Combined oral contraceptive pill

The combined oral contraceptive pill (COCP), often referred to as the birth control pill or colloquially as "the pill", is a type of birth control that is designed to be taken orally by women. It is the oral form of combined hormonal contraception. The pill contains two important hormones: a progestin (a synthetic form of the hormone progestogen/progesterone) and estrogen (usually ethinylestradiol or 17β estradiol). When taken correctly, it alters the menstrual cycle to eliminate ovulation and prevent pregnancy. Combined oral contraceptive pills were first approved for contraceptive use in the United States in 1960, and remain a very popular form of birth control. They are used by more than 100 million women worldwide including about 9 million women in the United States. From 2015 to 2017, 12.6% of women aged 15–49 in the US reported using combined oral contraceptive pills, making it the second most common method of contraception in this age range (female sterilization is the most common method). Use of combined oral contraceptive pills, however, varies widely by country, age, education, and marital status. For example, one third of women aged 16–49 in the United Kingdom use either the combined pill or progestogen-only pill (POP), compared with less than 3% of women in Japan (as of 1950–2014). Combined oral contraceptives are on the World Health Organization's List of Essential Medicines. The pill was a catalyst for the sexual revolution.

== Background ==

=== Oral contraceptives ===

Hormonal oral contraceptives are preventive medications taken orally by females to avoid pregnancy by manipulating their sex hormones. The first oral contraceptive was approved by the US Food and Drug Administration (FDA) and sold to the market in 1960. There are two types of hormonal oral contraceptives, namely combined oral contraceptives and progesterone-only pills. Oral contraceptives, whether combined or progesterone-only, can effectively prevent pregnancy by regulating hormonal changes in the menstrual cycle, inhibiting ovulation, and altering cervical mucus to impede sperm mobility; combined pills have extra effects in menstrual cycle regulation and menstrual pain relief. Common off-label uses include menstrual suppression and acne relief, with combined oral contraceptives having additional benefits in relieving menstrual migraines.

=== Variants === Progesterone-only pills (POPs) utilise progestin, the synthetic form of progesterone, as the only active pharmaceutical ingredient in the formulation. In the US, drospirenone and norethindrone are the most commonly used compounds in formulations. Combined oral contraceptives (COCs) are commonly classified into generations, referring to their order of development in history. This discussion may also help identify some key features in a variety of products. According to the European Medicines Agency, the first generation of combined oral contraceptives, which made use of a high concentration of estrogen only, were those invented in the 1960s. In the second generation of products, progestogens were introduced into the formulation while the concentration of estrogen was reduced. Starting from the 1990s, the progression in the development of combined oral contraceptives has been directed towards varying the type of progestogen incorporated. These products are referred as the third and fourth generation. Estrogen ingredients: estradiol, ethinylestradiol, estetrol. 1st generation progestin: norethindrone acetate, ethynodiol diacetate, lynestrenol, norethynodrel. 2nd generation progestin: levonorgestrel, dl-norgestrel. 3rd generation progestin: norgestimate, gestodene, desogestrel.

=== The menstrual cycle ===

Hormonal oral contraceptives (HOCs) interact with hormonal changes in the menstrual cycle in females to prevent ovulation, and hence achieve contraception. In a 28-day menstrual cycle, there are the proliferative phase, ovulation, and then the secretory phase. Menstruation marks the beginning of proliferative phase in day 1-14. In this period, the pituitary gland located near the brain secretes follicle-stimulating hormone (FSH) into the bloodstream to signal the development of follicle in ovary in the female reproductive system. While follicle serves as the chamber of ovum development, it secretes estrogen, a hormone that not only triggers the thickening of uterine lining in preparation for implantation, but also inhibits the secretion of FSH in pituitary via a negative feedback mechanism. Specifically in ovulation, transient positive feedback by estrogen on FSH and luteinizing hormone (LH) secretion from pituitary is permitted so that the release of mature ovum from follicle is triggered. In secretory phase on day 14-28, this follicle then transforms into corpus luteum and continues releasing estrogen with progesterone into bloodstream. While estrogen and progesterone primarily aid the maintenance of thickness in uterine lining, the negative feedback in pituitary allows them to inhibit FSH and LH secretion. In the absence of LH, corpus luteum degenerates and ultimately causes blood estrogen and progesterone levels to decline. Without these thickness maintaining agents, uterine lining breaks down and hence the presentation of menstruation.

