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Dr. r santos   evidence-based contraceptive methods
 

Dr. r santos evidence-based contraceptive methods

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  • Very informative slides, Dr. Santos. You have mentioned the FDA black box warning on limiting use of DMPA to 2 years only but I've read from the ACOG Committee Opinion no. 415, Sept. 2008 Depot Medroxyprogesterone Acetate and Bone effects. They stated that evidence suggest that the rate of BMD loss may slow with longer term DMPA use.
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  • Hello, Dr. Santos. There are newer data on combined oral contraceptives (COC) and cancer risk. The International Agency for Research on Cancer (IARC), the cancer research agency of WHO, in its press release of the 29th of July 2005, informed of the publication of Monograph 91 on the carcinogenicity of combined estrogen-progestogen oral contraceptives (COC) and combined estrogen-progestogen menopausal therapy (HRT), based on the conclusions of an international Working Group of 21 scientists from 8 countries. Please see http://www.who.int/reproductivehealth/publications/ageing/cocs_hrt_statement.pdf and http://www.iarc.fr/en/media-centre/pr/2005/pr167.html.
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  • Congratulations on your slideshows very interesting !!! ...Thank for sharing.
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  • Menopause. 2002 Jan-Feb;9(1):6-15.Progestogens in hormonal replacement therapy: new molecules, risks, and benefits.Sitruk-Ware R.Center for Biomedical Research, Population Council, 1230 York Ave., New York, NY 10021, USA. regine@popcbr.rockefeller.edu.Comment in:Menopause. 2002 Jan-Feb;9(1):1-2. While the benefits of progestogen use in hormone replacement therapy (HRT) are well recognized as far as endometrial protection is concerned, their risks and drawbacks have generated controversial articles. Several risks are attributed to progestogens as a class-effect; however, the progestogens used in HRT have varying pharmacological properties and do not induce the same side effects. Natural progesterone (P) and some of its derivatives, such as the 19-norprogesterones (Nestorone, nomegestrol acetate, trimegestone), do not bind to the androgen receptor and, hence, do not exert androgenic side effects. Newly synthesized molecules such as drospirenone or dienogest have no androgenic effect but do have a partial antiandrogenic effect. Drospirenone derives from spironolactone and binds to the mineralocorticoid receptor. When the cardiovascular risk factors are considered, some molecules with a higher androgenic potency than others attenuate the beneficial effects of estrogens on the lipid profile as well as the vasomotion. On the other hand, other progestogens devoid of androgenic properties do not exert these deleterious effects. The epidemiological data do not suggest any negative effect of the progestogens administered together with estrogens on cardiovascular morbidity or mortality. However, recent results suggest that in women with established coronary heart disease, HRT may not protect against further heart attacks when the progestogen selected possesses androgenic properties. The data related to the progestogen effect on breast tissue has been interpreted differently from country to country. However, it has been admitted that, according to the type of progestogen used and the dose and duration of its application, a predominant antiproliferative effect is observed in the human breast cells. As far as breast cancer risk is concerned, most epidemiological studies do not suggest any significant difference between the estrogens given alone or combined with progestogens in HRT. Complying with the classic contraindications of HRT and selecting molecules devoid of estrogenic, androgenic, or glucocorticoid effect should allow a larger use of the progestins without any major drawback.PMID: 11791081 [PubMed - indexed for MEDLINE]
  • Initially indicated for rape and sexually assault casesNausea and vomiting due to high estrogen doseOral antiemetic drugs given 1 hour before the EC dose
  • SEXUAL ACTIVITY PRETERM DELIVERY WITH PROM TERM WITH PROM PRETERM DELIVERY WITHOUT PROM FEMALE SUPERIOR 1.50 (0.80-2.82) 0.88 (0.41-1.67) 1.08 (0.51-2.29) MALE SUPERIOR 1.84 (1.05-3.22) 1.59 (0.93-2.71) 2.05 (1.20-3.50) SIDE BY SIDE 1.19 (0.71-1.98) 0.84 (0.48-1.36) 1.19 (0.71-2.01) REAR ENTRY 1.40 (0.72-2.72) 0.88 (0.43-1.79) 1.06 (0.55-2.01) ORGASM 1.91 (1.12-3.23) 1.12 (0.70-1.79) 0.93 (0.60-1.41)
  • Display Settings:AbstractFormatSummarySummary (text)AbstractAbstract (text)MEDLINEXMLPMID ListApplySendto:ChooseDestinationFileClipboardCollectionsE-mailOrderFormatSummary (text)Abstract (text)MEDLINEXMLPMID ListCreate File1 selected item: 8293847FormatSummarySummary (text)AbstractAbstract (text)MEDLINEXMLPMID ListE-mailAdditional textE-mail"SPAM" filtering software noticeAdd to ClipboardAdd to CollectionsOrder articlesFertilSteril. 1994 Jan;61(1):70-7.Health during prolonged use of levonorgestrel 20 micrograms/d and the copper TCu 380Ag intrauterine contraceptive devices: a multicenter study. International Committee for Contraception Research (ICCR).Sivin I, Stern J.Center for Biomedical Research, Population Council, New York, New York 10021.OBJECTIVES: To measure and compare the incidence of adverse events during use of two medicated intrauterine devices (IUDs). DESIGN: A multicenter prospective 7-year randomized study. SETTING: Family planning clinics, primarily in developing countries. SUBJECTS: Women age 18 to 38 years at admission, desiring contraception and without contraindications to IUDs. MAIN OUTCOME MEASURES: Incidence of complaints, conditions, and rates of specific termination for each IUD. METHODS: Subjects recorded menstrual events, and clinical staff registered all complaints and conditions found on examination at four first-year clinic visits and at semiannual visits thereafter. Difference in rates were analyzed by chi 2 statistics. RESULTS: Annual pregnancy rates for each IUD averaged 0.2/100 women whereas upper genital tract infection occurred at rates of 0.6 to 0.7 per 100 years of use. The levonorgestrel-releasing IUD significantly decreased bleeding and spotting days in comparison with historical data for noncontraceptors and with the copper-medicated IUD. Dysmenorrhea, vaginitis, and myoma in women with the levonorgestrel IUD were markedly decreased in comparison with the experience of copper IUD users. Significantly higher rates of amenorrhea, delayed ovarian follicular atresia, skin and hair conditions, and headache were observed with the steroid IUD than with the copper-releasing IUD. Rates of reported adverse effects for either IUD were highest in the first 2 years of use and among women under age 25. CONCLUSIONS: Long-term use of copper or levonorgestrel IUDs is characterized by very low rates of pregnancy and by a low and declining annual incidence of side effects, including pelvic infection and borderline anemia. The levonorgestrel-releasing IUD reduced the incidence of bleeding and, in the long term, of myoma and myoma-related surgery in comparison with the copper T IUD. Both IUDs proved highly acceptable and had few unanticipated side effects.PMID: 8293847 [PubMed - indexed for MEDLINE]
  • 57Am J Obstet Gynecol. 2002 Dec;187(6):1699-708.Mechanisms of action of intrauterine devices: update and estimation of postfertilization effects.Stanford JB, Mikolajczyk RT.Department of Family and Preventive Medicine, University of Utah Health Research Center, Salt Lake City 84108, USA. jstanford@dfpm.utah.eduThere are many potential mechanisms of action for the intrauterine device (IUD), which vary by type of IUD (inert, copper, or hormonal). This paper reviews the evidence for each potential mechanism of action. On the basis of available data for fertilization rates and clinical pregnancy rates, the relative contribution of mechanisms acting before or after fertilization were quantitatively estimated. These estimates indicate that, although prefertilization effects are more prominent for the copper IUD, both prefertilization and postfertilization mechanisms of action contribute significantly to the effectiveness of all types of intrauterine devices.PMID: 12501086 [PubMed - indexed for MEDLINE]58Fertil Steril. 1988 May;49(5):768-73.New insights on the mode of action of intrauterine contraceptive devices in women.Alvarez F, Brache V, Fernandez E, Guerrero B, Guiloff E, Hess R, Salvatierra AM, Zacharias S.Profamilia, Santo Domingo, RepublicaDominicana.To gain a better understanding of the mechanism of action of intrauterine devices (IUDs), a search was made for ova in the genital tracts of 115 women using no contraception and of 56 women using IUDs, all of whom volunteered for study in conjunction with surgical sterilization. Ova were recovered from tubal flushings between 48 and 120 hours after the midcycle peak of luteinizing hormone in 39% of the IUD users compared with 56% of women in the control group (0.05 less than P less than 0.10). This suggests an action of the IUD before the ovum reaches the uterus. Eggs with a microscopic appearance consistent with fertilization were recovered from the fallopian tubes of half of the women using no contraception who had intercourse within the fertile period of the reproductive cycle and from whom ova were recovered. In contrast (P less than 0.01), no eggs with this appearance were recovered in IUD users who had intercourse within the fertile period. No ova were recovered from the body of the uterus of any of the IUD users. Fertilized ova are less likely to reach the uterine cavity containing an IUD. Thus, the principal mode of IUDs is by a method other than destruction of live embryos.PMID: 3360166 [PubMed - indexed for MEDLINE]59Fertil Steril. 1985 Aug;44(2):214-8.Absence of chorionic gonadotropin in sera of women who use intrauterine devices.Segal SJ, Alvarez-Sanchez F, Adejuwon CA, Brache de Mejia V, Leon P, Faundes A.A controlled study was undertaken to determine whether unnoticed pregnancies routinely occur in users of the intrauterine contraceptive device (IUD). Starting on day 10 of the menstrual cycle and continuing through the onset of menstruation or until the diagnosis of pregnancy, we collected daily blood samples from three groups of normally menstruating young women. The study groups were (A) IUD users (n = 30), (B) women with tubal ligation (n = 30), and (C) women trying to become pregnant (n = 15). The sequential serum samples were analyzed by radioimmunoassay for progesterone (P), human luteinizing hormone (hLH), and human chorionic gonadotropin (hCG). No positive hCG assays in luteal phase blood sera of IUD users were observed. The only positive hCG determinations of IUD users coincided with the preovulatory surge of hLH. Two subjects who became pregnant, as judged by progressive increases in hCG and P levels in the luteal phase, belonged to the group planning pregnancy. The finding of two pregnancies in 15 months of exposure is consistent with the assumption of natural fertility. The probability of no pregnancies in 30 months at risk, as observed among the IUD users, is between 1 in 200 and 1 in 100,000, depending on the assumption made for natural fertility. The study demonstrates that IUD users do not retain their natural fertility, and that IUDs do not exert their antifertility effect as abortifacient agents. If a confirmed pregnancy is detected in an IUD user, it may be assumed to represent an isolated case of contraceptive failure.PIP: A controlled study was undertaken to determine whether unnoticed pregnancies routinely occur in users of the IUD. Beginning on day 10 of the menstrual cycle and continuing through the onset of menstruation or until the diagnosis of pregnancy, the authors collected daily blood samples from 3 groups of normally menstruating young women. The study groups were: a) IUD users (n=30); b) women with tubal ligation (n=30); and c) women trying to become pregnant (n=15). The sequential serum samples were analyzed by radioimmunoassay for progesterone (P), human luteinizing hormone (hLH), and human chorionic gonadotropin (hCG). No positive hCG assays in luteal phase blood sera of IUD users were observed. The only positive hCG determinations of IUD users coincided with the preovulatory surge of hLH. 2 subjects who become pregnant as judged by progressive increases in hCG and P levels in the luteal phase belonged to the group planning pregnancy. The finding of 2 pregnancies in 15 months of exposure is consistent with the assumption of natural fertility. The probability of no pregnancies in 30 months at risk, as observed among the IUD users, is between 1 in 200 and 1 in 100,000, depending on the assumption made for natural fertility. The study demonstrates that IUD users do not retain their natural fertility, and that IUDs do not exert their antifertility effect as abortifacient agents. If a confirmed pregnancy is detected in an IUD user, it may be assumed to represent an isolated case of contraceptive failure. author's modifiedPMID: 4018277 [PubMed - indexed for MEDLINE]
  • 58Fertil Steril. 1988 May;49(5):768-73.New insights on the mode of action of intrauterine contraceptive devices in women.Alvarez F, Brache V, Fernandez E, Guerrero B, Guiloff E, Hess R, Salvatierra AM, Zacharias S.Profamilia, Santo Domingo, RepublicaDominicana.To gain a better understanding of the mechanism of action of intrauterine devices (IUDs), a search was made for ova in the genital tracts of 115 women using no contraception and of 56 women using IUDs, all of whom volunteered for study in conjunction with surgical sterilization. Ova were recovered from tubal flushings between 48 and 120 hours after the midcycle peak of luteinizing hormone in 39% of the IUD users compared with 56% of women in the control group (0.05 less than P less than 0.10). This suggests an action of the IUD before the ovum reaches the uterus. Eggs with a microscopic appearance consistent with fertilization were recovered from the fallopian tubes of half of the women using no contraception who had intercourse within the fertile period of the reproductive cycle and from whom ova were recovered. In contrast (P less than 0.01), no eggs with this appearance were recovered in IUD users who had intercourse within the fertile period. No ova were recovered from the body of the uterus of any of the IUD users. Fertilized ova are less likely to reach the uterine cavity containing an IUD. Thus, the principal mode of IUDs is by a method other than destruction of live embryos.
