Combined oral contraceptives (COCs) are combined steroid hormone preparations containing estrogen and progestin for birth control. The first COC formulation was successfully developed and approved for marketing in 1960, and after more than 50 years of development, COC has become one of the commonly used contraceptive methods worldwide, with a pregnancy rate of only 0.3 per 100 women per year when used correctly. However, in China, many clinical staff often have some confusion when applying COC, especially in terms of long-term use, safety effects on reproductive function and offspring, and the risk of gynecologic malignancies, resulting in a low probability of recommending the use of COC for contraception. In this article, we explain several focused, common clinical perception issues regarding COC. The first COC, Enovid, was introduced in the United States in 1960. Over the next 50 years, COCs have become one of the most widely used contraceptive methods worldwide because of their effectiveness, simplicity, reversibility, and benefits beyond contraception. The aim of COC is to reduce the number of adverse effects that may occur during use, while increasing the health benefits beyond contraception. COC is designed to achieve fertility control by inhibiting ovulation, changing cervical mucus properties, altering endometrial morphology and function, and interfering with fallopian tube function. In some countries in Europe and the United States, the use rate of COC among women of childbearing age has reached more than 30%, while in China, due to the long-standing lack of awareness of COC within and outside the industry, or the existence of multiple barriers, the use rate among married women who have used contraception is only about 1%. First, is long-term use of COC harmful to health, and should it be used intermittently? Since its introduction, COC has been accepted by women in developed countries because of its contraceptive efficiency, but the safety of long-term uninterrupted use of COC on a cyclical basis has been a constant concern. the safety of COC use mainly involves three aspects, including cardiovascular disease, carcinogenesis and reproductive safety. Currently, there is some clinical evidence and expert consensus that the safety risk associated with COC use is venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism, and that the increased risk of VTE occurs within 3 to 6 months of taking the drug and does not continue to increase with the duration of COC use. Contrary to concerns, the following evidence also suggests a benefit from long-term COC use. Basic research and clinical practice have consistently focused on the association between COC use and the occurrence of VTE, and numerous studies have been conducted over a long period of time showing that the risk of VTE is elevated in women taking COC at 9 per 10,000 woman-years, which is 1-fold higher than in women who are not pregnant and not taking COC, but much lower than the risk of VTE during pregnancy and the puerperium (30 per 10,000 woman-years and 65 per 10,000 woman-years, respectively). Moreover, the mortality rate due to VTE is much lower than that due to abortion. In addition, in 2007, Dinger et al [3] found that a very low risk of VTE was more likely to occur in the initial period of COC use, especially in the first 3 months; if it is used again after a period of discontinuation, the risk of VTE increases again. the risk of VTE also includes factors such as smoking, history of diabetes, obesity, and hypertension, and women with these risk factors should avoid COC use. Long-term COC use has been found to be beneficial for women’s bone mineral density. in 2011, Wei et al [4] reported a cross-sectional study of a randomly selected population between the ages of 50 and 80 years in which 491 women completed questionnaires and bone mineral density testing, and 460 of these women also underwent spinal deformity analysis. The results showed that after adjusting for confounding factors, women who had taken COC had significantly higher whole-body and spinal BMD than those who had not used COC; and the longer the duration of COC use, the more pronounced the protective effect on their reduced whole-body and spinal BMD. The risk of spinal deformation was significantly lower with 5 to 10 years of COC use. In 2013, Nagy et al [5] performed fetal chromosome genetic analysis by amniocentesis in 5,222 pregnant women and detected 119 chromosomal abnormalities, including chromosomal structural or numerical abnormalities, and selected 37 elderly pregnant women with complete data and amniocentesis results confirming fetal trisomy 21, trisomy 18 or trisomy 13 as the study group, as well as selected women with amniocentesis results confirming The study group was selected from the 92 cases with normal fetal karyotype confirmed by amniocentesis, and detailed information on factors affecting the number of ovulation during the reproductive period was obtained from both groups. The results showed that pregnant women with trisomic fetuses had a shorter mean duration of COC use prior to pregnancy (3.4 and 6.0 years, respectively, P=0.001 4) and a higher mean number of ovulation __ assessed (274.6 and 224.0, respectively, P=0.000 3). This suggests that the longer the duration of previous COC use and the lower the number of ovulatory cycles, the lower the incidence of trisomy 21 fetuses. In summary, the results of studies addressing the safety of long-term COC use suggest that the use of COC is safe and that long-term use may provide additional benefits. There is no evidence to suggest the need for intermittent COC use, and the risk of unintended pregnancy is only increased during intermittent discontinuation. Can an unplanned pregnancy while taking COC lead to fetal malformation or death? COC has been widely used abroad since it was marketed. As early as 1990, Bracken [6] used a meta-analysis (Meta-analysis) to assess the risk of congenital malformations in the offspring of women