== Mechanism of action == Progesterone and estrogen, either in combination or with progesterone alone, are the active ingredients found in a hormonal oral contraceptive formulation. These medications are orally administered for systemic absorption to exert their effects. An artificially enhanced level of Progesterone throughout the menstrual cycle inhibits the pituitary secretion of FSH and LH such that their actions in stimulating follicular development and ovulation are prevented. Similarly, a boosted estrogen level activates the negative feedback mechanism in reducing FSH secretion from pituitary and therefore prevents follicular development. In the absence of a developed follicle, ovulation cannot occur so that fertilisation is made impossible and contraception is achieved. In comparison, progesterone is more efficacious than estrogen not only because of its additional action in impeding LH, but also its ability to modulate the cervical mucus into sperm-repellent. Combined oral contraceptive pills were developed to prevent ovulation by suppressing the release of gonadotropins. Combined hormonal contraceptives, including combined oral contraceptive pills, inhibit follicular development and prevent ovulation as a primary mechanism of action. Under normal circumstances, luteinizing hormone (LH) stimulates the theca cells of the ovarian follicle to produce androstenedione. The granulosa cells of the ovarian follicle then convert this androstenedione to estradiol. This conversion process is catalyzed by aromatase, an enzyme produced as a result of follicle-stimulating hormone (FSH) stimulation. In individuals using oral contraceptives, progestogen negative feedback decreases the pulse frequency of gonadotropin-releasing hormone (GnRH) release by the hypothalamus, which decreases the secretion of FSH and greatly decreases the secretion of LH by the anterior pituitary. Decreased levels of FSH inhibit follicular development, preventing an increase in estradiol levels. Progestogen negative feedback and the lack of estrogen positive feedback on LH secretion prevent a mid-cycle LH surge. Inhibition of follicular development and the absence of an LH surge prevent ovulation. Estrogen was originally included in oral contraceptives for better cycle control (to stabilize the endometrium and thereby reduce the incidence of breakthrough bleeding), but was also found to inhibit follicular development and help prevent ovulation. Estrogen negative feedback on the anterior pituitary greatly decreases the secretion of FSH, which inhibits follicular development and helps prevent ovulation. Another primary mechanism of action of all progestogen-containing contraceptives is inhibition of sperm penetration through the cervix into the upper genital tract (uterus and fallopian tubes) by decreasing the water content and increasing the viscosity of the cervical mucus. The estrogen and progestogen in combined oral contraceptive pills have other effects on the reproductive system, but these have not been shown to contribute to their contraceptive efficacy:

Slowing tubal motility and ova transport, which may interfere with fertilization. Endometrial atrophy and alteration of metalloproteinase content, which may impede sperm motility and viability, or theoretically inhibit implantation. Endometrial edema, which may affect implantation. Insufficient evidence exists on whether changes in the endometrium could actually prevent implantation. The primary mechanisms of action are so effective that the possibility of fertilization during combined oral contraceptive pill use is very small. Since pregnancy occurs despite endometrial changes when the primary mechanisms of action fail, endometrial changes are unlikely to play a significant role, if any, in the observed effectiveness of combined oral contraceptive pills.

== Formulations ==

Oral contraceptives come in a variety of formulations, some containing both estrogen and progestins, and some only containing progestin. Doses of component hormones also vary among products, and some pills are monophasic (delivering the same dose of hormones each day) while others are multiphasic (doses vary each day). combined oral contraceptive pills can also be divided into two groups, those with progestins that possess androgen activity (norethisterone acetate, etynodiol diacetate, levonorgestrel, norgestrel, norgestimate, desogestrel, gestodene) or antiandrogen activity (cyproterone acetate, chlormadinone acetate, drospirenone, dienogest, nomegestrol acetate). Combined oral contraceptive pills have been somewhat inconsistently grouped into "generations" in the medical literature based on when they were introduced.