  • Lancet. 1992 Mar 28;339(8796):785-8.Intrauterine devices and pelvic inflammatory disease: an international perspective.Farley TM, Rosenberg MJ, Rowe PJ, Chen JH, Meirik O.Special Programme of Research, Development, and Research Training in Human Reproduction, World Health Organisation, Geneva, Switzerland.Comment in:Lancet. 1992 May 23;339(8804):1306. Lancet. 1992 May 23;339(8804):1306. Lancet. 1992 Jul 25;340(8813):248-9. Lancet. 1992 Mar 28;339(8796):783-4. The risk of pelvic inflammatory disease (PID) associated with use of an intrauterine device (IUD) has been an important concern that has dominated decisions on its use throughout the world, especially in the USA. Early research that suggested such an association led to both a dramatic decline in use of the method and its withdrawal from the US market by two manufacturers. However, factors other than use of an IUD are now thought to be major determinants of PID risk. To address these concerns, we have reviewed the World Health Organisation's IUD clinical trial data to explore the incidence and patterns of PID risk with use of an IUD. The overall rate of PID among 22,908 IUD insertions and during 51,399 woman-years of follow-up was 1.6 cases per 1000 woman-years of use. After adjustment for confounding factors, PID risk was more than six times higher during the 20 days after insertion than during later times (unadjusted rates, 9.7 vs 1.4 per 1000 woman-years, respectively); the risk was low and constant for up to eight years of follow-up. Rates varied according to geographical area (highest in Africa and lowest in China) and were inversely associated with age. PID rates were lower among women who had IUDs inserted more recently. Our findings indicate that PID among IUD users is most strongly related to the insertion process and to background risk of sexually transmissible disease. PID is an infrequent event beyond the first 20 days after insertion. Because of this increased risk with insertion, IUDs should be left in place up to their maximum lifespan and should not routinely be replaced earlier, provided there are no contraindications to continued use and the woman wishes to continue with the device.PIP: The risk of pelvic inflammatory disease (PID) associated with the use of an IUD has been an important concern that has dominated decisions on its use throughout the world, especially in the US. Early research that suggested such an association led to both a dramatic decline in the use of the method and its withdrawal from the US market by 2 manufacturers. However, factors other than use of an IUD are now thought to be major determinants of PID risk. To address these concerns, the authors reviewed the WHO's IUD clinical trial data to explore the incidence and patterns of PID risk with the use of an IUD. The overall rate of PID among 22,908 IUD insertions and during 51,399 woman-years of followup was 1.6 cases/1000 woman-years of use. After adjusting for confounding factors, PID risk was more than 6 times higher during the 20 days postinsertion than during later times (unadjusted rates, 9.7 vs 1.4/1000 woman-years, respectively); the risk was low and constant for up to 8 years of followup. Rates varied according to geographical area (highest in Africa and lowest in China) and were inversely associated with age. PID rates were lower among women who had IUDs inserted more recently. These findings indicate that PID among IUD users is most strongly related to the insertion process and to background risk of sexually transmissible disease. PID is an infrequent event beyond the 1st 20 days after insertion. Because of this increased risk with insertion, IUDs should be left in place up to their maximum lifespan and should not routinely be replaced earlier, provided there are no contraindications to continued use and the woman desires to continue with the device. author's modified
  • BMJ. 2009 Aug 13;339:b2890. doi: 10.1136/bmj.b2890.Hormonal contraception and risk of venous thromboembolism: national follow-up study.Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C.Gynaecological Clinic, Rigshospitalet, Copenhagen University, DK-2100 Copenhagen, Denmark. Lidegaard@rh.regionh.dkComment in:BMJ. 2009;339:b3164. OBJECTIVE: To assess the risk of venous thrombosis in current users of different types of hormonal contraception, focusing on regimen, oestrogen dose, type of progestogen, and route of administration. DESIGN: National cohort study. SETTING: Denmark, 1995-2005. PARTICIPANTS: Danish women aged 15-49 with no history of cardiovascular or malignant disease. MAIN OUTCOME MEASURES: Adjusted rate ratios for all first time deep venous thrombosis, portal thrombosis, thrombosis of caval vein, thrombosis of renal vein, unspecified deep vein thrombosis, and pulmonary embolism during the study period. RESULTS: 10.4 million woman years were recorded, 3.3 million woman years in receipt of oral contraceptives. In total, 4213 venous thrombotic events were observed, 2045 in current users of oral contraceptives. The overall absolute risk of venous thrombosis per 10 000 woman years in non-users of oral contraceptives was 3.01 and in current users was 6.29. Compared with non-users of combined oral contraceptives the rate ratio of venous thrombembolism in current users decreased with duration of use (4 years 2.76, 2.53 to 3.02; P<0.001) and with decreasing dose of oestrogen. Compared with oral contraceptives containing levonorgestrel and with the same dose of oestrogen and length of use, the rate ratio for oral contraceptives with norethisterone was 0.98 (0.71 to 1.37), with norgestimate 1.19 (0.96 to 1.47), with desogestrel 1.82 (1.49 to 2.22), with gestodene 1.86 (1.59 to 2.18), with drospirenone 1.64 (1.27 to 2.10), and with cyproterone 1.88 (1.47 to 2.42). Compared with non-users of oral contraceptives, the rate ratio for venous thromboembolism in users of progestogen only oral contraceptives with levonorgestrel or norethisterone was 0.59 (0.33 to 1.03) or with 75 mug desogestrel was 1.12 (0.36 to 3.49), and for hormone releasing intrauterine devices was 0.90 (0.64 to 1.26). CONCLUSION: The risk of venous thrombosis in current users of combined oral contraceptives decreases with duration of use and decreasing oestrogen dose. For the same dose of oestrogen and the same length of use, oral contraceptives with desogestrel, gestodene, or drospirenone were associated with a significantly higher risk of venous thrombosis than oral contraceptives with levonorgestrel. Progestogen only pills and hormone releasing intrauterine devices were not associated with any increased risk of venous thrombosis.
  • BMJ. 2009 Aug 13;339:b2890. doi: 10.1136/bmj.b2890.Hormonal contraception and risk of venous thromboembolism: national follow-up study.Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C.Gynaecological Clinic, Rigshospitalet, Copenhagen University, DK-2100 Copenhagen, Denmark. Lidegaard@rh.regionh.dkComment in:BMJ. 2009;339:b3164. OBJECTIVE: To assess the risk of venous thrombosis in current users of different types of hormonal contraception, focusing on regimen, oestrogen dose, type of progestogen, and route of administration. DESIGN: National cohort study. SETTING: Denmark, 1995-2005. PARTICIPANTS: Danish women aged 15-49 with no history of cardiovascular or malignant disease. MAIN OUTCOME MEASURES: Adjusted rate ratios for all first time deep venous thrombosis, portal thrombosis, thrombosis of caval vein, thrombosis of renal vein, unspecified deep vein thrombosis, and pulmonary embolism during the study period. RESULTS: 10.4 million woman years were recorded, 3.3 million woman years in receipt of oral contraceptives. In total, 4213 venous thrombotic events were observed, 2045 in current users of oral contraceptives. The overall absolute risk of venous thrombosis per 10 000 woman years in non-users of oral contraceptives was 3.01 and in current users was 6.29. Compared with non-users of combined oral contraceptives the rate ratio of venous thrombembolism in current users decreased with duration of use (4 years 2.76, 2.53 to 3.02; P<0.001) and with decreasing dose of oestrogen. Compared with oral contraceptives containing levonorgestrel and with the same dose of oestrogen and length of use, the rate ratio for oral contraceptives with norethisterone was 0.98 (0.71 to 1.37), with norgestimate 1.19 (0.96 to 1.47), with desogestrel 1.82 (1.49 to 2.22), with gestodene 1.86 (1.59 to 2.18), with drospirenone 1.64 (1.27 to 2.10), and with cyproterone 1.88 (1.47 to 2.42). Compared with non-users of oral contraceptives, the rate ratio for venous thromboembolism in users of progestogen only oral contraceptives with levonorgestrel or norethisterone was 0.59 (0.33 to 1.03) or with 75 mug desogestrel was 1.12 (0.36 to 3.49), and for hormone releasing intrauterine devices was 0.90 (0.64 to 1.26). CONCLUSION: The risk of venous thrombosis in current users of combined oral contraceptives decreases with duration of use and decreasing oestrogen dose. For the same dose of oestrogen and the same length of use, oral contraceptives with desogestrel, gestodene, or drospirenone were associated with a significantly higher risk of venous thrombosis than oral contraceptives with levonorgestrel. Progestogen only pills and hormone releasing intrauterine devices were not associated with any increased risk of venous thrombosis.OR 2.03 (1.91 to 2.16)RR 1.54 (1.48 to 1.58)
  • BMJ. 2009 Aug 13;339:b2890. doi: 10.1136/bmj.b2890.Hormonal contraception and risk of venous thromboembolism: national follow-up study.Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C.Gynaecological Clinic, Rigshospitalet, Copenhagen University, DK-2100 Copenhagen, Denmark. Lidegaard@rh.regionh.dkComment in:BMJ. 2009;339:b3164. OBJECTIVE: To assess the risk of venous thrombosis in current users of different types of hormonal contraception, focusing on regimen, oestrogen dose, type of progestogen, and route of administration. DESIGN: National cohort study. SETTING: Denmark, 1995-2005. PARTICIPANTS: Danish women aged 15-49 with no history of cardiovascular or malignant disease. MAIN OUTCOME MEASURES: Adjusted rate ratios for all first time deep venous thrombosis, portal thrombosis, thrombosis of caval vein, thrombosis of renal vein, unspecified deep vein thrombosis, and pulmonary embolism during the study period. RESULTS: 10.4 million woman years were recorded, 3.3 million woman years in receipt of oral contraceptives. In total, 4213 venous thrombotic events were observed, 2045 in current users of oral contraceptives. The overall absolute risk of venous thrombosis per 10 000 woman years in non-users of oral contraceptives was 3.01 and in current users was 6.29. Compared with non-users of combined oral contraceptives the rate ratio of venous thrombembolism in current users decreased with duration of use (4 years 2.76, 2.53 to 3.02; P<0.001) and with decreasing dose of oestrogen. Compared with oral contraceptives containing levonorgestrel and with the same dose of oestrogen and length of use, the rate ratio for oral contraceptives with norethisterone was 0.98 (0.71 to 1.37), with norgestimate 1.19 (0.96 to 1.47), with desogestrel 1.82 (1.49 to 2.22), with gestodene 1.86 (1.59 to 2.18), with drospirenone 1.64 (1.27 to 2.10), and with cyproterone 1.88 (1.47 to 2.42). Compared with non-users of oral contraceptives, the rate ratio for venous thromboembolism in users of progestogen only oral contraceptives with levonorgestrel or norethisterone was 0.59 (0.33 to 1.03) or with 75 mug desogestrel was 1.12 (0.36 to 3.49), and for hormone releasing intrauterine devices was 0.90 (0.64 to 1.26). CONCLUSION: The risk of venous thrombosis in current users of combined oral contraceptives decreases with duration of use and decreasing oestrogen dose. For the same dose of oestrogen and the same length of use, oral contraceptives with desogestrel, gestodene, or drospirenone were associated with a significantly higher risk of venous thrombosis than oral contraceptives with levonorgestrel. Progestogen only pills and hormone releasing intrauterine devices were not associated with any increased risk of venous thrombosis.OR 2.03 (1.91 to 2.16)RR 1.54 (1.48 to 1.58)
  • BMJ. 2009 Aug 13;339:b2890. doi: 10.1136/bmj.b2890.Hormonal contraception and risk of venous thromboembolism: national follow-up study.Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C.Gynaecological Clinic, Rigshospitalet, Copenhagen University, DK-2100 Copenhagen, Denmark. Lidegaard@rh.regionh.dkComment in:BMJ. 2009;339:b3164. OBJECTIVE: To assess the risk of venous thrombosis in current users of different types of hormonal contraception, focusing on regimen, oestrogen dose, type of progestogen, and route of administration. DESIGN: National cohort study. SETTING: Denmark, 1995-2005. PARTICIPANTS: Danish women aged 15-49 with no history of cardiovascular or malignant disease. MAIN OUTCOME MEASURES: Adjusted rate ratios for all first time deep venous thrombosis, portal thrombosis, thrombosis of caval vein, thrombosis of renal vein, unspecified deep vein thrombosis, and pulmonary embolism during the study period. RESULTS: 10.4 million woman years were recorded, 3.3 million woman years in receipt of oral contraceptives. In total, 4213 venous thrombotic events were observed, 2045 in current users of oral contraceptives. The overall absolute risk of venous thrombosis per 10 000 woman years in non-users of oral contraceptives was 3.01 and in current users was 6.29. Compared with non-users of combined oral contraceptives the rate ratio of venous thrombembolism in current users decreased with duration of use (4 years 2.76, 2.53 to 3.02; P<0.001) and with decreasing dose of oestrogen. Compared with oral contraceptives containing levonorgestrel and with the same dose of oestrogen and length of use, the rate ratio for oral contraceptives with norethisterone was 0.98 (0.71 to 1.37), with norgestimate 1.19 (0.96 to 1.47), with desogestrel 1.82 (1.49 to 2.22), with gestodene 1.86 (1.59 to 2.18), with drospirenone 1.64 (1.27 to 2.10), and with cyproterone 1.88 (1.47 to 2.42). Compared with non-users of oral contraceptives, the rate ratio for venous thromboembolism in users of progestogen only oral contraceptives with levonorgestrel or norethisterone was 0.59 (0.33 to 1.03) or with 75 mug desogestrel was 1.12 (0.36 to 3.49), and for hormone releasing intrauterine devices was 0.90 (0.64 to 1.26). CONCLUSION: The risk of venous thrombosis in current users of combined oral contraceptives decreases with duration of use and decreasing oestrogen dose. For the same dose of oestrogen and the same length of use, oral contraceptives with desogestrel, gestodene, or drospirenone were associated with a significantly higher risk of venous thrombosis than oral contraceptives with levonorgestrel. Progestogen only pills and hormone releasing intrauterine devices were not associated with any increased risk of venous thrombosis.OR 2.03 (1.91 to 2.16)RR 1.54 (1.48 to 1.58)
  • The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study.van HylckamaVlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJ, Rosendaal FR. BMJ. 2009 Aug 13;339:b2921. doi: 10.1136/bmj.b2921. Department of Clinical Epidemiology, Leiden University Medical Center, C7-P, PO Box 9600, NL-2300 RC Leiden, Netherlands.OBJECTIVE: To assess the thrombotic risk associated with oral contraceptive use with a focus on dose of oestrogen and type of progestogen of oral contraceptives available in the Netherlands. DESIGN: Population based case-control study. SETTING: Six participating anticoagulation clinics in the Netherlands (Amersfoort, Amsterdam, The Hague, Leiden, Rotterdam, and Utrecht). PARTICIPANTS: Premenopausal women <50 years old who were not pregnant, not within four weeks postpartum, and not using a hormone excreting intrauterine device or depot contraceptive. Analysis included 1524 patients and 1760 controls. MAIN OUTCOME MEASURES: First objectively diagnosed episodes of deep venous thrombosis of the leg or pulmonary embolism. Odds ratios calculated by cross-tabulation with a 95% confidence interval according to Woolf's method; adjusted odds ratios estimated by unconditional logistic regression, standard errors derived from the model. RESULTS: Currently available oral contraceptives increased the risk of venous thrombosis fivefold compared with non-use (odds ratio 5.0, 95% CI 4.2 to 5.8). The risk clearly differed by type of progestogen and dose of oestrogen. The use of oral contraceptives containing levonorgestrel was associated with an almost fourfold increased risk of venous thrombosis (odds ratio 3.6, 2.9 to 4.6) relative to non-users, whereas the risk of venous thrombosis compared with non-use was increased 5.6-fold for gestodene (5.6, 3.7 to 8.4), 7.3-fold for desogestrel (7.3, 5.3 to 10.0), 6.8-fold for cyproterone acetate (6.8, 4.7 to 10.0), and 6.3-fold for drospirenone (6.3, 2.9 to 13.7). The risk of venous thrombosis was positively associated with oestrogen dose. We confirmed a high risk of venous thrombosis during the first months of oral contraceptive use irrespective of the type of oral contraceptives. CONCLUSIONS: Currently available oral contraceptives still have a major impact on thrombosis occurrence and many women do not use the safest brands with regard to risk of venous thrombosis.
