of the irregular cycle (hormonal disorders, infection).
  • The course of previous pregnancies.
  • Abortions.
• Previous use of hormonal contraceptives (oral or other):
  • were there any side effects, if so what were they;
  • For what reasons did the patient stop using hormonal contraceptives?
• Personal history: age, blood pressure, body mass index, smoking, medication intake, liver disease, vascular disease and thrombosis, diabetes, cancer.
• Family history (diseases in relatives that developed before the age of 40): arterial hypertension, venous thrombosis or hereditary thrombophilia, breast cancer.

According to the WHO conclusion, the following examination methods are not relevant to assessing the safety of COC use.

• Examination of the mammary glands.
• Gynecological examination.
• Examination for the presence of atypical cells.
• Standard biochemical tests.
• Tests for inflammatory diseases of the pelvic organs, AIDS. The drug of first choice should be a monophasic COC with an estrogen content of no more than 35 mcg/day and a low-androgen gestagen. Such COCs include Logest, Femoden, Janine, Yarina, Mercilon, Marvelon, Novinet, Regulon, Belara, Miniziston, Lindinet, Silest.

Three-phase COCs can be considered as reserve drugs when signs of estrogen deficiency appear against the background of monophasic contraception (poor cycle control, dry vaginal mucosa, decreased libido). In addition, three-phase drugs are indicated for primary use in women with signs of estrogen deficiency.

When choosing a drug, the patient's health condition should also be taken into account.

In the first months after starting to take COCs, the body adapts to hormonal changes. During this period, intermenstrual spotting or, less commonly, breakthrough bleeding may occur (in 30–80% of women), as well as other side effects associated with hormonal imbalance (in 10–40% of women). If adverse effects do not go away within 3–4 months, the contraceptive may need to be changed (after excluding other causes - organic diseases of the reproductive system, missed pills, drug interactions). It should be emphasized that at present, the choice of COCs is large enough to select them for most women who are indicated for this method of contraception. If a woman is not satisfied with the drug of first choice, the drug of second choice is selected taking into account the specific problems and side effects that the patient has experienced.

Choosing COC

Clinical situation	Preparations
Acne and/or hirsutism, hyperandrogenism	Drugs with antiandrogenic progestogens: "Diane-35" (for severe acne, hirsutism), "Zhanin", "Yarina" (for mild and moderate acne), "Belara"
Menstrual cycle disorders (dysmenorrhea, dysfunctional uterine bleeding, oligomenorrhea)	COCs with a pronounced progestogenic effect (Microgynon, Femoden, Marvelon, Janine), in combination with hyperandrogenism - Diane-35. In combination with DMC with recurrent hyperplastic processes of the endometrium, the duration of treatment should be at least 6 months
Endometriosis	Monophasic COCs with dienogest (Zhanin), or levonorgestrel, or gestodene or progestogen oral contraceptives are indicated for long-term use. The use of COCs can help restore reproductive function
Diabetes mellitus without complications	Preparations with a minimum estrogen content - 20 mcg/day (intrauterine hormonal system "Mirena")
Initial or re-introduction of oral contraceptives to a patient who smokes	For smoking patients under 35 years of age - COCs with a minimum estrogen content, COCs are contraindicated for smoking patients over 35 years of age
Previous use of oral contraceptives was accompanied by weight gain, fluid retention, and mastodynia	"Yarina"
Poor menstrual cycle control observed during previous oral contraceptive use (in cases where causes other than oral contraceptives have been excluded)	Monophasic or three-phase COCs

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Basic principles of monitoring patients using COCs