First generation combined oral contraceptive pills are sometimes defined as those containing the progestins noretynodrel, norethisterone, norethisterone acetate, or etynodiol acetate; and sometimes defined as all combined oral contraceptive pills containing ≥ 50 μg ethinylestradiol. Second generation combined oral contraceptive pills are sometimes defined as those containing the progestins norgestrel or levonorgestrel; and sometimes defined as those containing the progestins norethisterone, norethisterone acetate, etynodiol acetate, norgestrel, levonorgestrel, or norgestimate and < 50 μg ethinylestradiol. Third generation combined oral contraceptive pills are sometimes defined as those containing the progestins desogestrel or gestodene; and sometimes defined as those containing desogestrel, gestodene, or norgestimate. Fourth generation combined oral contraceptive pills are sometimes defined as those containing the progestin drospirenone; and sometimes defined as those containing drospirenone, dienogest, or nomegestrol acetate.

== Medical use ==

=== Contraceptive use === Combined oral contraceptive pills are a type of oral medication that were originally designed to be taken every day at the same time of day in order to prevent pregnancy. There are many different formulations or brands, but the average pack is designed to be taken over a 28-day period (also known as a cycle). For the first 21 days of the cycle, users take a daily pill that contains two hormones, estrogen and progestogen. During the last 7 days of the cycle, users take daily placebo (biologically inactive) pills and these days are considered hormone-free days. Although these are hormone-free days, users are still protected from pregnancy during this time. Some combined oral contraceptive pill packs only contain 21 pills and users are advised to take no pills for the last 7 days of the cycle. Other combined oral contraceptive pill formulations contain 91 pills, consisting of 84 days of active hormones followed by 7 days of placebo (Seasonale). Combined oral contraceptive pill formulations can contain 24 days of active hormone pills followed by 4 days of placebo pills (e.g. Yaz 28 and Loestrin 24 Fe) as a means to decrease the severity of placebo effects. These combined oral contraceptive pills containing active hormones and a placebo/hormone-free period are called cyclic combined oral contraceptive pills. Once a pack of cyclical combined oral contraceptive pill treatment is completed, users start a new pack and new cycle. Most monophasic combined oral contraceptive pills can be used continuously such that patients can skip placebo days and continuously take hormone active pills from a combined oral contraceptive pill pack. One of the most common reasons users do this is to avoid or diminish withdrawal bleeding. The majority of women on cyclic combined oral contraceptive pills have regularly scheduled withdrawal bleeding, which is vaginal bleeding mimicking users' menstrual cycles with the exception of lighter menstrual bleeding compared to bleeding patterns prior to combined oral contraceptive pill commencement. As such, a study reported that out of 1003 women taking combined oral contraceptive pills approximately 90% reported regularly scheduled withdrawal bleeds over a 90-day standard reference period. Withdrawal bleeding usually occurs during the placebo, hormone-free days. Therefore, avoiding placebo days can diminish withdrawal bleeding among other placebo effects.

=== Regimen === This section demonstrates the overall rationalisation of dosing route and intervals of hormonal oral contraceptives, please seek advice and follow instructions from healthcare professionals in administering specific hormonal oral contraceptives. Considering the menstrual cycle as a 28-day cycle, hormonal oral contraceptives are available in packages of 21, 28, or 91 tablets. These pills have typically undergone unit dose optimisation so that they follow the administration pattern of once daily, every day or almost every day on a regular basis. Since they are formulated into daily doses, it is recommended that the medication should be taken at the same time every day to maximise efficacy.