  • Factor V Leiden mutation is present in 4.85% of white women. The prevalence among other races is too low to differentiate the prevalence in men and women (1.23% of blacks, 0.45% of Asians, 2.21% of Hispanics, and 1.25% of Native Americans) (12). Most individuals with factor V Leiden mutation are heterozygous, only 0.02% are homozygous. This translates to a prevalence for homozygosity of 0.0008% in white women and far lower values in nonwhite women. in the United States.Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women: implications for venous thromboembolism screening. J Am Med Assoc 1997;277:1305–7.
  • 117 Contraception. 2001 Aug;64(2):125-33.Risk of venous thromboembolism from oral contraceptives containing gestodene and desogestrel versus levonorgestrel: a meta-analysis and formal sensitivity analysis.Hennessy S, Berlin JA, Kinman JL, Margolis DJ, Marcus SM, Strom BL.Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. shenness@cceb.med.upenn.eduControversy exists regarding whether oral contraceptives (OCs) containing desogestrel and gestodene are associated with an increased risk of venous thromboembolism (VTE) versus OCs containing levonorgestrel. We were interested in synthesizing the available data, exploring explanations for mixed results, and characterizing the degree of uncontrolled confounding that could have produced a spurious association. We performed a meta-analysis and formal sensitivity analysis of studies that examined the relative risk of VTE for desogestrel and gestodene versus levonorgestrel. Twelve studies, all observational, were included. The summary relative risk (95% CI) was 1.7 (1.3-2.1; heterogeneity p = 0.09). If real, the incremental risk of VTE would be about 11 per 100,000 women per year. An association was present when accounting for duration of use and when restricted to the first year of use in new users. However, in the sensitivity analysis, the association abated in many, but not all, scenarios in which an unmeasured confounding factor increased the risk of VTE three to fivefold and in nearly all examined scenarios in which the factor increased the risk 10-fold. The summary relative risk of 1.7 does not appear to be caused by depletion of susceptibles, but is sensitive to a modest degree of unmeasured confounding. Whether such confounding occurred is unknown. However, given this sensitivity, this issue probably cannot be settled unequivocally with observational data. In the absence of a definitive answer, this apparent increased risk, together with its uncertainty and small magnitude and its important consequences, should be considered when selecting an OC for a given woman.
  • 123 N Engl J Med. 1988 Nov 17;319(20):1313-7.A prospective study of past use of oral contraceptive agents and risk of cardiovascular diseases.Stampfer MJ, Willett WC, Colditz GA, Speizer FE, Hennekens CH.Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA.We evaluated the effects of past use of oral contraceptive agents on the risk of various cardiovascular diseases among women in the Nurses' Health Study cohort. We studied 119,061 women who were 30 to 55 years of age in 1976, who provided information on their use of oral contraceptives, and who at entry had had no previous coronary disease or stroke. End points were documented by medical records. During eight years of follow-up (484,096 person-years among those who had never used oral contraceptives, 415,488 among past users, and 22,376 among current users), there were 485 new cases of major coronary disease (380 nonfatal myocardial infarctions and 105 deaths from coronary disease), 282 strokes (205 nonfatal and 77 fatal), and 48 other deaths from cardiovascular causes. We found no evidence to suggest an increase in the risk of cardiovascular diseases among past users of oral contraceptives, even with prolonged previous use. After adjustment for a variety of risk factors, the relative risk of major coronary disease for women who had used oral contraceptives in the past, as compared with those who had never used such agents, was 0.8 (95 percent confidence interval, 0.6 to 1.0); of stroke, 1.0 (95 percent confidence interval, 0.7 to 1.3); and of death from all cardiovascular causes, 0.9 (95 percent confidence interval, 0.7 to 1.2). We found neither evidence of increased risk with longer use nor any trend with the amount of time since the last use. According to these prospective data, the use of oral contraceptive agents in the past does not materially raise a woman's risk of subsequent cardiovascular disease.J Am CollCardiol. 2009 Jan 20;53(3):221-31.Contraceptive hormone use and cardiovascular disease.Shufelt CL, BaireyMerz CN.Women's Heart Center, Division of Cardiology, Department of Medicine, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.Erratum in:J Am CollCardiol. 2009 Mar 10;53(10):904. Contraceptive hormones, most commonly prescribed as oral contraceptives (OCs), are a widely utilized method to prevent ovulation, implantation, and, therefore, pregnancy. The Women's Health Initiative demonstrated cardiovascular risk linked to menopausal hormone therapy among women without pre-existing cardiovascular disease, prompting a review of the safety, efficacy, and side effects of other forms of hormone therapy. A variety of basic science, animal, and human data suggests that contraceptive hormones have antiatheromatous effects; however, relatively less is known regarding the impact on atherosclerosis, thrombosis, vasomotion, and arrhythmogenesis. Newer generation OC formulations in use indicate no increased myocardial infarction risk for current users, but a persistent increased risk of venous thromboembolism. There are no cardiovascular data available for the newest generation contraceptive hormone formulations, including those that contain newer progestins that lower blood pressure, as well as the nonoral routes (transdermal and vaginal). Current guidelines indicate that, as with all medication, contraceptive hormones should be selected and initiated by weighing risks and benefits for the individual patient. Women 35 years and older should be assessed for cardiovascular risk factors including hypertension, smoking, diabetes, nephropathy, and other vascular diseases, including migraines, prior to use. Existing data are mixed with regard to possible protection from OCs for atherosclerosis and cardiovascular events; longer-term cardiovascular follow-up of menopausal women with regard to prior OC use, including subgroup information regarding adequacy of ovulatory cycling, the presence of hyperandrogenic conditions, and the presence of prothrombotic genetic disorders is needed to address this important issue.129 Lancet. 1996 Aug 24;348(9026):498-505.Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.[No authors listed]Comment in:Lancet. 1999 Nov 6;354(9190):1610. Lancet. 2001 May 26;357(9269):1706-7. BACKGROUND: The association between use of oral contraceptives (OCs) and cerebral infarction was established in studies from northern Europe and the USA during the 1960s and 1970s. Since then, the constituents of hormonal OCs have changed and now contain lower doses of oestrogen and progestagen. Current recommendations restrict OC use to younger women who do not have other risk factors for cardiovascular disease. In this international study we assessed the risk of OC-associated first stroke in women from Europe and other countries throughout the world. METHODS: In this hospital-based, case-control study, we assessed the risk of ischaemic stroke in association with current use of combined OCs in 697 cases, aged 20-44 years, and 1962 age-matched hospital controls in 21 centres in Africa, Asia, Europe, and Latin America. The diagnosis of ischaemic stroke was almost exclusively based on computed tomography (CT), magnetic resonance imaging (MRI), or cerebral angiography carried out within 3 weeks of the clinical event. All cases and controls were interviewed while in hospital with the same questionnaire, which included information on medical and personal history, details of lifetime contraceptive use, and blood-pressure measurements before the most recent episode of OC use. FINDINGS: The overall odds ratio of ischaemic stroke was 2.99 (95% CI 1.65-5.40) in Europe and 2.93 (2.15-4.00) in the non-European (developing) countries. Odds ratios were lower in younger women and those who did not smoke, and less than 2 in women who did not have hypertension and who reported that their blood pressure had been checked before the current episode of OC use. By contrast, among current OC users with a history of hypertension, the odds ratio was 10.7 (2.04-56.6) in Europe and 14.5 (5.36-39.0) in the developing countries. In Europe, the odds ratio associated with current use of low-dose OCs (< 50 micrograms oestrogen) was 1.53 (0.71-3.31), whereas for higher-dose preparations it was 5.30 (2.56-11.0). In the developing countries, there was no significant difference between overall estimates of risk associated with use of low-dose or higher-dose OCs (3.26 [2.19-4.86] vs 2.71 [1.75-4.19]). This differential effect of dose in Europe and the developing countries is likely to be due to different levels of other risk factors among users of low-dose and higher-dose OCs in the two groups of countries. There was no significant increase in odds ratios with increasing duration of OC use among current users; odds ratios were not significantly increased after cessation of OC use. INTERPRETATION: The incidence of ischaemic stroke is low in women of reproductive age and any risk attributable to OC use is small. The risk can be further reduced if users are younger than 35 years, do not smoke, do not have a history of hypertension, and have blood pressure measured before the start of OC use. In such women OC preparations with low oestrogen doses may be associated with even lower risk.
  • 122Circulation. 1998 Sep 15;98(11):1058-63.Myocardial infarction and use of low-dose oral contraceptives: a pooled analysis of 2 US studies.Sidney S, Siscovick DS, Petitti DB, Schwartz SM, Quesenberry CP, Psaty BM, Raghunathan TE, Kelaghan J, Koepsell TD.From the Division of Research, Kaiser Permanente Medical Care Program, Northern California, Oakland, CA 94611, USA. sxs@dor.kaiser.orgBACKGROUND: Population-based case-control studies to assess the relationship of low-dose oral contraceptive (OC) use with myocardial infarction (MI) were performed at 2 sites in the United States (California and Washington state). The purpose of the present study was to estimate risk of MI in relation to use of low-dose OCs in a pooled analysis combining results from the 2 sites. METHODS AND RESULTS: The study included as cases women aged 18 to 44 years with incident MI who had no prior history of ischemic heart disease or cerebrovascular disease. Women in the case and control groups were interviewed in person regarding OC use and cardiovascular risk factors. The analysis included 271 MI cases and 993 controls. Compared with noncurrent users, the adjusted pooled odds ratio for MI in current OC users was 0.94 (95% CI, 0.44, 2.20) after adjustment for major risk factors and sociodemographic factors. Compared with never users, the adjusted pooled odds ratio for MI was 0.56 (0.21, 1.49) in current OC users and 0.54 (0.31, 0.95) in past OC users. Among past OC users, duration and recency of use were unrelated to MI risk as was current hormone replacement therapy. There was no evidence of interaction between OC use and age, presence of cardiovascular risk factors (hypercholesterolemia, hypertension, diabetes), obesity, or smoking. CONCLUSIONS: We conclude that low-dose OCs as used in these populations are safe with respect to risk of MI in women.PMID: 9736591 [PubMed - indexed for MEDLINE]
  • 132 3.Br J ObstetGynaecol. 1995 Feb;102(2):153-9.Oral contraceptives, pregnancy and the risk of cerebral thromboembolism: the influence of diabetes, hypertension, migraine and previous thrombotic disease.Lidegaard O.Department of Obstetrics and Gynaecology, Hvidovre Hospital, University of Copenhagen, Denmark.Comment in:Br J ObstetGynaecol. 1996 Jan;103(1):93-4. OBJECTIVE: To assess the risk of developing cerebral thromboembolism among pregnant women and among fertile women with hypertension, migraine, diabetes, and previous thrombotic disease, and to investigate the interaction of these risk factors with the use of oral contraceptives. DESIGN: A retrospective case-control study. SETTING: All gynaecological, medical, neurological, and neurosurgical departments in Danish hospitals. SUBJECTS: Seven hundred and ninety-four women in Denmark aged 15 to 44 who suffered a cerebral thromboembolic attack during the period 1985 to 1989 and 1588 age-matched, randomly selected controls. RESPONSE: Of the 692 case and 1584 control questionnaires sent out, 590 (85.1%) and 1396 (88.1%), respectively, were returned. Of the 590 cases, nine had had cerebral thrombosis before 1980, 15 refused to participate, 44 had a revised diagnosis (primarily multiple sclerosis) and 25 had an unreliable diagnosis, leaving 497 with a reliable cerebral thromboembolic diagnosis. Among the 1396 controls, 26 either refused to participate, were mentally handicapped, lived abroad or returned an uncompleted questionnaire, leaving 1370 controls included in the study. RESULTS: After multivariate analysis, pregnancy implied an odds ratio (OR) for a cerebral thromboembolic attack of 1.3 (nonsignificant), diabetes an OR of 5.4 (P < 0.001), hypertension an OR of 3.1 (P < 0.001) and migraine an OR of 2.8 (P < 0.01). Women with previous non-cerebral thrombotic disease had an OR for cerebral thrombo-embolism of 5.3 (P < 0.001). Women with other predisposing medical diseases had an OR of 8.3 (P < 0.001). These ORs were identical among users and non-users of combined oral contraceptives. CONCLUSION: In this study pregnancy implied a non-significant elevated odds ratio of 1.3 for cerebral thromboembolism whereas diabetes, hypertension, migraine and past thromboembolic events increased the risk of cerebral thromboembolism significantly. Women with these increased thrombotic risks should use oestrogen-containing oral contraceptives only after careful considerations of the risks, if at all.
  • WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Acute myocardial infarction and combined oral contraceptives: results of an international, multicentre, case-control study. Lancet 1997;349:1202-9.Croft P, Hannaford P. Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners’ oral contraceptive study. BMJ 1989;298:165-8.Rosenberg L, Palmer J, Lesko S, Shapiro S. Oral contraceptive use and the risk of myocardial infarction. Am J Epidemiol 1990;131:1009-16.Acute myocardial infarction and combined oral contraceptives: results of an international multicentre case-control study. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.[No authors listed] Lancet. 1997 Apr 26;349(9060):1202-9.BACKGROUND: The association between oral contraceptive (OC) use and acute myocardial infarction (AMI) was established in studies from northern Europe and the USA, which took place during the 1960s and 1970s. Few data are available to quantify the risk worldwide of AMI associated with use of OCs introduced since those early studies. This hospital-based case-control study examined the association between a first AMI and current OC use in women from Africa, Asia, Europe, and Latin America (21 centres). METHODS: Cases were women aged 20-44 years who had definite or possible AMI (classified by history, electrocardiographic, and cardiac-enzyme criteria), who were admitted to hospital, and who survived for at least 24 h. Up to three hospital controls matched by 5-year age-band were recruited for each of the 368 cases (941 controls). All participants were interviewed while in hospital with the same questionnaire, which included information on medical and personal history, lifetime contraceptive use, and blood-pressure screening before the most recent episode of OC use. Odds ratios compared the risk of AMI in current OC users and in non-users (past users and never-users combined). FINDINGS: The overall odds ratio for AMI was 5.01 (95% CI 2.54-9.90) in Europe and 4.78 (2.52-9.07) in the non-European (developing) countries; however, these risk estimates reflect the frequent coexistence of other risk factors among OC users who have AMI. Very few AMIs were identified among women who had no cardiovascular risk factors and who reported that their blood pressure had been checked before OC use; odds ratios associated with OC use in such women were not increased in either Europe or the developing countries. Among OC users who smoked ten or more cigarettes per day, the odds ratios in Europe and in the developing countries were over 20. Similarly, among OC users with a history of hypertension (during pregnancy or at any other time), odds ratios were at least ten in both groups of countries. No consistent association between odds ratios for AMI and age of OC users or oestrogen dose was apparent in either group of countries. No significant increase in odds ratios was apparent with increasing duration of OC use among current users, and odds ratios were not significantly increased in women who had stopped using OCs, even after long exposure. The study had insufficient power to examine whether progestagen dose or type had any effect on AMI risk. INTERPRETATION: Current use of combined OCs is associated with an increased risk of AMI among women with known cardiovascular risk factors and among those who have not been effectively screened, particularly for blood pressure. AMI is extremely rare in younger (< 35 years) non-smoking women who use OCs, and the estimated excess risk of AMI in such women in the European centres is about 3 per 10(6) woman-years. The risk is likely to be even lower if blood pressure is screened before, and presumably during, OC use. Only among older women who smoke is the degree of excess risk associated with OCs substantial (about 400 per 10(6) woman-years).Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners' oral contraception study.Croft P, Hannaford PC. BMJ. 1989 Jan 21;298(6667):165-8. Industrial and Community Health Research Centre, Medical Institute, Hartshill, Stoke on Trent.To determine the pattern of risk factors for acute myocardial infarction associated solely with women a nested case-control study was carried out on cohort data collected during the Royal College of General Practitioners' oral contraception study. Smoking (adjusted relative risk 1.7 for light smokers and 4.3 for heavy smokers), hypertension (2.4), toxaemia of pregnancy (2.8), and diabetes mellitus (6.9) were associated with a significantly increased risk of myocardial infarction. There was no significant trend of risk with social class. Current use of the pill increased the risk only among women who also smoked (relative risk 20.8 for heavy smokers). Previous use of the pill did not influence the risk of myocardial infarction. If heavy smokers also had a history of toxaemia of pregnancy their risk of myocardial infarction was further increased (relative risk 41.0). Other variables associated solely with women, such as parity, hysterectomy, and hormone replacement therapy, had little effect on the risk of having a myocardial infarction. Overall, smoking was the most important independent risk factor and had a strong influence on risks associated with other factors.Oral contraceptive use and the risk of myocardial infarction.Rosenberg L, Palmer JR, Lesko SM, Shapiro S. Am J Epidemiol. 1990 Jun;131(6):1009-16. Slone Epidemiology Unit, Boston University School of Medicine, Brookline, MA 02146.The relation of oral contraceptive use to the risk of myocardial infarction was assessed in a hospital-based case-control study of women aged 25-64 years conducted from 1985 to 1988 in New England; 910 women with first myocardial infarctions were compared with 1,760 control women. Oral contraceptive use, after discontinuation, was not associated with an increased risk of myocardial infarction, whether use had ceased in the distant past or more recently. The overall relative risk estimate for women who had used oral contraceptives in the past for at least 5 years compared with nonusers was 1.1 (95% confidence interval 0.8-1.5) after allowance for confounding factors. Past use was not associated with risk in any age group, in subgroups of women with predisposing factors, or in women at low risk because of the absence of predisposing factors. The results suggest that long-term oral contraceptive use, after discontinuation, does not influence the risk of myocardial infarction. There were few current users and the results for current use were inconclusive: for premenopausal women who had used oral contraceptives in the previous month relative to those who had not, the age-adjusted relative risk estimate was 1.1 (95% confidence interval 0.4-3.1).
  • FertilSteril. 1969 Mar-Apr;20(2):335-9.The effect of an oral contraceptive on tests of thyroid function.Mishell DR Jr, Colodny SZ, Swanson LA.PIP: To determine the effect of a combined oral progestin on 5 tests of thyroid function, 21 parous women at least 8 weeks postpartum and with histories of regular menses were studied. A complete physical examination showed all to be normal. The 5 tests performed were radioactive iodine uptake (RAI) at 2 and 24 hours, serum protein-bound iodine (PBI), thyroxine iodine by column, triiodothyronine absorption test, and serum cholesterol. 2 baseline determinations of each test except the RAI were performed on each subject on separate days. Only euthyroid subjects were further tested. Of these 16 were given 10 mg of medroxyprogesterone acetate in combination with .05 mg of ethinylestradiol cyclically for 20 days. Thyroid function tests were repeated at various intervals from the end of the first week of therapy to over 4 months after starting therapy. Cholesterol and RAI determinations were extremely variable precluding any evidence of drug effect. The other 3 tests showed consistent changes in all patients studied. The serum PBI and thyrozine-iodine by column tests both showed slight elevation within the first week of therapy and further elevation 1 months thereafter. These changes approached hyperthyroidism levels. The triiodothyronine absorption test showed little change in the first week but a definite downward shift thereafter with a maximum depression at 3 months of therapy. This change reached hypothyroidism level. If test were done during the 1 week each month patients were not taking the drug, results were the same. These changes are thought to be due to the estrogen component of the contraceptive drugs. Those physicians depending on these thyroid tests for diagnosis should be aware of these changes in patients taking these drugs.
  • 153 Lancet. 1996 Jun 22;347(9017):1713-27.Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Collaborative Group on Hormonal Factors in Breast Cancer.[No authors listed]Collaborative Group on Hormonal Factors in Breast Cancer, ICRF Cancer Epidemiology Unit, Radcliffe Infirmary, Oxford, UK.Comment in:ACP J Club. 1996 Nov-Dec;125(3):77. Lancet. 1996 Sep 7;348(9028):682; author reply 683. Lancet. 1996 Sep 7;348(9028):682-3. Lancet. 2000 Aug 5;356(9228):513-4. Lancet. 1996 Jun 22;347(9017):1707. BACKGROUND The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed the worldwide epidemiological evidence on the relation between breast cancer risk and use of hormonal contraceptives. METHODS Individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 studies conducted in 25 countries were collected, checked, and analysed centrally. Estimates of the relative risk for breast cancer were obtained by a modification of the Mantel-Haenszel method. All analyses were stratified by study, age at diagnosis, parity, and, where appropriate, the age a woman was when her first child was born, and the age she was when her risk of conception ceased. FINDINGS The results provide strong evidence for two main conclusions. First, while women are taking combined oral contraceptives and in the 10 years after stopping there is a small increase in the relative risk of having breast cancer diagnosed (relative risk [95 percent CI] in current users 1.24 [1.15-1.33], 2p<0.00001; 1-4 years after stopping 1.16 [1.08-1.23], 2p=0.00001; 5-9 years after stopping 1.07 [1.02-1.13], 2p=0.009). Second, there is no significant excess risk of having breast cancer diagnosed 10 or more years after stopping use (relative risk 1.01 [0.96-1.05], NS). The cancers diagnosed in women who had used combined oral contraceptives were less advanced clinically than those diagnosed in women who had never used these contraceptives for ever-users compared with never-users, the relative risk for tumours that had spread beyond the breast compared with localisedtumours was 0.88 (0.81-0.95; 2p=0.002). There was no pronounced variation in the results for recency of use between women with different background risks of breast cancer, including women from different countries and ethnic groups, women with different reproductive histories, and those with or without a family history of breast cancer. The studies included in this collaboration represent about 90 percent of the epidemiological information on the topic, and what is known about the other studies suggests that their omission has not materially affected the main conclusions. Other features of hormonal contraceptive use such as duration of use, age at first use, and the dose and type of hormone within the contraceptives had little additional effect on breast cancer risk, once recency of use had been taken into account. Women who began use before age 20 had higher relative risks of having breast cancer diagnosed while they were using combined oral contraceptives and in the 5 years after stopping than women who began use at older ages, but the higher relative risks apply at ages when breast cancer is rare and, for a given duration of use, earlier use does not result in more cancers being diagnosed than use beginning at older ages. Because breast cancer incidence rises steeply with age, the estimated excess number of cancers diagnosed in the period between starting use and 10 years after stopping increases with age at last use: for example, among 10 000 women from Europe or North America who used oral contraceptives from age 16 to 19, from age 20 to 24, and from age 25 to 29, respectively, the estimated excess number of cancers diagnosed up to 10 years after stopping use is 0.5 (95 percent CI 0.3-0.7), 1.5 (0.7-2.3), and 4.7 (2.7-6.7). Up to 20 years after cessation of use the difference between ever-users and never-users is not so much in the total number of cancers diagnosed, but in their clinical presentation, with the breast cancers diagnosed in ever-users being less advanced clinically than those diagnosed in never-users. The relation observed between breast cancer risk and hormone exposure is unusual, and it is not possible to infer from these data whether it is due to an earlier diagnosis of breast cancer in ever-users, the biological effects of hormonal contraceptives, or a combination of reasons...
  • N Engl J Med. 2002 Jun 27;346(26):2025-32.Oral contraceptives and the risk of breast cancer.Marchbanks PA, McDonald JA, Wilson HG, Folger SG, Mandel MG, Daling JR, Bernstein L, Malone KE, Ursin G, Strom BL, Norman SA, Wingo PA, Burkman RT, Berlin JA, Simon MS, Spirtas R, Weiss LK.Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, USA.Comment in:N Engl J Med. 2006 Apr 13;354(15):1647-8; author reply 1647-8. N Engl J Med. 2002 Jun 27;346(26):2078-9. N Engl J Med. 2002 Oct 31;347(18):1448-9; author reply 1448-9. N Engl J Med. 2002 Oct 31;347(18):1448-9; author reply 1448-9. N Engl J Med. 2002 Oct 31;347(18):1448-9; author reply 1448-9. CMAJ. 2002 Oct 1;167(7):782. BACKGROUND: It is uncertain whether the use of an oral contraceptive increases the risk of breast cancer later in life, when the incidence of breast cancer is increased. We conducted a population-based, case-control study to determine the risk of breast cancer among former and current users of oral contraceptives. METHODS: We interviewed women who were 35 to 64 years old. A total of 4575 women with breast cancer and 4682 controls were interviewed. Conditional logistic regression was used to calculate odds ratios as estimates of the relative risk (incidence-density ratios) of breast cancer. RESULTS: The relative risk was 1.0 (95 percent confidence interval, 0.8 to 1.3) for women who were currently using oral contraceptives and 0.9 (95 percent confidence interval, 0.8 to 1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. The results were similar among white and black women. Use of oral contraceptives by women with a family history of breast cancer was not associated with an increased risk of breast cancer, nor was the initiation of oral-contraceptive use at a young age. CONCLUSIONS: Among women from 35 to 64 years of age, current or former oral-contraceptive use was not associated with a significantly increased risk of breast cancer.
  • N Engl J Med. 2002 Jun 27;346(26):2025-32.Oral contraceptives and the risk of breast cancer.Marchbanks PA, McDonald JA, Wilson HG, Folger SG, Mandel MG, Daling JR, Bernstein L, Malone KE, Ursin G, Strom BL, Norman SA, Wingo PA, Burkman RT, Berlin JA, Simon MS, Spirtas R, Weiss LK.Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, USA.Comment in:N Engl J Med. 2006 Apr 13;354(15):1647-8; author reply 1647-8. N Engl J Med. 2002 Jun 27;346(26):2078-9. N Engl J Med. 2002 Oct 31;347(18):1448-9; author reply 1448-9. N Engl J Med. 2002 Oct 31;347(18):1448-9; author reply 1448-9. N Engl J Med. 2002 Oct 31;347(18):1448-9; author reply 1448-9. CMAJ. 2002 Oct 1;167(7):782. BACKGROUND: It is uncertain whether the use of an oral contraceptive increases the risk of breast cancer later in life, when the incidence of breast cancer is increased. We conducted a population-based, case-control study to determine the risk of breast cancer among former and current users of oral contraceptives. METHODS: We interviewed women who were 35 to 64 years old. A total of 4575 women with breast cancer and 4682 controls were interviewed. Conditional logistic regression was used to calculate odds ratios as estimates of the relative risk (incidence-density ratios) of breast cancer. RESULTS: The relative risk was 1.0 (95 percent confidence interval, 0.8 to 1.3) for women who were currently using oral contraceptives and 0.9 (95 percent confidence interval, 0.8 to 1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. The results were similar among white and black women. Use of oral contraceptives by women with a family history of breast cancer was not associated with an increased risk of breast cancer, nor was the initiation of oral-contraceptive use at a young age. CONCLUSIONS: Among women from 35 to 64 years of age, current or former oral-contraceptive use was not associated with a significantly increased risk of breast cancer.