• Annual gynecological examination, including colposcopy and cytological examination.
• Once or twice a year, a breast examination (for women with a history of benign breast tumors and/or breast cancer in the family), and once a year, a mammogram (for perimenopausal patients).
• Regular measurement of blood pressure. If diastolic blood pressure increases to 90 mm Hg or higher, COC intake is stopped.
• Special examinations according to indications (if side effects develop, complaints appear).
• In case of menstrual dysfunction - exclusion of pregnancy and transvaginal ultrasound scanning of the uterus and its appendages. If intermenstrual bleeding persists for more than three cycles or appears during further intake of COCs, it is necessary to adhere to the following recommendations.
  • Eliminate errors in taking COCs (missing pills, not following the regimen).
  • Rule out pregnancy, including ectopic pregnancy.
  • Exclude organic diseases of the uterus and appendages (fibroids, endometriosis, hyperplastic processes in the endometrium, cervical polyps, cancer of the cervix or body of the uterus).
  • Rule out infection and inflammation.
  • If the above reasons are excluded, change the drug in accordance with the recommendations.
  • In the absence of withdrawal bleeding, the following should be excluded:
    • taking COCs without 7-day breaks;
    • pregnancy.
  • If these causes are excluded, the most likely reason for the absence of withdrawal bleeding is endometrial atrophy caused by the influence of progestogen, which can be detected by endometrial ultrasound. This condition is called "silent menstruation" or "pseudoamenorrhea". It is not associated with hormonal disorders and does not require discontinuation of COCs.

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Rules for taking COCs

Women with regular menstrual cycles

• The initial intake of the drug should be started within the first 5 days after the onset of menstruation - in this case, the contraceptive effect is already provided in the first cycle, additional measures of contraception are not necessary. The intake of monophasic COCs begins with a tablet marked with the corresponding day of the week, multiphasic COCs - with a tablet marked "start of intake". If the first tablet is taken later than 5 days after the onset of menstruation, an additional method of contraception for a period of 7 days is required in the first cycle of COC intake.
• Take 1 tablet (pill) daily at approximately the same time of day for 21 days. If you miss a tablet, follow the “Forgotten and Missed Tablet Rules” (see below).
• After taking all (21) tablets from the pack, take a 7-day break, during which withdrawal bleeding (“menstruation”) occurs. After the break, start taking tablets from the next pack. For reliable contraception, the break between cycles should not exceed 7 days!

All modern COCs are available in "calendar" packages designed for one cycle of intake (21 tablets - 1 per day). There are also packages with 28 tablets; in this case, the last 7 tablets do not contain hormones ("dummy"). In this case, there is no break between packages: it is replaced by taking a placebo, since in this case patients are less likely to forget to start taking the next package on time.

Women with amenorrhea

• Start taking the pill at any time, provided that pregnancy has been reliably excluded. Use an additional method of contraception during the first 7 days.

Women who breastfeed

• Do not prescribe COCs earlier than 6 weeks after delivery!
• The period from 6 weeks to 6 months after childbirth, if the woman is breastfeeding, use COCs only in case of extreme necessity (the method of choice is the mini-pill).
• More than 6 months after birth:
  • for amenorrhea, the same as in the section “Women with amenorrhea”;
  • with restored menstrual cycle.

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"Forgotten and Missed Pill Rules"

• If 1 tablet is missed.
  • If you are less than 12 hours late taking the pill, take the missed pill and continue taking the medication until the end of the cycle according to the previous schedule.
  • Late arrival for more than 12 hours - the same actions as in the previous point, plus:
    • If you miss a pill in the 1st week, use a condom for the next 7 days;
    • If you miss a pill in the 2nd week, there is no need for additional contraception;
    • If you miss a tablet in the 3rd week, after finishing one pack, start the next one without a break; there is no need for additional means of contraception.
• If 2 or more tablets are missed.
  • Take 2 tablets daily until you are on your regular schedule, plus use additional contraception for 7 days. If you start bleeding after missing tablets, it is best to stop taking the tablets from the current pack and start a new pack after 7 days (counting from the start of the missed tablets).

Rules for prescribing COCs

• Primary prescription - from the 1st day of the menstrual cycle. If the intake is started later (but not later than the 5th day of the cycle), then additional methods of contraception must be used in the first 7 days.
• Prescription after abortion - immediately after abortion. Abortion in the first and second trimesters, as well as septic abortion, are considered category 1 conditions (there are no restrictions on the use of the method) for the prescription of COCs.
• Prescription after childbirth - in the absence of lactation, start taking COCs no earlier than the 21st day after childbirth (category 1). In the presence of lactation, do not prescribe COCs, use mini-pills no earlier than 6 weeks after childbirth (category 1).
• Switching from high-dose COCs (50 mcg EE) to low-dose COCs (30 mcg EE or less) - without a 7-day break (to avoid activation of the hypothalamic-pituitary system due to a decrease in dose).
• Switching from one low-dose COC to another is done after the usual 7-day break.
• Switching from mini-pill to COC - on the 1st day of the next bleeding.
• Switching from an injectable drug to a COC is done on the day of the next injection.