For 21-tablet packs, the general instruction is to take one tablet daily for 21 days, followed by a 7-day blank interval without taking hormonal oral contraceptives before initiating another 21-tablet pack. For 28-tablet packs, the 1st tablet from a new pack should be taken on the next day when the 28th tablet from an old pack was finished. While the 7-day blank period does not apply to 28-tablet packs, they will likely include tablets in distinctive colours indicating that they have an alternate amount of active ingredients, otherwise inactive ingredient or folate supplement only. The instruction for 91-tablet pack follows that of 28-tablet packs with some colour-distinguishable tablets which contain different amounts of medicine or supplement. To acquire immediate contraceptive effects, the initiation of hormonal oral contraceptive dosing is recommended within the 1st-5th day from menstruation in order to discard other means of contraception. Specific to progesterone only pills, even if dosing is initiated within five days, backup contraception is suggested in the first 48 hours since the first pill. In the case of dosing initiated after the 5th day from menstruation, effects usually take place after seven days and other contraceptive methods should remain in place until then.

==== Effectiveness ==== If used exactly as instructed, the estimated risk of getting pregnant is 0.3% which means that about 3 in 1000 women on combined oral contraceptive pills will become pregnant within one year. However, typical use of combined oral contraceptive pills by users often consists of timing errors, forgotten pills, or unwanted side effects. With typical use, the estimated risk of getting pregnant is about 9% which means that about 9 in 100 women on combined oral contraceptive pills will become pregnant in one year. The perfect use failure rate is based on a review of pregnancy rates in clinical trials, and the typical use failure rate is based on a weighted average of estimates from the 1995 and 2002 US National Surveys of Family Growth (NSFG), corrected for underreporting of abortions. Combined oral contraceptive pills provide effective contraception from the very first pill if started within five days of the beginning of the menstrual cycle (within five days of the first day of menstruation). If started at any other time in the menstrual cycle, combined oral contraceptive pills provide effective contraception only after 7 consecutive days of use of active pills, so a backup method of contraception (e.g. condoms) must be used in the interim. However, several factors account for typical use effectiveness being lower than perfect use effectiveness:

Mistakes on part of those providing instructions on how to use the method Mistakes on part of the user Conscious user non-compliance with instructions For instance, someone using combined oral contraceptive pills might have received incorrect information by a health care provider about medication frequency, forgotten to take the pill one day or not gone to the pharmacy in time to renew a combined oral contraceptive pill prescription.The effectiveness of combined oral contraceptive pills appears to be similar whether the active pills are taken continuously or if they are taken cyclically. Contraceptive efficacy, however, could be impaired by numerous means. Factors that may contribute to a decrease in effectiveness:

Missing more than one active pill in a packet, Delay in starting the next packet of active pills (i.e., extending the pill-free, inactive pill or placebo pill period beyond 7 days), Intestinal malabsorption of active pills due to vomiting or diarrhea, Drug-drug interactions among combined oral contraceptive pills and other medications of the user that decrease contraceptive estrogen and/or progestogen levels. In any of these instances, a backup contraceptive method should be used until hormone active pills have been consistently taken for 7 consecutive days or drug-drug interactions or underlying illnesses have been discontinued or resolved. According to the US Centers for Disease Control and Prevention (CDC) guidelines, a pill is considered "late" if a user takes the pill after the user's normal medication time, but no longer than 24 hours after this normal time. If 24 hours or more have passed since the time the user was supposed to take the pill, then the pill is considered "missed". CDC guidelines discuss potential next steps for users who missed their pill or took it late.

=== Role of placebo pills === The role of the placebo pills is two-fold: to allow the user to continue the routine of taking a pill every day and to simulate the average menstrual cycle. By continuing to take a pill every day, users remain in the daily habit even during the week without hormones. Failure to take pills during the placebo week does not impact the effectiveness of the pill, provided that daily ingestion of active pills is resumed at the end of the week. The placebo, or hormone-free, week in the 28-day pill package simulates an average menstrual cycle, though the hormonal events during a pill cycle are significantly different from those of a normal ovulatory menstrual cycle. Because the pill suppresses ovulation (to be discussed more in the Mechanism of action section), birth control users do not have true menstrual periods. Instead, it is the lack of hormones for a week that causes a withdrawal bleed. The withdrawal bleeding that occurs during the break from active pills has been thought to be reassuring, a physical confirmation of not being pregnant. The withdrawal bleeding is also predictable. Unexpected breakthrough bleeding can be a possible side effect of longer term active regimens. Since it is not uncommon for menstruating women to become anemic, some placebo pills may contain an iron supplement. This replenishes iron stores that may become depleted during menstruation. As well, birth control pills, such as combined oral contraceptive pills, are sometimes fortified with folic acid as it is recommended to take folic acid supplementation in the months prior to pregnancy to decrease the likelihood of neural tube defect in infants.