  • A Case-Control Study of Oral Contraceptive Use and Incident Breast CancerLynn Rosenberg, Yuqing Zhang, Patricia F. Coogan, Brian L. Strom, and Julie R. PalmerAmerican Journal of Epidemiology, Vol. 169, No. 4DOI: 10.1093/aje/kwn360Advance Access publication December 13, 2008
  • Oral Contraceptive Use as a Risk Factor for Premenopausal Breast Cancer:A Meta-analysisCHRIS KAHLENBORN, MD; FRANCESMARY MODUGNO, PHD, MPH; DOUGLAS M. POTTER, PHD;AND WALTER B. SEVERS, PHDOBJECTIVE: To perform a meta-analysis of case-control studiesthat addressed whether prior oral contraceptive (OC) use is associatedwith premenopausal breast cancer.METHODS: We searched the MEDLINE and PubMed databases andbibliography reviews to identify case-control studies of OCs andpremenopausal breast cancer published in or after 1980. Searchterms used included breast neoplasms, oral contraceptives, contraceptiveagents, and case-control studies. Studies reported inall languages were included. Thirty-four studies were identifiedthat met inclusion criteria. Two reviewers extracted data fromoriginal research articles or additional data provided by studyauthors. We used the DerSimonian-Laird method to computepooled odds ratios (ORs) and confidence intervals (CIs) and theMantel-Haenszel test to assess association between OC use andcancer.RESULTS: Use of OCs was associated with an increased risk ofpremenopausal breast cancer in general (OR, 1.19; 95% CI, 1.09-1.29) and across various patterns of OC use. Among studies thatprovided data on nulliparous and parous women separately, OCuse was associated with breast cancer risk in both parous (OR,1.29; 95% CI, 1.20-1.40) and nulliparous (OR, 1.24; 95% CI, 0.92-1.67) women. Longer duration of use did not substantially alterrisk in nulliparous women (OR, 1.29; 95% CI, 0.85-1.96). Amongparous women, the association was stronger when OCs were usedbefore first full-term pregnancy (FFTP) (OR, 1.44; 95% CI, 1.28-1.62) than after FFTP (OR, 1.15; 95% CI, 1.06-1.26). The associationbetween OC use and breast cancer risk was greatest forparous women who used OCs 4 or more years before FFTP (OR,1.52; 95% CI, 1.26-1.82).CONCLUSION: Use of OCs is associated with an increased risk ofpremenopausal breast cancer, especially with use before FFTP inparous women.Mayo Clin Proc. 2006;81(10):1290-1302CI = confidence interval; FFTP = first full-term pregnancy; OC = oral contraceptive;OR = odds ratio
  • 146 Lancet. 2003 Apr 5;361(9364):1159-67.Cervical cancer and use of hormonal contraceptives: a systematic review.Smith JS, Green J, Berrington de Gonzalez A, Appleby P, Peto J, Plummer M, Franceschi S, Beral V.International Agency for Research on Cancer, Lyon, France.Comment in:Lancet. 2003 May 31;361(9372):1915. BACKGROUND: Human papillomavirus (HPV) is believed to be the most important cause of cervical cancer. Recent studies suggest that long duration use of oral contraceptives increases the risk of cervical cancer in HPV positive women. METHODS: Results from published studies were combined to examine the relationship between invasive and in situ cervical cancer and duration and recency of use of hormonal contraceptives, with particular attention to HPV infection. FINDINGS: 28 eligible studies were identified, together including 12531 women with cervical cancer. Compared with never users of oral contraceptives, the relative risks of cervical cancer increased with increasing duration of use: for durations of approximately less than 5 years, 5-9 years, and 10 or more years, respectively, the summary relative risks were 1.1 (95% CI 1.1-1.2), 1.6 (1.4-1.7), and 2.2 (1.9-2.4) for all women; and 0.9 (0.7-1.2), 1.3 (1.0-1.9), and 2.5 (1.6-3.9) for HPV positive women. The results were broadly similar for invasive and in situ cervical cancers, for squamous cell and adenocarcinoma, and in studies that adjusted for HPV status, number of sexual partners, cervical screening, smoking, or use of barrier contraceptives. The limited available data suggest that the relative risk of cervical cancer may decrease after use of oral contraceptives ceases. However, study designs varied and there was some heterogeneity between study results. INTERPRETATION: Although long duration use of hormonal contraceptives is associated with an increased risk of cervical cancer, the public health implications of these findings depend largely on the extent to which the observed associations remain long after use of hormonal contraceptives has ceased, and this cannot be evaluated properly from published data.147 Contraception. 2004 May;69(5):347-51.Oral contraceptives and cervical cancer: critique of a recent review.Miller K, Blumenthal P, Blanchard K.Ibis Reproductive Health, 2 Brattle Square, Cambridge, MA 02138, USA. kmiller@ibisreproductivehealth.orgA recent review article by Smith et al. in The Lancet purports to find a causal relationship between long-term use of oral contraceptives (OCs) and cervical cancer. While we endorse the search for such a relationship, we felt it important to critically examine Smith et al.'s review process and, as a result, we have questions about the validity of their conclusions. In our view, the findings of published articles as presented by Smith et al. do not confirm a causal connection between long-term use of OCs and cervical cancer. Our goal is not to conduct another formal review of the evidence, but to evaluate whether Smith et al. have met the burden of proof for establishing a causal relationship. Given the importance of OCs to women the world over, we urge reproductive health professionals to consider this issue carefully before accepting that a causal relationship exists.PMID: 15105055 [PubMed - indexed for MEDLINE]
  • 146 Lancet. 2003 Apr 5;361(9364):1159-67.Cervical cancer and use of hormonal contraceptives: a systematic review.Smith JS, Green J, Berrington de Gonzalez A, Appleby P, Peto J, Plummer M, Franceschi S, Beral V.International Agency for Research on Cancer, Lyon, France.Comment in:Lancet. 2003 May 31;361(9372):1915. BACKGROUND: Human papillomavirus (HPV) is believed to be the most important cause of cervical cancer. Recent studies suggest that long duration use of oral contraceptives increases the risk of cervical cancer in HPV positive women. METHODS: Results from published studies were combined to examine the relationship between invasive and in situ cervical cancer and duration and recency of use of hormonal contraceptives, with particular attention to HPV infection. FINDINGS: 28 eligible studies were identified, together including 12531 women with cervical cancer. Compared with never users of oral contraceptives, the relative risks of cervical cancer increased with increasing duration of use: for durations of approximately less than 5 years, 5-9 years, and 10 or more years, respectively, the summary relative risks were 1.1 (95% CI 1.1-1.2), 1.6 (1.4-1.7), and 2.2 (1.9-2.4) for all women; and 0.9 (0.7-1.2), 1.3 (1.0-1.9), and 2.5 (1.6-3.9) for HPV positive women. The results were broadly similar for invasive and in situ cervical cancers, for squamous cell and adenocarcinoma, and in studies that adjusted for HPV status, number of sexual partners, cervical screening, smoking, or use of barrier contraceptives. The limited available data suggest that the relative risk of cervical cancer may decrease after use of oral contraceptives ceases. However, study designs varied and there was some heterogeneity between study results. INTERPRETATION: Although long duration use of hormonal contraceptives is associated with an increased risk of cervical cancer, the public health implications of these findings depend largely on the extent to which the observed associations remain long after use of hormonal contraceptives has ceased, and this cannot be evaluated properly from published data.147 Contraception. 2004 May;69(5):347-51.Oral contraceptives and cervical cancer: critique of a recent review.Miller K, Blumenthal P, Blanchard K.Ibis Reproductive Health, 2 Brattle Square, Cambridge, MA 02138, USA. kmiller@ibisreproductivehealth.orgA recent review article by Smith et al. in The Lancet purports to find a causal relationship between long-term use of oral contraceptives (OCs) and cervical cancer. While we endorse the search for such a relationship, we felt it important to critically examine Smith et al.'s review process and, as a result, we have questions about the validity of their conclusions. In our view, the findings of published articles as presented by Smith et al. do not confirm a causal connection between long-term use of OCs and cervical cancer. Our goal is not to conduct another formal review of the evidence, but to evaluate whether Smith et al. have met the burden of proof for establishing a causal relationship. Given the importance of OCs to women the world over, we urge reproductive health professionals to consider this issue carefully before accepting that a causal relationship exists.PMID: 15105055 [PubMed - indexed for MEDLINE]
  • 146 Lancet. 2003 Apr 5;361(9364):1159-67.Cervical cancer and use of hormonal contraceptives: a systematic review.Smith JS, Green J, Berrington de Gonzalez A, Appleby P, Peto J, Plummer M, Franceschi S, Beral V.International Agency for Research on Cancer, Lyon, France.Comment in:Lancet. 2003 May 31;361(9372):1915. BACKGROUND: Human papillomavirus (HPV) is believed to be the most important cause of cervical cancer. Recent studies suggest that long duration use of oral contraceptives increases the risk of cervical cancer in HPV positive women. METHODS: Results from published studies were combined to examine the relationship between invasive and in situ cervical cancer and duration and recency of use of hormonal contraceptives, with particular attention to HPV infection. FINDINGS: 28 eligible studies were identified, together including 12531 women with cervical cancer. Compared with never users of oral contraceptives, the relative risks of cervical cancer increased with increasing duration of use: for durations of approximately less than 5 years, 5-9 years, and 10 or more years, respectively, the summary relative risks were 1.1 (95% CI 1.1-1.2), 1.6 (1.4-1.7), and 2.2 (1.9-2.4) for all women; and 0.9 (0.7-1.2), 1.3 (1.0-1.9), and 2.5 (1.6-3.9) for HPV positive women. The results were broadly similar for invasive and in situ cervical cancers, for squamous cell and adenocarcinoma, and in studies that adjusted for HPV status, number of sexual partners, cervical screening, smoking, or use of barrier contraceptives. The limited available data suggest that the relative risk of cervical cancer may decrease after use of oral contraceptives ceases. However, study designs varied and there was some heterogeneity between study results. INTERPRETATION: Although long duration use of hormonal contraceptives is associated with an increased risk of cervical cancer, the public health implications of these findings depend largely on the extent to which the observed associations remain long after use of hormonal contraceptives has ceased, and this cannot be evaluated properly from published data.147 Contraception. 2004 May;69(5):347-51.Oral contraceptives and cervical cancer: critique of a recent review.Miller K, Blumenthal P, Blanchard K.Ibis Reproductive Health, 2 Brattle Square, Cambridge, MA 02138, USA. kmiller@ibisreproductivehealth.orgA recent review article by Smith et al. in The Lancet purports to find a causal relationship between long-term use of oral contraceptives (OCs) and cervical cancer. While we endorse the search for such a relationship, we felt it important to critically examine Smith et al.'s review process and, as a result, we have questions about the validity of their conclusions. In our view, the findings of published articles as presented by Smith et al. do not confirm a causal connection between long-term use of OCs and cervical cancer. Our goal is not to conduct another formal review of the evidence, but to evaluate whether Smith et al. have met the burden of proof for establishing a causal relationship. Given the importance of OCs to women the world over, we urge reproductive health professionals to consider this issue carefully before accepting that a causal relationship exists.PMID: 15105055 [PubMed - indexed for MEDLINE]
  • Lancet. 2007 Nov 10;370(9599):1609-21.Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies.International Collaboration of Epidemiological Studies of Cervical Cancer, Appleby P, Beral V, Berrington de González A, Colin D, Franceschi S, Goodhill A, Green J, Peto J, Plummer M, Sweetland S.Cancer Research UK Epidemiology Unit, Oxford, UK.Comment in:Lancet. 2007 Nov 10;370(9599):1591-2. BACKGROUND: Combined oral contraceptives are classified by the International Agency for Research on Cancer as a cause of cervical cancer. As the incidence of cervical cancer increases with age, the public-health implications of this association depend largely on the persistence of effects long after use of oral contraceptives has ceased. Information from 24 studies worldwide is pooled here to investigate the association between cervical carcinoma and pattern of oral contraceptive use. METHODS: Individual data for 16,573 women with cervical cancer and 35,509 without cervical cancer were reanalysed centrally. Relative risks of cervical cancer were estimated by conditional logistic regression, stratifying by study, age, number of sexual partners, age at first intercourse, parity, smoking, and screening. FINDINGS: Among current users of oral contraceptives the risk of invasive cervical cancer increased with increasing duration of use (relative risk for 5 or more years' use versus never use, 1.90 [95% CI 1.69-2.13]). The risk declined after use ceased, and by 10 or more years had returned to that of never users. A similar pattern of risk was seen both for invasive and in-situ cancer, and in women who tested positive for high-risk human papillomavirus. Relative risk did not vary substantially between women with different characteristics. INTERPRETATION: The relative risk of cervical cancer is increased in current users of oral contraceptives and declines after use ceases. 10 years' use of oral contraceptives from around age 20 to 30 years is estimated to increase the cumulative incidence of invasive cervical cancer by age 50 from 7.3 to 8.3 per 1000 in less developed countries and from 3.8 to 4.5 per 1000 in more developed countries.
  • BMJ. 2007 Sep 29;335(7621):651. Epub 2007 Sep 11.Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioner's oral contraception study.Hannaford PC, Selvaraj S, Elliott AM, Angus V, Iversen L, Lee AJ.Department of General Practice and Primary Care, University of Aberdeen, Aberdeen AB25 2AY. p.hannaford@abdn.ac.ukComment in:J FamPract. 2008 Feb;57(2):83. BMJ. 2008 Jan 12;336(7635):59-60; author reply 60. BMJ. 2007 Sep 29;335(7621):621-2. Natl Med J India. 2008 Sep-Oct;21(5):234-5. OBJECTIVE: To examine the absolute risks or benefits on cancer associated with oral contraception, using incident data. DESIGN: Inception cohort study. SETTING: Royal College of General Practitioners' oral contraception study. PARTICIPANTS: Directly standardised data from the Royal College of General Practitioners' oral contraception study. MAIN OUTCOME MEASURES: Adjusted relative risks between never and ever users of oral contraceptives for different types of cancer, main gynaecological cancers combined, and any cancer. Standardisation variables were age, smoking, parity, social class, and (for the general practitioner observation dataset) hormone replacement therapy. Subgroup analyses examined whether the relative risks changed with user characteristics, duration of oral contraception usage, and time since last use of oral contraception. RESULTS: The main dataset contained about 339,000 woman years of observation for never users and 744,000 woman years for ever users. Compared with never users ever users had statistically significant lower rates of cancers of the large bowel or rectum, uterine body, and ovaries, tumours of unknown site, and other malignancies; main gynaecological cancers combined; and any cancer. The relative risk for any cancer in the smaller general practitioner observation dataset was not significantly reduced. Statistically significant trends of increasing risk of cervical and central nervous system or pituitary cancer, and decreasing risk of uterine body and ovarian malignancies, were seen with increasing duration of oral contraceptive use. Reduced relative risk estimates were observed for ovarian and uterine body cancer many years after stopping oral contraception, although some were not statistically significant. The estimated absolute rate reduction of any cancer among ever users was 45 or 10 per 100,000 woman years, depending on whether the main or general practitioner observation dataset was used. CONCLUSION: In this UK cohort, oral contraception was not associated with an overall increased risk of cancer; indeed it may even produce a net public health gain. The balance of cancer risks and benefits, however, may vary internationally, depending on patterns of oral contraception usage and the incidence of different cancers.