Recommendations for patients taking COCs

• It is advisable to reduce the number of cigarettes you smoke or quit smoking altogether.
• Follow the medication regimen: do not miss taking pills, strictly adhere to the 7-day break.
• The drug should be taken at the same time (in the evening before bedtime), with a small amount of water.
• Have the "Forgotten and Missed Pill Guide" handy.
• During the first months of taking the drug, intermenstrual bleeding of varying intensity is possible, usually disappearing after the third cycle. If intermenstrual bleeding continues at a later date, you should consult a doctor to determine the cause.
• If there is no menstrual-like reaction, continue taking the tablets as usual and consult a doctor immediately to rule out pregnancy; if pregnancy is confirmed, stop taking the COC immediately.
• After stopping taking the drug, pregnancy can occur as early as the first cycle.
• The simultaneous use of antibiotics and anticonvulsants leads to a decrease in the contraceptive effect of COCs.
• If vomiting occurs (within 3 hours after taking the drug), you must take another tablet.
• Diarrhea that lasts for several days requires the use of an additional method of contraception until the next menstrual-like reaction occurs.
• In case of sudden localized severe headache, migraine attack, chest pain, acute visual impairment, difficulty breathing, jaundice, increased blood pressure above 160/100 mm Hg, immediately stop taking the drug and consult a doctor.

Disadvantages of combined oral contraceptives

• The method depends on the user (requires motivation and discipline)
• Nausea, dizziness, breast tenderness, headaches, and spotting or moderate bloody discharge from the genital tract in the middle of the cycle are possible.
• The effectiveness of the method may be reduced when taken simultaneously with certain medications.
• Thrombolytic complications are possible, although very rare.
• Need to replenish your contraceptive supply
• Does not protect against STIs, including hepatitis and HIV infection

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Contraindications to the use of combined oral contraceptives

Absolute contraindications

• Deep vein thrombosis, pulmonary embolism (including history), high risk of thrombosis and thromboembolism (during extensive surgery associated with prolonged immobilization, in case of congenital thrombophilia with pathological levels of coagulation factors).
• Ischemic heart disease, stroke (history of cerebrovascular crisis).
• Arterial hypertension with systolic blood pressure of 160 mmHg and above and/or diastolic blood pressure of 100 mmHg and above and/or with the presence of angiopathy.
• Complicated diseases of the valvular apparatus of the heart (hypertension of the pulmonary circulation, atrial fibrillation, history of septic endocarditis).
• A combination of several factors in the development of arterial cardiovascular diseases (age over 35 years, smoking, diabetes, hypertension).
• Liver diseases (acute viral hepatitis, chronic active hepatitis, liver cirrhosis, hepatocerebral dystrophy, liver tumor).
• Migraine with focal neurological symptoms.
• Diabetes mellitus with angiopathy and/or disease duration of more than 20 years.
• Breast cancer, confirmed or suspected.
• Smoking more than 15 cigarettes a day after age 35.
• Lactation.
• Pregnancy. Relative contraindications
• Arterial hypertension with systolic blood pressure below 160 mmHg and/or diastolic blood pressure below 100 mmHg (a single increase in blood pressure is not a basis for diagnosing arterial hypertension - a primary diagnosis can be made when blood pressure increases to 159/99 mmHg during three visits to the doctor).
• Confirmed hyperlipidemia.
• Vascular headache or migraine that appears while taking COCs, as well as migraine without focal neurological symptoms in women over 35 years of age.
• Gallstone disease with clinical manifestations in the anamnesis or at present.
• Cholestasis associated with pregnancy or COC use.
• Systemic lupus erythematosus, systemic scleroderma.
• History of breast cancer.
• Epilepsy and other conditions requiring the use of anticonvulsants and barbiturates - phenytoin, carbamazepine, phenobarbital and their analogues (anticonvulsants reduce the effectiveness of COCs by inducing liver microsomal enzymes).
• Taking rifampicin or griseofulvin (eg, for tuberculosis) due to their effect on liver microsomal enzymes.
• Lactation from 6 weeks to 6 months after birth, postpartum period without lactation up to 3 weeks.
• Smoking less than 15 cigarettes per day after age 35. Conditions requiring special monitoring while taking COCs
• Increased blood pressure during pregnancy.
• Family history of deep vein thrombosis, thromboembolism, death from myocardial infarction before the age of 50 years (first degree of kinship), hyperlipidemia (an assessment of hereditary factors of thrombophilia and lipid profile is necessary).
• Upcoming surgical intervention without long-term immobilization.
• Thrombophlebitis of superficial veins.
• Uncomplicated diseases of the valvular apparatus of the heart.
• Migraine without focal neurological symptoms in women under 35 years of age, headache that began while taking COCs.
• Diabetes mellitus without angiopathy with a disease duration of less than 20 years.
• Gallstone disease without clinical manifestations; condition after cholecystectomy.
• Sickle cell anemia.
• Bleeding from the genital tract of unknown etiology.
• Severe dysplasia and cervical cancer.
• Conditions that make it difficult to take pills (mental illnesses associated with memory impairment, etc.).
• Age over 40 years.
• Lactation for more than 6 months after birth.
• Smoking before age 35.
• Obesity with a body mass index of more than 30 kg/ ^m2.