=== No or less frequent placebos ===

If the pill formulation is monophasic, meaning each hormonal pill contains a fixed dose of hormones, it is possible to skip withdrawal bleeding and still remain protected against conception by skipping the placebo pills altogether and starting directly with the next packet. Attempting this with bi- or tri-phasic pill formulations carries an increased risk of breakthrough bleeding and may be undesirable. It will not, however, increase the risk of getting pregnant. Starting in 2003, women have also been able to use a three-month version of the pill. Similar to the effect of using a constant-dosage formulation and skipping the placebo weeks for three months, Seasonale gives the benefit of less frequent periods, at the potential drawback of breakthrough bleeding. Seasonique is another version in which the placebo week every three months is replaced with a week of low-dose estrogen. A version of the combined pill has also been packaged to eliminate placebo pills and withdrawal bleeds. Marketed as Anya or Lybrel, studies have shown that after seven months, 71% of users no longer had any breakthrough bleeding, the most common side effect of going longer periods of time without breaks from active pills. While more research needs to be done to assess the long term safety of using combined oral contraceptive pills continuously, studies have shown there may be no difference in short term adverse effects when comparing continuous use versus cyclic use of birth control pills.

=== Non-contraceptive use === The hormones in the pill have also been used to treat other medical conditions, such as polycystic ovary syndrome (PCOS), endometriosis, adenomyosis, acne, hirsutism, amenorrhea, menstrual cramps, menstrual migraines, menorrhagia (excessive menstrual bleeding), menstruation-related or fibroid-related anemia and dysmenorrhea (painful menstruation). Besides acne, no oral contraceptives have been approved by the US FDA for the previously mentioned uses despite extensive use for these conditions.

==== Polycystic ovary syndrome ==== The cause of polycystic ovary syndrome (PCOS), is multifactorial and not well-understood. Women with PCOS often have higher than normal levels of luteinizing hormone (LH) and androgens that impact the normal function of the ovaries. While multiple small follicles develop in the ovary, none are able to grow in size enough to become the dominant follicle and trigger ovulation. This leads to an imbalance of LH, follicle stimulating hormone, estrogen, and progesterone. Without ovulation, unopposed estrogen can lead to endometrial hyperplasia, or overgrowth of tissue in the uterus. This endometrial overgrowth is more likely to become cancerous than normal endometrial tissue. Thus, although the data varies, it is generally agreed upon by most gynecological societies that due to the unopposed estrogen, women with PCOS are at higher risk for endometrial cancer. To reduce the risk of endometrial cancer, it is often recommended that women with PCOS who do not desire pregnancy take hormonal contraceptives to prevent the effects of unopposed estrogen. Both combined oral contraceptive pills and progestin-only methods are recommended. It is the progestin component of combined oral contraceptive pills that protects the endometrium from hyperplasia, and thus reduces a woman with PCOS's endometrial cancer risk. Combined oral contraceptive pills are preferred to progestin-only methods in women who also have uncontrolled acne, symptoms of hirsutism, and androgenic alopecia, because combined oral contraceptive pills can help treat these symptoms.