  • 158 Contraception. 1997 Nov;56(5):275-84.Oral contraceptives and liver cancer. Results of the Multicentre International Liver Tumor Study (MILTS).[No authors listed]Many, but not all, previous epidemiological studies indicated a greater risk of hepatocellular cancer (HCC) in women who have used combined oral contraceptives for a long period of time, but no one has analyzed this risk based upon use of different formulations. It was decided to analyze specifically the risk of OC containing cyproterone acetate (CPA) after toxicological experiments in animals found hints for a potential genotoxicity. This report describes the risk associated with ever having used combined oral contraceptives (OC) among 317 cases of primary hepatocellular cancer (HCC) in women under age 65, compared with 1060 age-matched hospital and 719 population controls in a case-control study, which was conducted in six European countries. The adjusted odds ratio (unconditional logistic regression) for ever having used any OC was found to be 0.75 (0.54 to 1.03) when all cases were compared with all controls, and compared to hospital and population controls separately: 1.13 (0.86 to 1.48) and 0.78 (0.59 to 1.03), respectively. The adjusted odds ratios for OC containing all progestins of the CPA group were 0.89 (0.49 to 1.61); and 0.89 (0.37 to 2.18) for OC containing only CPA. There was no increase in risk for HCC with increasing duration of OC use among the different groups of OCs in the total group of cases with pooled controls. The risk estimates were not related to time since first or last use of any of the types of OCs considered. The most important risk factors for HCC were confirmed as a prior history of hepatitis B and C (adjusted odds ratio 3.1 (2.2; 4.3) and 37.9 (20.2; 70.9) for HBV and HCV, respectively). In the small subgroup of HCC cases without liver cirrhosis and with negative serology for HBV and HCV, there was evidence of an association with duration of OC use. No such trend was observed for the CPA group of OCs. Altogether, there is no evidence for an increased risk of HCC associated with CPA or CPA-like OCs. Oral contraceptives in the aggregate may enhance the risk of liver carcinomas not associated with HBV or HCV infection, but if so, this is an extremely rare adverse effect of their use.
  • 160 Am J Obstet Gynecol. 1990 Oct;163(4 Pt 1):1120-3.Contraception and ectopic pregnancy risk.Franks AL, Beral V, Cates W Jr, Hogue CJ.Division of Reproductive Health, Centers for Disease Control, Atlanta, GA 30333.Comment in:Am J Obstet Gynecol. 1991 Dec;165(6 Pt 1):1900. Studies of the association of ectopic pregnancy with contraception have generated a conflicting array of results because of methodologic differences between studies. We estimated the absolute incidence rates of ectopic pregnancy for various contraceptives by multiplying the pregnancy rate by the proportion of pregnancies with ectopic implantation for each method. Our results indicated a more than 500-fold difference in ectopic pregnancy incidence, from a low of 0.005 ectopic pregnancies per 1000 women years of oral contraception or vasectomy to a high of 2.6 per 1000 women years of no contraception. These estimated incidence rates should be useful for clinicians and patients seeking to better understand the risks and benefits of contraceptives.PIP: Studies of the association of ectopic pregnancy with contraception have generated a conflicting array of results because of methodological differences between studies. We believed that absolute rates of occurrence are useful in clinical decision-making for expressing risks of disease. We estimated the absolute incidence rates of ectopic pregnancy for various contraceptives by multiplying the pregnancy rate by the proportion of pregnancies with ectopic implantation for each method. It is assumed that no differences exist in the proportion of ectopic pregnancies among women using combination oral contraceptives, women using barrier methods, women whose partners had vasectomies, and women using no contraception. It was also assumed that the ectopic pregnancy rate is the product of the pregnancy rate and the likelihood of ectopic implantation. Our results indicated a more than 500-fold difference in ectopic pregnancy incidence, from a low of 0.005 ectopic pregnancies/1000 women years of oral contraception or vasectomy to a high of 2.6/1000 women years include 0.100 for condoms, 0.150 for diaphragms, 0.318 for tubal sterilization, and 1.020 for IUDs. These estimated incidence rates should be useful for clinicians and patients seeking to better understand the risks and benefits of contraceptives. (author's modified).179 J Am AcadDermatol. 1997 May;36(5 Pt 1):705-10.Oral contraceptive failure rates and oral antibiotics.Helms SE, Bredle DL, Zajic J, Jarjoura D, Brodell RT, Krishnarao I.Department of Internal Medicine, Northeastern Ohio Universities College of Medicine, USA.BACKGROUND: Despite anecdotal evidence of a possibility of decreased effectiveness of oral contraceptives (OCs) with some antibiotics, it is not known whether antibiotic use in dermatologic practices engenders any increased risk of accidental pregnancy. OBJECTIVE: Our purpose was to examine the effect of commonly prescribed oral antibiotics (tetracyclines, penicillins, cephalosporins) on the failure rate of OCs. METHODS: The records from three dermatology practices were reviewed, and 356 patients with a history of combined oral antibiotic/OC use were surveyed retrospectively. Of these patients, 263 also provided "control" data (during the times they used OCs alone). An additional 162 patients provided control data only. RESULTS: Five pregnancies occurred in 311 woman-years of combined antibiotic/OC exposure (1.6% per year failure rate) compared with 12 pregnancies in 1245 woman-years of exposure (0.96% per year) for the 425 control patients. This difference was not significant (p = 0.4), and the 95% confidence interval on the difference (-0.81, 2.1) ruled out a substantial difference (> 2.1% per year). There was also no significant difference between OC failure rates for the women who provided data under both conditions, nor between the two control groups. All our data groups had failure rates below the 3% or higher per year, which are typically found in the United States. CONCLUSION: The difference in failure rates of OCs when taken concurrently with antibiotics commonly used in dermatology versus OC use alone suggests that these antibiotics do not increase the risk of pregnancy. Physicians and patients need to recognize that the expected OC failure rate, regardless of antibiotic use, is at least 1% per year and it is not yet possible to predict in whom OCs may fail.PIP: Although some antibiotics are assumed to compromise the effectiveness of oral contraceptives (OCs), it is unknown whether the antibiotics used in dermatologic practice are associated with such a risk. To address this issue, a review was conducted in three US dermatologic practices of the records of 356 patients with a history of combined oral antibiotic/OC use in 1990-95 who responded to a follow-up questionnaire. 263 of these patients provided control data during the times they used OCs alone and an additional 162 patients were controls only. There were five pregnancies in 311 woman-years of combined antibiotic/OC exposure (1.6% annual failure rate) compared with 12 pregnancies in 1245 woman-years of exposure among controls (0.96% annual failure rate)--a nonsignificant difference. In addition, there were no significant differences between OC failure rates among women who served as both cases and controls or between the two control groups. All five cases who became pregnant had been taking an antibiotic (microcycline or a cephalosporin) for at least 3 months. Side effects potentially linked to reduced OC effectiveness (e.g., diarrhea, breakthrough menstrual bleeding) were not reported by the women who became pregnant. It is presumed that inter-individual differences in steroid plasma levels are a more important cause of OC failure than concomitant antibiotic therapy.Obstet Gynecol. 2001 Nov;98(5 Pt 1):853-60.Drug interactions between oral contraceptives and antibiotics.Dickinson BD, Altman RD, Nielsen NH, Sterling ML; Council on Scientific Affairs, American Medical Association.Council on Scientific Affairs, American Medical Association, Chicago, Illinois 60610, USA. barry_dickinson@ama-assn.orgComment in:Obstet Gynecol. 2002 May;99(5 Pt 1):841-2; author reply 842. OBJECTIVE: To evaluate the evidence on possible drug interactions between antibiotics and oral contraceptives (OCs) that may lead to OC failure. DATA SOURCES: MEDLINE and Lexis/Nexis Medical Library searches for 1966-1999 using the key word "oral contraceptives," cross-indexed with the terms "antibiotics," "adverse effects," and "pregnancy," and MEDLINE search using the additional MeSH term "drug interactions." No language restrictions were used. METHODS OF STUDY SELECTION: A total of 167 articles were retrieved for analysis. Another 32 articles were identified by review of the references cited in these publications. Articles were selected based on their ability to provide information on the relationship between antibiotic therapy and OC efficacy in otherwise compliant users (defined as women with unplanned pregnancies who reported compliance with their OC regimen). Additionally, studies that either directly measured the effects of antibiotics on the pharmacokinetics of OC components, or that analyzed the effects of antibiotics on measures of ovulation in OC users were accepted. TABULATION, INTEGRATION, AND RESULTS: At least 30 cases have been reported of pregnancies occurring in women taking OCs and antibiotics, particularly rifampin. Approximately 20% of pregnant women reporting to family planning or abortion clinics reported concomitant OC and antibiotic use. Information from adverse event reporting databases generally mirrors the types of information gleaned from these case reports and clinical surveys and accounts for approximately one-third of reported cases. Retrospective surveys, primarily from dermatology-based practices, also have reported 24 pregnancies in OC users who concomitantly received therapy with antibiotics, most commonly tetracyclines and penicillins. Apparent OC failure rates in clinical surveys were within the usual range expected for patterns of typical use. In pooled results obtained from relatively small populations, oral antibiotics, with the exception of rifampin, have not significantly affected the pharmacokinetics of ethinylestradiol, levonorgestrel, and norethindrone or reduced the serum concentrations of gonadotropins. However, individual patients have been identified who experienced significant decreases in the plasma concentration of these components of OCs and who appeared to ovulate. CONCLUSION: Rifampin impairs the effectiveness of OCs. Pharmacokinetic studies of other antibiotics have not shown any systematic interaction between antibiotics and OC steroids. However, individual patients do show large decreases in the plasma concentrations of ethinylestradiol when they take certain other antibiotics, notably tetracycline and penicillin derivatives. Because it is not possible to identify these women in advance, a cautious approach is advised.
  • 14 Int J Cancer. 2003 Jun 20;105(3):390-3.Effect of lifetime lactation on breast cancer risk: a Korean women's cohort study.Lee SY, Kim MT, Kim SW, Song MS, Yoon SJ.Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. solee@jhsph.eduThe objective of our study was to examine the effect of lifetime lactation on breast cancer risk among premenopausal women. The data were from a prospective cohort study with a follow-up period of 6 years in Korea (1995-2000). The cohort was composed of 110,604 premenopausal parous Korean women, aged 20 years and older, who received health insurance from the Korea Medical Insurance Corporation and who had medical evaluations in 1992 and 1994. Multivariate Cox proportional hazard models were tested, controlling for age, age at menarche, number of children, age at first pregnancy, oral contraceptive use, smoking, exercise and obesity. At baseline, 57,440 (51.9%) reported breastfeeding and 4,584 (4.1%) reported breastfeeding more than 24 months. From 1995-2000, 360 incident cases of breast cancer (61.8/100,000 person-years) occurred. Compared to parous women who had no history of lactation, a period of lactation of 13-24 months decreased the risk of breast cancer (RR, 0.7; 95% CI, 0.5-1.1), and this risk was decreased even further for those who breastfed for more than 24 months (RR, 0.6; 95% CI, 0.3-1.0). There was a clear trend of decreasing breast cancer risk with the duration of lactation (p for trend <0.001). In conclusion, our study of a large Korean cohort provides additional empirical evidence to current theoretical conjecture that lactation decreases the risk of breast cancer among premenopausal women. Copyright 2003 Wiley-Liss, Inc.
  • 14 Int J Cancer. 2003 Jun 20;105(3):390-3.Effect of lifetime lactation on breast cancer risk: a Korean women's cohort study.Lee SY, Kim MT, Kim SW, Song MS, Yoon SJ.Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA. solee@jhsph.eduThe objective of our study was to examine the effect of lifetime lactation on breast cancer risk among premenopausal women. The data were from a prospective cohort study with a follow-up period of 6 years in Korea (1995-2000). The cohort was composed of 110,604 premenopausal parous Korean women, aged 20 years and older, who received health insurance from the Korea Medical Insurance Corporation and who had medical evaluations in 1992 and 1994. Multivariate Cox proportional hazard models were tested, controlling for age, age at menarche, number of children, age at first pregnancy, oral contraceptive use, smoking, exercise and obesity. At baseline, 57,440 (51.9%) reported breastfeeding and 4,584 (4.1%) reported breastfeeding more than 24 months. From 1995-2000, 360 incident cases of breast cancer (61.8/100,000 person-years) occurred. Compared to parous women who had no history of lactation, a period of lactation of 13-24 months decreased the risk of breast cancer (RR, 0.7; 95% CI, 0.5-1.1), and this risk was decreased even further for those who breastfed for more than 24 months (RR, 0.6; 95% CI, 0.3-1.0). There was a clear trend of decreasing breast cancer risk with the duration of lactation (p for trend <0.001). In conclusion, our study of a large Korean cohort provides additional empirical evidence to current theoretical conjecture that lactation decreases the risk of breast cancer among premenopausal women. Copyright 2003 Wiley-Liss, Inc.
  • Arch Intern Med. 2009 Aug 10;169(15):1364-71.Lactation and incidence of premenopausal breast cancer: a longitudinal study.Stuebe AM, Willett WC, Xue F, Michels KB.Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, School of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. astuebe@med.unc.eduBACKGROUND: Findings from observational studies suggest an inverse association between lactation and premenopausal breast cancer risk, but results are inconsistent, and data from large prospective cohort studies are lacking. METHODS: We used information from 60,075 parous women participating in the prospective cohort study of the Nurses' Health Study II from 1997 to 2005. Our primary outcome was incident premenopausal breast cancer. RESULTS: We ascertained 608 incident cases of premenopausal breast cancer during 357,556 person-years of follow-up. Women who had ever breastfed had a covariate-adjusted hazard ratio (HR) of 0.75 (95% confidence interval [CI], 0.56-1.00) for premenopausal breast cancer compared with women who had never breastfed. No linear trend was found with duration of total lactation (P = .95), exclusive lactation (P = .74), or lactation amenorrhea (P = .88). The association between lactation and premenopausal breast cancer was modified by family history of breast cancer (P value for interaction = .03). Among women with a first-degree relative with breast cancer, those who had ever breastfed had a covariate-adjusted HR of 0.41 (95% CI, 0.22-0.75) for premenopausal breast cancer compared with women who had never breastfed, whereas no association was observed among women without a family history of breast cancer. CONCLUSION: In this large, prospective cohort study of parous premenopausal women, having ever breastfed was inversely associated with incidence of breast cancer among women with a family history of breast cancer.