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Side effects of combined oral contraceptives

Side effects are usually mild and occur in the first months of taking COCs (in 10–40% of women), and subsequently their frequency decreases to 5–10%.

The side effects of COCs are usually divided into clinical and those depending on the mechanism of action of hormones. Clinical side effects of COCs in turn are divided into general and those causing menstrual cycle disorders.

General:

• headache;
• dizziness;
• nervousness, irritability;
• depression;
• discomfort in the gastrointestinal tract;
• nausea, vomiting;
• flatulence;
• dyskinesia of the bile ducts, exacerbation of cholelithiasis;
• tension in the mammary glands (mastodynia);
• arterial hypertension;
• changes in libido;
• thrombophlebitis;
• leukorrhea;
• chloasma;
• leg cramps;
• weight gain;
• decreased tolerance of contact lenses;
• dryness of the vaginal mucosa;
• increasing the overall coagulation potential of the blood;
• an increase in the transfer of fluid from the vessels into the intercellular space with compensatory retention of sodium and water in the body;
• changes in glucose tolerance;
• hypernatremia, increased osmotic pressure of blood plasma. Menstrual cycle disorders:
• intermenstrual spotting;
• breakthrough bleeding;
• amenorrhea during or after taking COCs.

If side effects persist for more than 3-4 months after the start of treatment and/or intensify, the contraceptive drug should be changed or discontinued.

Serious complications when taking COCs are extremely rare. These include thrombosis and thromboembolism (deep vein thrombosis, pulmonary embolism). For women's health, the risk of these complications when taking COCs with an EE dose of 20-35 mcg/day is very small - lower than during pregnancy. However, at least one risk factor for thrombosis (smoking, diabetes, high obesity, hypertension, etc.) is a relative contraindication to taking COCs. A combination of two or more of the listed risk factors (for example, a combination of obesity and smoking at the age of over 35) completely excludes the use of COCs.

Thrombosis and thromboembolism both during COC use and during pregnancy may be manifestations of latent genetic forms of thrombophilia (resistance to activated protein C, hyperhomocysteinemia, deficiency of antithrombin III, protein C, protein S, antiphospholipid syndrome). In this regard, it should be emphasized that routine determination of prothrombin in the blood does not provide information on the hemostasis system and cannot be a criterion for prescribing or canceling COCs. If latent forms of thrombophilia are suspected, a special hemostasis study should be performed.