==== Acne and hirsutism ==== Combined oral contraceptive pills are sometimes prescribed to treat symptoms of androgenization, including acne and hirsutism. The estrogen component of combined oral contraceptive pills appears to suppress androgen production in the ovaries. Estrogen also leads to increased synthesis of sex hormone binding globulin, which causes a decrease in the levels of free testosterone. Ultimately, the drop in the level of free androgens leads to a decrease in the production of sebum, which is a major contributor to development of acne. Four different oral contraceptives have been approved by the US FDA to treat moderate acne if the patient is at least 14 or 15 years old, has already begun menstruating, and needs contraception. These include Ortho Tri-Cyclen, Estrostep, Beyaz, and YAZ. Hirsutism is the growth of coarse, dark hair where women typically grow only fine hair or no hair at all. This hair growth on the face, chest, and abdomen is also mediated by higher levels or action of androgens. Therefore, combined oral contraceptive pills also work to treat these symptoms by lowering the levels of free circulating androgens. Studies have shown that combined oral contraceptives are effective in reducing both inflammatory and non-inflammatory facial acne lesions. However, comparisons between different combined oral contraceptives have not been studied to understand if any brand is superior than the others. Estrogen decreases sebum production by shrinking the sebaceous gland, increasing sex hormone-binding globulin (SHBG) production to reduce unbound testosterone, and regulating LH and FSH levels. Studies have not shown that POPs are effective against acne lesions.

==== Endometriosis ==== For pelvic pain associated with endometriosis, combined oral contraceptive pills are considered a first-line medical treatment, along with NSAIDs, GnRH agonists, and aromatase inhibitors. Combined oral contraceptive pills work to suppress the growth of the extra-uterine endometrial tissue. This works to lessen its inflammatory effects. Combined oral contraceptive pills, along with the other medical treatments listed above, do not eliminate the extra-uterine tissue growth, they just reduce the symptoms. Surgery is the only definitive treatment. Studies looking at rates of pelvic pain recurrence after surgery have shown that continuous use of combined oral contraceptive pills is more effective at reducing the recurrence of pain than cyclic use.

==== Adenomyosis ==== Similar to endometriosis, adenomyosis is often treated with combined oral contraceptive pills to suppress the growth the endometrial tissue that has grown into the myometrium. Unlike endometriosis however, levonorgestrel containing IUDs are more effective at reducing pelvic pain in adenomyosis than combined oral contraceptive pills.

==== Menorrhagia ==== In the average menstrual cycle, a woman typically loses 35 to 40 milliliters of blood. However, up to 20% of women experience much heavier bleeding, or menorrhagia. This excess blood loss can lead to anemia, with symptoms of fatigue and weakness, as well as disruption in their normal life activities. Combined oral contraceptive pills contain progestin, which causes the lining of the uterus to be thinner, resulting in lighter bleeding episodes for those with heavy menstrual bleeding.

==== Amenorrhea ==== Although the pill is sometimes prescribed to induce menstruation on a regular schedule for women bothered by irregular menstrual cycles, it actually suppresses the normal menstrual cycle and then mimics a regular 28-day monthly cycle. Women who are experiencing menstrual dysfunction due to female athlete triad are sometimes prescribed oral contraceptives as pills that can create menstrual bleeding cycles. However, the condition's underlying cause is energy deficiency and should be treated by correcting the imbalance between calories eaten and calories burned by exercise. Oral contraceptives should not be used as an initial treatment for female athlete triad.

=== Menstrual suppression === Menstrual bleeding is not necessary in women who do not wish to conceive, therefore menstrual suppression may be implemented in women who do not want to have menstrual bleeding for convenience, gynecologic disorders, bleeding disorders or other medical conditions. In the two types of hormonal oral contraceptives, only combined oral contraceptives can achieve amenorrhea, while POPs can only reduce the amount of blood. The method of using combined oral contraceptives for menstrual suppression is to skip the 7 placebo pills and continue taking active pills after the 21 active pills. This can be used in extended method or continuous method. For extended method, patients who take active pills for 3, 4, or 6 months and then take placebo pills for a period of time will more likely experience withdrawal bleeding. The interval can be decided by the patients according to their own preferences. For continuous method, people can take combined oral contraceptives for a year continuously without any placebo pills. In the first few months of extended or continuous use of combined oral contraceptives, unscheduled bleeding or spotting may occur. However, the bleeding or spotting is expected to resolve after a few months of use. Menstrual suppression is commonly used for convenience especially when women go on vacation. It is also used for gynecologic disorders such as dysmenorrhea (commonly known as menstrual pain), symptoms related to premenstrual hormone change and excessive bleeding related to uterine fibroids. Patients can also benefit from menstrual suppression for bleeding disorders or chronic anemia.