  • Arch Intern Med. 2009 Aug 10;169(15):1364-71.Lactation and incidence of premenopausal breast cancer: a longitudinal study.Stuebe AM, Willett WC, Xue F, Michels KB.Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, School of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. astuebe@med.unc.eduBACKGROUND: Findings from observational studies suggest an inverse association between lactation and premenopausal breast cancer risk, but results are inconsistent, and data from large prospective cohort studies are lacking. METHODS: We used information from 60,075 parous women participating in the prospective cohort study of the Nurses' Health Study II from 1997 to 2005. Our primary outcome was incident premenopausal breast cancer. RESULTS: We ascertained 608 incident cases of premenopausal breast cancer during 357,556 person-years of follow-up. Women who had ever breastfed had a covariate-adjusted hazard ratio (HR) of 0.75 (95% confidence interval [CI], 0.56-1.00) for premenopausal breast cancer compared with women who had never breastfed. No linear trend was found with duration of total lactation (P = .95), exclusive lactation (P = .74), or lactation amenorrhea (P = .88). The association between lactation and premenopausal breast cancer was modified by family history of breast cancer (P value for interaction = .03). Among women with a first-degree relative with breast cancer, those who had ever breastfed had a covariate-adjusted HR of 0.41 (95% CI, 0.22-0.75) for premenopausal breast cancer compared with women who had never breastfed, whereas no association was observed among women without a family history of breast cancer. CONCLUSION: In this large, prospective cohort study of parous premenopausal women, having ever breastfed was inversely associated with incidence of breast cancer among women with a family history of breast cancer.
  • N Engl J Med. 1975 Sep 18;293(12):573-5.Spontaneous abortion and aging of human ova and spermatozoa.Guerrero R, Rojas OI.To test the hypothesis that aging of human gametes within the genital tract increases the chance of abortion, we measured the probabilities of abortion after insemination on a given day of the menstrual cycle in relation to the day of the shift in the basal body temperature in 965 patients. Cases came from family-planning and sterility clinics where basal body temperature and coital records are kept routinely. The probability of abortion diminished significantly (P less than 0.001) as the shift in temperature was approached and the increased to its highest point (24 per cent) three days later. Animal experiments have shown that aging of both spermatozoa and ova before fertilization is accompanied by higher probabilities of abortion. Present evidence indicates that this higher prevalence is also true for human beings.PIP: The basal body temperature in 965 patients were subject to analysis with coital records in order to determine the probability of abortion after insemination on a given day of the menstrual cycle in relation to the shift in basal body temperature. Coital records were examined to assign a responsible insemination, and basal body temperature charts examined to determine a thermal shift. There were 890 term deliveries and 75 spontaneous abortions. The overall probability of abortion was 7 .8%. The lowest corresponded to Day -2 (3.2%) and the highest to Day +3 (24%). The probability of abortion diminished significantly (P less than .001) as the shift in temperature was approached and then increased to its highest point 3 days later. These results strongly suggest that aging of human spermatozoa in the female genital tract is associated with an increased frequency of spontaneous abortions.
  • Contraception. 1994 Mar;49(3):211-22.Breast cancer and depot-medroxyprogesterone acetate: a review.Chilvers C.Department of Public Health Medicine and Epidemiology, University of Nottingham Medical School, Queen's Medical Centre, United Kingdom.Depot-medroxyprogesterone acetate (DMPA) has been used world-wide since 1964 as a contraceptive in spite of the fact that it was only in 1992 licensed for contraceptive use in the USA due to concern about a possible breast cancer risk. Two recent studies have considered DMPA use and risk of breast cancer and these and earlier studies are reviewed here. Overall, the results are reassuring but there is some evidence that breast cancer risk may be increased in women using DMPA when very young and particularly in recent users. Current knowledge of the biology of human breast cancer is such that it is difficult to judge the biological plausibility of this evidence. There is no doubt that DMPA is a highly effective form of contraception and any overall assessment must take into account all the relevant risks and benefits. Thus, the risk-benefit equations in developed and developing countries must allow for different levels of maternal mortality and morbidity, as well as differing underlying cancer rates.Display Settings:AbstractFormatSummarySummary (text)AbstractAbstract (text)MEDLINEXMLPMID ListApplySendto:ChooseDestinationFileClipboardCollectionsE-mailOrderFormatSummary (text)Abstract (text)MEDLINEXMLPMID ListCreate File1 selected item: 1681212FormatSummarySummary (text)AbstractAbstract (text)MEDLINEXMLPMID ListE-mailAdditional textE-mail"SPAM" filtering software noticeAdd to ClipboardAdd to CollectionsOrder articlesLancet. 1991 Oct 5;338(8771):833-8.Breast cancer and depot-medroxyprogesterone acetate: a multinational study. WHO Collaborative Study of Neoplasia and Steroid Contraceptives.[No authors listed]Comment in:Lancet. 1991 Oct 12;338(8772):942. Lancet. 1991 Oct 5;338(8771):856-7. AbstractTo determine whether the long-acting injectableprogestational contraceptive DMPA, depot-medroxyprogesterone acetate, alters the risk of breast cancer in women, a hospital-based case-control study was conducted in five participating hospitals in Nairobi, Kenya, Mexico City, Mexico, Bangkok, Thailand (two hospitals), and Chiang Mai, Thailand. 869 women with newly diagnosed breast cancer who were young enough to have used DMPA for contraception, and 11,890 women of similar age who had been admitted to hospital for conditions unrelated to steroid contraceptive use, were interviewed to obtain information about previous use of steroid contraceptives and suspected risk factors for breast cancer. DMPA had been used by 12.5% of cases and 12.2% of controls. Relative risk (95% Cl) in women who had ever used DMPA was 1.21 (0.96, 1.52). Risk was increased within the first 4 years of initial exposure, mainly in women under 35 years. This observation did not seem to result from selective surveillance for breast cancer in DMPA users. Risk did not increase with duration of use, and was not increased in women who had started to use DMPA more than 5 years previously. These results provide reassurance that women who have used DMPA for a long time and who initiated use many years previously are not at increased risk of breast cancer.PMID: 1681212 [PubMed - indexed for MEDLINE]
  • 216 Am J Obstet Gynecol. 2004 Apr;190(4 Suppl):S60-8.Male hormonal contraception.Wang C, Swerdloff RS.Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center and Research and Education Institute, Torrance, CA 90509, USA. wang@gcrc.rei.eduMale hormonal contraception, based on the suppression of both gonadotropins, follicle-stimulating hormone and luteinizing hormone, resulting in marked decrease in sperm production, is designed for couples in stable relationships where the male partner desires to assume family planning responsibilities using reversible methods. Two large scale, multicenter studies that used testosterone injections as the prototype male hormonal contraceptive demonstrated when azoospermia and/or very severe oligozoospermia were attained, contraceptive efficacy was equivalent to female hormonal methods. Current studies aim to find the androgen alone or androgen plus progestin preparations that are most efficacious, user friendly, and with least potential adverse effects. It is likely that injections or implants of androgens either alone or with progestins will become the first male hormonal contraceptive available within this decade. Further research and development include the use of selective androgen and/or progestin receptor modulators, nonpeptideGnRH antagonists, and agents with local actions on the testis for male contraception.PMID: 15105800 [PubMed - indexed for MEDLINE]219 Int J Androl. 1992 Oct;15(5):416-24.Residual sperm function in oligozoospermia induced by testosterone enanthate administered as a potential steroid male contraceptive.Wallace EM, Aitken RJ, Wu FC.MRC Reproductive Biology Unit, Centre for Reproductive Biology, Edinburgh, Scotland.To investigate the fertility of men who remain oligozoospermic despite sex steroid suppression, the in-vitro fertilizing capacity of residual spermatozoa was assessed in 30 men receiving intramuscular testosterone enanthate (TE). Spermatozoa were prepared by either Percoll or repetitive centrifugation/washing. Although the mean (+/- SEM) pretreatment zona-free hamster oocyte penetration (HOP) rates were similar (59.4 +/- 10.1 and 63.8 +/- 10.8%), following the induction of oligozoospermia the Percoll-prepared spermatozoa exhibited a penetration rate (26.9 +/- 10.2%) which was markedly greater than that obtained for sperm prepared by repetitive washing (0 +/- 0%). In addition, the partners of two men exhibiting a HOP test with Percoll-prepared spermatozoa, conceived despite a sperm concentration of 3 x 10(6) ml-1 and a negative HOP test with spermatozoa prepared by repetitive washing. These results suggest that Percoll preparation optimizes the assessment of in-vitro sperm function and that the fertility of men with TE-induced severe oligozoospermia is suppressed but not abolished.PMID: 1428200 [PubMed - indexed for MEDLINE]

Dr. r santos   evidence-based contraceptive methods Dr. r santos evidence-based contraceptive methods Presentation Transcript

  • CONTRACEPTIVE FACTS AND FAMILY PLANNING RONALDO R. SANTOS, MD, FPOGS Departments of Obstetrics and Gynecology, FEU-NRMF and JRRMMC MODULE 3 Updates on Family Planning Methods
  • Is sex important?  WHO reports: 42 B coitus/year  115 million/day: 250,000/day  4.8 million/hr: 10,000/day  1,331 ejaculations / sec: 2.8 
  • Contraceptive Prevalence Rate in the Phil. (2000 - 2008) 60 49.8 49.4 49.3 50.6 50.7 50 47 40 35.1 36 35.9 32.3 33 34 30 20 16.8 14.8 16.7 14.7 14.2 13.2 10 0 2000 2001 2004 2005 2006 2008 Total Modern Trad
  • Contraceptive Use according to methods in the Phil among women 15 - 45 years
  • Effectiveness
  • Outline of Presentation 1. Understand the new methods of contraception  New generation progestogens  Combined injectable contraception  Extended and continuous use oral contraceptives  Levonorgestrel intrauterine system  Single rod implant  Essure  Frameless IUD  Female condom  Emergency contraception
  • Outline of Presentation 2. Understand the mechanism of action of the IUD 3. Define the following relationships:  IUD and PID, Ectopic pregnancy  Hormonal contraception and breast, cervical and ovarian cancers  DMPA and breast cancer  LAM and breast cancer  Calendar method and abortion 4. Apply the WHO Medical Eligibility Criteria
  • References:  Vern L. Katz, MD, Gretchen M. Lentz, MD, Rogerio A. Lobo, MD and David M. Gershenson, MD, Comprehensive Gynecology 5th ed, Mosby, an affiliate of Elsevier Inc., Philadelphia, PA, 2007  Berek, Jonathan S. Berek & Novak's Gynecology, 14th Edition, Lippincott Williams & Wilkins, 2007  John O. Schorge, MD, Joseph I. Schaffer, MD, Lisa M. Halvorson, MD, Barbara L. Hoffman, MD, Karen D. Bradshaw, MD, F. Gary Cunningham, MD, Editors, Williams Gynecology, Williams Gynecology, The McGraw-Hill Companies, Inc, 2008  Family Planning: A global Handbook for Providers, WHO Department of Reproductive Health and Research, Johns Hopkins Bloomberg School of Public Health/Center for Communication Programs, 2007  WHO Medical Eligibility Criteria for contraception, 4th ed, 2009  Cunningham, Leveno, Bloom, Hauth, Rouse, Spong, eds, Williams Obstetrics 23rd ed, McGraw-Hill Companies, USA, 2010  The Philippine Clinical Standards Manual on Family Planning, Dept of Health, 2006
  • New Progestins: Notable characteristics  Dienogest: antiandrogenic  Drospirenone: antimineralocorticoid  Trimegestone: highly progestational  Nestorone: highly progestational and antigonadotrophic  Nomogestrol acetate: highly antigonadotrophic
  • Classification PROGESTERONE DERIVATED TESTOSTERONE DERIVATED 17-OH PROG 19-NORPROG ESTRANE GONANES PREGNANE NON-PREGNANE OHprogesterone Nomegestrol Lynestrenol Norgestrel caproate acetate OHprogesterone Demegestone Levonorgestrel Desogestrel heptanoate Gestonorone Promegestone Norethisterone Gestodene caproate Chlormadinone Nestorone Norethisterone Norgestimate acetate acetate Medrogestone Trimegestone Ethinodiol diacetate MPA Norgestrienone CPA Dienogest
  • Dienogest  Anti-androgenic: 40% potency of cyproterone acetate  As OCP with EE 30 ug: Pearl index of 0.2  Also used for HRT in combination with estradiol valerate
  • Drospirenone  Derived from spirolactone  Antimineralocorticoid  Competes with aldosterone receptors  30% potency of cyproterone acetate  Available as  Yasmin: 30 ug EE  Yasminelle: 20 ug EE  Yas: 20 ug EE x 24 days (2008) Indicated for PMDD
  • Trimegestone (TMG)  High progesterone receptor affinity  30x more potent than MPA  Used for HRT
  • Nomegestrol Acetate  20% potency of CPA  Component of HRT  Highly antigonadotrophic: can be use for inhibition of ovulation
  • Nestorone  Not active orally but in target tissues only  Used in sustained release implants, vaginal rings or transdermal systems  Highly antigonadotrophic
  • Progestogens: Relative potencies MPA Progestational activity Norgestimate TMG DSG NOMAc NET Drospirenone McPhail NES 100 > LNG 10 > Progesterone 1 index Ovulation NES 30 > LNG 10 > Progesterone 1 inhibition DSG MPA NET Drospirenone Norgestimate CPA Sitruk-Ware R. Menopause 9:6, 2002 Dienogest
  • Antiandrogenic potency CMA  Highest antiandrogen DRSP ic potency of CPA vs. DNG other progestagen CPA s 0 20 40 60 80 100 Relative antiandrogenic potency (Hershberger test) Muhn P. et al. Drospirenone: a novel progestogen with antimineralocorticoid and antiandrogenic activity. Contraception 1995; 51: 99-110 Stölzer W. et al. Tierexperimentelle Charakterisierung des Gestagens Dienogest (STS 557). II. Antigonadotrope, gestagene, estrogene und antiandrogene Wirkungen. III Jenaer Symposium zur hormonalen Kontrazeption, 1985
  • Continuous-Use Oral Contraceptives Seasonale  150 µg levonorgestrel and 30 µg ethinyl estradiol.  a pill every day for 84 days (12 weeks) and then take hormone- free pills for 7 days.