delivered after misuse of COC in early pregnancy, and analyzed congenital heart defects and short limb defects separately. The risk of developing short limb defects was 1.04, suggesting that there was no correlation between COC administration in early pregnancy and neonatal physical defects. In 2009, N?rgaard et al [7] conducted a case-control study on the association between maternal COC administration in early gestation and the risk of hypospadias in male offspring, using medical data from the whole of Denmark. Ten cases without hypospadias were randomly selected as controls among infants from the same hospital and of comparable age (n=15,650), and the results of the study did not support an association between COC administration early in pregnancy and an increased risk of hypospadias in male offspring. In 2008, Jellesen et al [8] followed a cohort of 92 719 pregnant women in Denmark from 1996 to 2002 to study the association between COC use during pregnancy and fetal mortality and showed that COC use during pregnancy did not increase the risk of fetal death (HR=1.01, 95% CI 0.71 to 1.45). The use of COC before and during pregnancy was not associated with increased fetal mortality. In conclusion, COC administration before or during pregnancy did not increase the risk of fetal physiological defects or death. 3. Is it necessary to stop taking COC for 3-6 months after use before pregnancy? To date, there is no evidence that women taking COC need to stop taking the drug for 3-6 months before pregnancy. As early as 1985, Harlap et al. observed 33,545 pregnant women and found that among 8,522 women who had taken COC and became pregnant within one month of stopping the drug, the incidence of malformations in their babies was 17.2 per 1,000, which was not statistically significant when compared with the incidence of malformations in babies born to 25,023 women who used other contraceptives or no contraception (1.50%-2.01%). The difference was not statistically significant. Neither the use of COC in women of childbearing age nor the misuse of COC during pregnancy was found to be teratogenic in newborns. Moreover, the COC currently used in clinical practice is excreted or cleared within a short period of time after taking the drug. Ovulation can be resumed about 2 weeks after discontinuation of COC. Therefore, pregnancy can be considered after discontinuation of COC, without waiting for 3-6 months. Does the use of COC have any effect on fertility? The use of COC not only has no adverse effect on women’s reproductive function, but even has a significant protective effect, mainly through the following aspects of direct or indirect effects: 1, women adhere to and correct use of COC, the pregnancy rate in the first year is only 0.3 per 100 women per year, can effectively avoid unwanted pregnancy and abortion, especially repeated abortion, which is the best protection for women’s reproductive function. 2. COC can effectively reduce the risk of pelvic inflammatory disease. The main mechanism is that COC can increase the viscosity of cervical mucus and stop the upward movement of pathogenic microorganisms in the lower reproductive tract. On the other hand, COC can inhibit the endometrium, reduce menstrual flow and decrease the risk of pelvic inflammatory disease due to menstrual blood reflux. Foreign observation shows that taking COC can reduce the incidence of pelvic inflammatory disease by 50% to 60%; not only that, among the pelvic inflammatory diseases diagnosed by laparoscopy, the degree of inflammatory reaction is mild in the pelvic inflammatory disease occurred during taking COC. 3. COC can effectively prevent the occurrence of ectopic pregnancy. The main mechanism is that COC can almost completely inhibit ovulation and can effectively interfere with fertilization.COC can reduce the incidence of ectopic pregnancy by 90%, and the literature reports that the incidence of ectopic pregnancy among COC users is only 0.005 per 1,000 woman-years, which is similar to that of women whose partners use vasectomy contraception, and much lower than that of women who use condoms, vaginal diaphragms, copper intrauterine devices and tubal sterilization.COC The strong contraceptive effect results in a very low incidence of ectopic pregnancy even if the contraception fails. In addition to these direct effects, COC may protect reproductive function by reducing the risk of endometrial cancer and ovarian epithelial cancer (ovarian cancer). V. Does the use of COC increase the risk of gynecological malignancies and breast cancer? Whether long-term COC use has an effect on the occurrence of common gynecologic malignancies is a hot topic of research by scholars in various countries. 2010, Hannaford et al [13] published a prospective cohort study in which 46,112 women from 1,400 medical institutions in the UK were followed up for up to 39 years, including 819,175 women-years in the group that had taken COC and 378,006 women-years in the group that had never taken The results showed a significant reduction in all-cause mortality in women who had taken COC (RR=0.88, 95% CI 0.82-0.93); furthermore, mortality from all malignancies (including colon, rectal, endometrial and ovarian cancers) was also significantly reduced. 1.COC and ovarian cancer: The incidence of ovarian cancer is the third most common malignant tumor in female reproductive organs, and its pathogenesis is complex. 1 major factor may be related to the abnormal proliferation of ovarian surface epithelial cells caused by repeated ovulation of the ovary. 