=== Menstrual migraine === Patients who experience menstrual estrogen-related migraines, but without aura and additional risk factors to stroke, can benefit from combined oral contraceptives. However, older women and those with a strong family history of problematic headaches may find that using hormonal oral contraceptives worsens their headache.

== Benefits == The distinctive feature of hormonal oral contraceptives when compared to other contraceptive methods is that they are less invasive and do not interfere with sex. Conclusive data suggest that the failure rate of contraception in using hormonal oral contraceptives for the first year is 9% in typical use which allows missed doses, and <1% in perfect use. The efficacy of hormonal oral contraceptives in preventing pregnancy is high overall. Furthermore, the regular use of hormonal oral contraceptive tends to not only ease premenstrual syndrome, but also allow lighter and less painful menstruation. In addition, the association between a suppressed risk of developing ovarian cancer and hormonal oral contraceptive use is proven.

== Contraindications == While combined oral contraceptives are generally considered to be a relatively safe medication, they are contraindicated for those with certain medical conditions. The World Health Organization and the US Centers for Disease Control and Prevention publish guidance, called medical eligibility criteria, on the safety of birth control in the context of medical conditions. In terms of protection in sexual intercourse, a sole reliance on hormonal oral contraceptives does not defend one from sexually transmitted infections such as human papillomavirus infection (HPV). Additionally, breakthrough bleeding and spotting are exceptionally prevalent in the early stage of using hormonal oral contraceptives. Although most reported side effects including nausea, headache, or mood swings will disappear as the therapy progresses or upon switching formulation, elevated blood pressure or blood clots in patients with cardiovascular conditions are documented side effects that requires medical attention if not termination of hormonal oral contraceptives. It is because combined oral contraceptives uses have been found to be related to an increased risk of ischemic stroke or myocardial infarction, especially in combined oral contraceptives with >50 μg estrogen. There are also ongoing studies showing evidence for an association between hormonal oral contraceptive use and escalated breast cancer risks. According to the World Health Organization's Medical Eligibility Criteria for Contraceptive Use 2015, Category 3 implies that the use of such contraception is usually not recommended, unless other more appropriate methods are neither available nor acceptable and with good resources of clinical judgment; Category 4 implies that the contraceptive method should not be used even with good resources of clinical judgment. Both categories suggest that the contraceptive method should not be used with limited resources for clinical judgment. The tables below summarise conditions of category 3 and 4 from World Health Organization Medical Eligibility Criteria for Contraceptive Use 2015.

=== Precautions and contraindications for combined oral contraceptives ===

*The category should be assessed according to the severity of the condition.

=== Hypercoagulability === Estrogen in high doses can increase risk of blood clots. All combined oral contraceptive pill users have a small increase in the risk of venous thromboembolism compared with non-users; this risk is greatest within the first year of combined oral contraceptive pill use. Individuals with any pre-existing medical condition that also increases their risk for blood clots have a more significant increase in risk of thrombotic events with combined oral contraceptive pill use. These conditions include but are not limited to high blood pressure, pre-existing cardiovascular disease (such as valvular heart disease or ischemic heart disease), history of thromboembolism or pulmonary embolism, cerebrovascular accident, and a familial tendency to form blood clots (such as familial factor V Leiden). There are conditions that, when associated with combined oral contraceptive pill use, increase risk of adverse effects other than thrombosis. For example, women with a history of migraine with aura have an increased risk of stroke when using combined oral contraceptive pills, and women who smoke over age 35 and use combined oral contraceptive pills are at higher risk of myocardial infarction.

=== Pregnancy and postpartum === Women who are known to be pregnant should not take combined oral contraceptive pills. Those in the postpartum period who are breastfeeding are also advised not to start combined oral contraceptive pills until 4 weeks after birth due to increased risk of blood clots. While studies have demonstrated conflicting results about the effects of combined oral contraceptive pills on lactation duration and milk volume, there exist concerns about the transient risk of combined oral contraceptive pills on breast milk production when breastfeeding is being established early postpartum. Due to the stated risks and additional concerns on lactation, women who are breastfeeding are not advised to start combined oral contraceptive pills until at least six weeks postpartum, while women who are not breastfeeding and have no other risks factors for blood clots may start combined oral contraceptive pills after 21 days postpartum.