1970, a study already reported that COC can reduce the risk of ovarian cancer. Subsequent studies conducted by scholars from various countries have shown that COC can reduce the risk of ovarian cancer, and this conclusion is well established. Hankinson et al. showed that the longer the duration of COC use, the lower the risk of ovarian cancer, with a 10% to 12% reduction in the risk of ovarian cancer after 1 year of use and about 50% reduction in the risk of ovarian cancer after 5 years of use. Numerous studies in recent years have also shown that COC has a protective effect on ovarian carcinogenesis, and that the protection of COC against ovarian carcinogenesis may work by inhibiting ovulation and lowering blood gonadotropin levels. In 2013, a Meta-analysis of 24 relevant studies in PubMed and other databases by Havrilesky et al. showed that taking COC reduced the risk of ovarian cancer by 27% compared with women who had never taken COC, and the degree of risk reduction was related to the duration of taking the drug, with those who took COC for 10 years or more reducing the risk of ovarian cancer by at least 50% The results also showed that the degree of risk reduction of ovarian cancer by COC was related to the age of the first dose and the length of time since the last dose, with the earlier the age of the first dose and the shorter the time since the last dose, the stronger the effect of reducing the risk of ovarian cancer. It has been recognized that the risk of ovarian cancer is reduced in women taking COC, and the earlier the age of the first dose and the longer the time between doses, the lower the risk of ovarian cancer, and the protective effect persists after stopping the drug. 2.COC and endometrial cancer: Endometrial cancer is one of the three common malignancies in gynecology, and most endometrial cancers are estrogen-dependent. This suggests that COC use significantly reduces the risk of endometrial cancer and that the protective effect continues to increase with continued use. The same findings also found that the relative risk of endometrial cancer was 0.33, 0.41, and 0.51 even after 5, 10, and even 20 years of COC discontinuation, respectively, confirming that the protective effect of COC against endometrial cancer persists. The mechanism of action of COC in reducing the risk of endometrial cancer may be that COC inhibits the stimulation of the endometrium by estrogen secreted by the ovaries themselves, and at the same time, the highly effective progesterone component in COC can sufficiently transform the endometrium to prevent excessive proliferation of the endometrium, and the cyclic use of COC also causes the endometrium to shed and discharge periodically to achieve the protective effect of the endometrium, thus reducing its probability of cancer. Recent studies by more scholars have further proved the protective effect of COC on the occurrence of endometrial cancer. 3. COC and cervical cancer: Cervical cancer is the most common clinical malignancy of the female genital organs, and persistent infection with high-risk HPV is now recognized as the most important causative agent. Other factors associated with its development include multiple sexual partners, first sexual intercourse <16< span=""> years of age, early childbirth, and multiple births, but the correlation between COC use and the risk of cervical cancer is unclear. Two UK prospective cohort studies, looking at more than 1 million woman-years and 500,000 woman-years, respectively, had a relative risk of cervical cancer of 1.3 (95% CI 0.9 to 1.9) and 3.4 (95% CI 1.6 to 8.9), suggesting that COC use increases the risk of cervical cancer. In 2009, Wang et al. conducted a Meta-analysis of the published literature by foreign scholars from 1999 to 2008 on the relationship between COC use and the development of squamous cervical cancer. 8 selected papers included 3,415 cases and 4,037 controls, but the results of the analysis could not yet conclude that the use of COC increased the risk of cervical cancer. Despite the inconsistent findings, the more internationally accepted conclusion is that women with HPV infection who use COC for a long time have an increased risk of cervical cancer. 4. COC and breast cancer: Breast cancer is the most common female malignancy, and excessive use of exogenous estrogen is one of the high-risk factors for the occurrence of breast cancer. A large number of studies in recent years have confirmed that taking COC does not increase the risk of breast cancer. In 2002, Marchbanks et al. conducted a comprehensive study and found that the incidence of breast cancer in women aged 35-64 years was not significantly different from that of women of the same age who did not take COC, regardless of whether they had used COC recently or previously, and the relative risk of breast cancer in the two groups was 1.0 and 0.9, respectively; in long-term COC use and use of high doses of estrogens containing (ethinyl estradiol content ≥50 μg) COC, the incidence of breast cancer was also not increased in women. In addition, there was no further increase in the incidence of breast cancer in women with a family history of breast cancer who took COCs. The WHO’s Medical Criteria for Choice of Contraceptive Method states that COC does not increase the risk of breast cancer and is an appropriate contraceptive choice not only for women of general reproductive age but also for women with a family history of breast cancer; for women with a family history of breast cancer, regular breast examinations are required during use. The above-mentioned problems are common cognitive problems in the clinical use of COC today, which have a wide impact and seriously disturb clinical staff, and also make women not able to choose the appropriate contraceptive method correctly, thus causing serious harm that should not be done. Here, we need to focus on clarifying that: for healthy women of reproductive age, long-term use of COC is generally safe without interruption; it has no adverse effects on reproductive function and has a protective effect; pregnancy is possible after stopping the drug, and even if COC is taken during pregnancy, it is not teratogenic to the fetus; moreover, COC can reduce the risk of some gynecological malignancies and play a protective role. In conclusion, COC is a safe, efficient and reversible contraceptive method for healthy women of reproductive age that can be used for a long time.