=== Breast cancer === The World Health Organization (WHO) does not recommend the use of combined oral contraceptive pills in women with breast cancer. Since combined oral contraceptive pills contain both estrogen and progestin, they are not recommended to be used in those with hormonally-sensitive cancers, including some types of breast cancer. Non-hormonal contraceptive methods, such as the Copper IUD or condoms, should be the first-line contraceptive choice for these patients instead of combined oral contraceptive pills.

=== Other === Women with known or suspected endometrial cancer or unexplained uterine bleeding should also not take combined oral contraceptive pills to avoid health risks. Combined oral contraceptive pills are also contraindicated for people with advanced diabetes, liver tumors, hepatic adenoma or severe cirrhosis of the liver. Combined oral contraceptive pills are metabolized in the liver and thus liver disease can lead to reduced elimination of the medication. Additionally, severe hypercholesterolemia and hypertriglyceridemia are also contraindications, but the evidence showing that combined oral contraceptive pills lead to worse outcomes in this population is weak. Obesity is not considered to be a contraindication to taking combined oral contraceptive pills.

== Side effects == It is generally accepted that the health risks of oral contraceptives are lower than those from pregnancy and birth, and "the health benefits of any method of contraception are far greater than any risks from the method". Some organizations have argued that comparing a contraceptive method to no method (pregnancy) is not relevant—instead, the comparison of safety should be among available methods of contraception.

=== Common === Different sources note different incidence of side effects. The most common side effect is breakthrough bleeding. Combined oral contraceptive pills can improve conditions such as dysmenorrhea, premenstrual syndrome, and acne, reduce symptoms of endometriosis and polycystic ovary syndrome, and decrease the risk of anemia. Use of oral contraceptives also reduces lifetime risk of ovarian and endometrial cancer. Nausea, vomiting, headache, bloating, breast tenderness, swelling of the ankles/feet (fluid retention), or weight change may occur. Vaginal bleeding between periods (spotting) or missed/irregular periods may occur, especially during the first few months of use.

=== Heart and blood vessels === Combined oral contraceptives are associated with an increased risk of venous thromboembolism, including deep vein thrombosis (DVT) and pulmonary embolism (PE). While lower doses of estrogen in combined oral contraceptive pills may have a lower risk of stroke and myocardial infarction compared to higher estrogen dose pills (50 μg/day), users of low estrogen dose combined oral contraceptive pills still have an increased risk compared to non-users. These risks are greatest in women with additional risk factors, such as smoking (which increases risk substantially) and long-continued use of the pill, especially in women over 35 years of age. The overall absolute risk of venous thrombosis per 100,000 woman-years in current use of combined oral contraceptives is approximately 60, compared with 30 in non-users. The risk of thromboembolism varies with different types of birth control pills; compared with combined oral contraceptives containing levonorgestrel (LNG), and with the same dose of estrogen and duration of use, the rate ratio of deep venous thrombosis for combined oral contraceptives with norethisterone is 0.98, with norgestimate 1.19, with desogestrel (DSG) 1.82, with gestodene 1.86, with drospirenone (DRSP) 1.64, and with cyproterone acetate 1.88. In comparison, venous thromboembolism occurs in 100–200 per 100.000 pregnant women every year. One study showed more than a 600% increased risk of blood clots for women taking combined oral contraceptive pills with drospirenone compared with non-users, compared with 360% higher for women taking birth control pills containing levonorgestrel. The US Food and Drug Administration (FDA) initiated studies evaluating the health of more than 800,000 women taking combined oral contraceptive pills and found that the risk of VTE was 93% higher for women who had been taking drospirenone combined oral contraceptive pills for 3 months or less and 290% higher for women taking drospirenone combined oral contraceptive pills for 7–12 months, compared with women taking other types of oral contraceptives. Based on these studies, in 2012, the FDA updated the label for drospirenone combined oral contraceptive pills to include a warning that contraceptives with drospirenone may ha