  • Lybrel: no menstruation pill  90 ug Levonorgestrel  20 ug ethinyl estradiol  365 days without pill- free interval
  • Extended use OCP  Goal: to prevent menstruation  Rationale: Amenorrhea leads to a reduction in: Premenstrual syndrome Dysmenorrhea
  • Combined Injectables  Monthly injection of Estrogen/Progestin:  less bleeding problems, better compliance  Earlier return to fertility  Cyclofem/Cyclo-Provera Feminena/Lunelle/Lunella: 5 mg estradiol and 25 mg MPA  Mesigyna/Norigynon: 5 mg estradiol and 50 mg Norethisterone enanthate  Norifam
  • rationale Negative effects in progestin injectables bleeding pattern disruption (Goldberg, 2007) return to fertility: 9 – 10 months (Schwallie 1974; Pardthaisong 1980; Kaunitz 2000) Regular cyclic endometrial shedding for combined estrogen – progesterone prep. (Kaunitz, 2000).
  • Composition: Norifam Estradiol valerate 5 mg Natural Less potent than ethinyl estradiol Norethisterone enanthate 50 mg o Available as Noristerat Indication: Contraception
  • Mechanism of Action: How does it prevent pregnancy  Inhibition of ovulation  Motility of the endometrium and fallopian tube is altered  Cervical mucus thickens preventing entry of sperms
  • Pharmacokinetics  Injected intramuscularly every month  Elevated estradiol levels for 7 – 11 days  Predominance of progesterone in the 2nd half of the cycle  Inhibits follicle maturation for 30 days  Inhibit ovulation and corpus luteum formation for 60 days Sang, Contraception, 1994 Apr;49(4):361-85.
  • Monthly Injectable (Lunelle)  MPA/E2C injection: 25 mg of medroxyprogesterone acetate and 5 mg of estradiol cypionate  Monthly intramuscular injection  Contraindications the same as oral contraceptive pills Kaunitz AM., Obstet Gynecol Clin North Am. 2000 Dec;27(4):741-80.
  • DMPA-SC  Lower dose: 104 mg  Subcutaneous injection every 3 months  Pre-filled Uniject syringe  Self administered
  • The NuvaRing  releases 120 µg of etonogestrel and 15 µg of ethinyl estradiol per day  1 ring every 3 weeks, 13 rings in a year  Pearl index of 0.65 (95% confidence interval 0.24-1.41)  32-40 US$  Nestorone 150 ug in one ring, x 3 wks, remove, reinserted, cycle repeated.  Can be removed for 3 hrs if bothersome during sex
  • Otho-Evra Patch  150 µg of the progestin norelgestromin and 20 µg of the estrogen ethinyl estradiol per day.  Weekly patch x 3 followed by patchless week  square patch, each side about 4.45 centimeters (1.75 inches) long, resembling a light brown bandage
  • Spray-On Contraceptives  Nestorone Metered Dose Transdermal System, a daily progestin-only spray-on contraceptive, began in Australia in 2004.  In a clinical trial a Nestorone gel applied to the skin daily for three months suppressed ovulation in 83% of participants applying 1.2 mg per day  Phase II studies
  • Implants  Levonorgestrel: Jadelle, 2 rods of 140 mg, 5 years effectiveness  Etonogestrel: Implanon, 1 rod, 3 years effectiveness  Nestorone: ST 1435, 1 rod, 2 years
  • Levonorgestrel - IUS  Levonorgestrel: 20 ug/day  5 years effective  Indicated for DUB  Some bleeding problems  Mirena, Femilis
  • Standard Days Method  Natural FP method  Color-coded beads: Cycle beads  Fertile period: 8 to 19 days  For women with cycles 26-32 days only  12/100 pregnancies
  • How to Use Day 1 Pre- ovulation (infertile) Post-ovulation (infertile) Fertile days (D8 –D19)
  • TwoDay method  Based on cervical secretions  Q1) “Did I notice secretions today?” and Q(2) “Did I notice secretions yesterday?  14/100 pregnancies
  • Emergency Contraception  Taken within 72 hours after unprotected intercourse  Plan B: 0.75 mg of levonorgestrel (postinor)  Yuzpe: 100 ug of EE and 1 mg norgestrel or 0.5 levonorgestrel taken 12 hours apart  IUD insertion  MOA: inhibition or delay of ovulation, alteration of the endometrium, sperm penetration, and tubal motility  Established pregnancies are not harmed.
  • Essure – Microcoil
  • FEMALE CONDOM
  • New Methods  Lower doses of Ethinyl Estradiol: safer  Newer Progestins: other non-contraceptive benefits  New routes of administration: compliance  New technology: effectiveness
  • ASSOCIATIONS AND RELATIONSHIPS
  • Mechanics:  5 groups of 5 members each  Identify your team with a innovative name for a new contraceptive  Objective: to earn points  Group earn points if they answer the questions correctly  The group with the highest points wins  Each member of the team can only answer a maximum of 2 questions  Decision of the judge is final  I am the judge
  • Relationships, Associations  IUD and:  Abortion  PID  Ectopic pregnancy  COC and:  VTE, MI and CVA  Breast, cervical and ovarian cancer  DMPA and Breast cancer  Calendar method and abortion
  • GROUPINGS
  • PRACTICE: HOW MANY DAYS BEFORE OVULATION CAN SEXUAL ABSTINENCE PREVENT PREGNANCY? A. 2 B. 3 C. 5 D. 7
  • Contraception: General  Because sperm may survive 5 to 7 days in the female genital tract, even a week's abstinence around the time of actual ovulation offers no guarantee against pregnancy  Ovulation can occur even in the absence of menstruation.  Pregnancies have occurred after a single act of coitus 7 days before apparent ovulation indicated by basal body temperature.
  • GRAPH, WHICH OF THE FOLLOWING COITAL POSITION IS ASSOCIATED WITH PRETERM DELIVER WITH PROM? A. FEMALE SUPERIOR B. MALE SUPERIOR C. SIDE BY SIDE D. REAR ENTRY
  • Risk of Preterm Delivery with PROM as to Coital Position ODD’S RATIO ACCORDING TO COITAL POSITION 4 3 2 1 0 FEMALE MALE SIDE BY SIDE REAR ENTRY ORGASM SUPERIOR SUPERIOR 51 Ekwo et al, ACOG 168:1, 1993
  • Clinical vs. Statistical Significance  STATISTICAL SIGNIFICANCE ◦ Hypothesis testing: expressed as probabilities or P value ◦ Confidence interval: expressed as a range of values  CLINICAL SIGNIFICANCE ◦ If RR = 1: no association ◦ If RR > 1: harm ◦ If RR < 1: protection
  • Relationship of Coitus to Pregnancy Outcome SEXUAL PRETERM TERM WITH PRETERM ACTIVITY DELIVERY WITH PROM DELIVERY PROM WITHOUT PROM FEMALE 1.50 (0.80-2.82) 0.88 (0.41-1.67) 1.08 (0.51-2.29) SUPERIOR MALE SUPERIOR 1.84 (1.05-3.22) 1.59 (0.93-2.71) 2.05 (1.20-3.50) SIDE BY SIDE 1.19 (0.71-1.98) 0.84 (0.48-1.36) 1.19 (0.71-2.01) REAR ENTRY 1.40 (0.72-2.72) 0.88 (0.43-1.79) 1.06 (0.55-2.01) ORGASM 1.91 (1.12-3.23) 1.12 (0.70-1.79) 0.93 (0.60-1.41) Ekwo et al, ACOG 168:1, 1993
  • IUD  It is approved for up to 10 years of continuous use.  The levonorgestrel T is approved in the United States for 5 years of use, although studies through 7 years of use show no loss of efficacy Sivin I, Stern J. Health during prolonged use of levonorgestrel 20 micrograms/d and the copper TCu 380A intrauterine contraceptive devices: a multicenter study. Fertil Steril 1994;61:70–77.)
  • 1. WHAT IS THE MAIN MECHANISM OF ACTION OF IUD AS A CONTRACEPTIVE METHOD? A.Prevents implantation B.Inhibits ovulation C.Impairs sperm and egg motility D.Thickens cervical mucus
  • Mechanism of Action:  Intrauterine devices cause the formation of biologic foam within the uterine cavity that contains strands of fibrin, phagocytic cells, and proteolytic enzymes.  Copper IUDs continuously release a small amount of the metal, producing an even greater inflammatory response.  All IUDs stimulate the formation of prostaglandins within the uterus, consistent with both smooth muscle contraction and inflammation.  Scanning electron microscopy studies of the endometrium of women wearing IUDs show alterations in the surface morphology of cells, especially of the microvilli of ciliated cells  There are major alterations in the composition of proteins within the uterine cavity, and new proteins and proteinase inhibitors are found in washings from the uterus  The altered intrauterine environment interferes with sperm passage
  • IUD and MOA  Sperm can be obtained by laparoscopy in washings from the fallopian tubes of control women at midcycle; fewer sperm are present in the tubal washings from women wearing IUDs (57Stanford JB, Mikolajczyk RT. Mechanism of action of the intrauterine device: update and estimation of post fertilization effect. Am J Obstet Gynecol 2002;187:1699- 1708).  Ova flushed from the tubes at tubal sterilization showed no evidence of fertilization in women wearing IUDs (58Alvarez F, Guiloff E, Brache V, et al. New insights on the mode of action of intrauterine devices in women. Fertil Steril 1989;49:768-773.  studies of serum β-human chorionic gonadotropin levels in women wearing IUDs do not indicate pregnancy (59Segal S, Alvarez-Sanchez F, Adejeuwon CA, et al. Absence of chorionic gonadotropin in sera of women who use intrauterine devices. Fertil Steril 1985;44:214-218).  The contraceptive effectiveness does not depend on interference with implantation, although this phenomenon also occurs and is the basis for using copper IUDs for emergency contraception.  The IUD is not an abortifacient.
  • New Insights on MOA of IUD No IUD IUD  115 women using no 60 contraception vs. 56 50 with IUDs for 40 surgical sterilization 30  Tubal flushings 48 20 and 120 hrs after midcycle LH peak 10 0 Ova Fertilized Alvarez F, et al, Fertil Steril. 1988 May;49(5):768-73.
  • STATEMENTS BEST DESCRIBE THE ASSOCIATION OF IUD AND PID? A. CURRENT IUD USE IS A RISK FACTOR FOR PID B. PID IS ASSOCIATED WITH IUD INSERTION C. IUD IS THE CAUSE FOR CHRONIC PID D. INCIDENCE OF PID IS DIRECTLY PROPORTIONAL TO DURATION OF IUD USE
  • IUD  Increased risk was detectable only within 4 months of insertion of the IUD.  A still larger, prospective World Health Organization study revealed that PID increased only during the first 20 days after insertion.  Thereafter, the rate of diagnosis of PID was about 1.6 cases per 1,000 women per year, the same as in the general population Farley TMM, Rosenberg MJ, Rowe PJ, et al. Intrauterine devices and pelvic inflammatory disease: an international perspective. Lancet 1992;339:785-788.
  • 3. IS IUD A RISK FACTOR FOR ECTOPIC PREGNANCY? A. No B. Yes, only if compared to other contraceptive methods C.Yes, only if compared to non- contraceptive user D.Yes, compared to other contraceptive methods and to non- contraceptive users
  • IUD  Ectopic Pregnancy: If pregnancy occurs in an IUD wearer, it will be ectopic in about 5% of cases. This is because the fallopian tubes are less well protected against pregnancy than is the uterus.  Compared with women using no contraception, however, women wearing either the copper T380A or the levonorgestrel T have an 80% to 90% reduction in the risk of ectopic pregnancy (53), which is a greater reduction than that seen for users of barrier methods.  Both the copper T 380A and the levonorgestrel T protect against ectopic pregnancy.
  • IUD and pregnancy  In case of pregnancy and the strings of the IUD are not visible, an ultrasound examination should be performed to localize the IUD and determine whether expulsion has occurred.  If the IUD is present, there are three options for management:  Therapeutic abortion  Ultrasound-guided intrauterine removal of the IUD  Continuation of the pregnancy with the device left in place  No recommendation on the time of insertion
  • Combined Oral Contraception  Typically, they are administered for 21 days beginning on the Sunday after a menstrual period, then discontinued for 7 days to allow for withdrawal bleeding that mimics the normal menstrual cycle.  Alternatively, OCs can be started on the first day of menstruation.  The 28-day version provides placebo tablets for the last 7 days of the cycle so the user simply takes one pill a day and starts a new pack as soon as the first pack is completed.
  • COC  Ovulation can be inhibited by estrogen or by progestin alone.  Pharmacologic synergism is exhibited when the two hormones are combined and ovulation is suppressed at a much lower dose of each agent.  Combination OCs, patches, and the NuvaRing suppress basal follicle-stimulating hormone FSH and LH. They diminish the ability of the pituitary gland to synthesize gonadotropins when it is stimulated by the hypothalamic GnRH (89).  Ovarian follicles do not mature, little estradiol is produced, and there is no midcycle LH surge. Ovulation does not occur, the corpus luteum does not form, and progesterone is not produced.  This blockade of ovulation is dose related.
  • 4. HOW CAN THE RISK OF VTE AMONG USERS OF COC BEST DESCRIBED? A. No clinical nor statistical risk B. Both Clinical and statistical risk C. Clinically significant risk only D. Statistically significant risk only
  • COC and thrombosis  The absolute risk of thrombosis in COC users taking pills containing 30 to 35 µg EE is 3 per 10,000 per year, compared with 1 per 10,000 reproductive-aged women not using OCs and 6 per 10,000 in pregnancy (106 Farmer RDT, Preston TD. The risk of venous thromboembolism associated with low oestrogen oral contraceptives. J Obstet Gynaecol 1995;15:195-200).  Thrombosis risk is apparent by 4 months after starting estrogen-containing OCs and does not increase further with continued use.  Risk is highest during the first year of use (107Sazelenko JK, Nace MC, Alving B. Women with thrombophilia: assessing the risks for thrombosis with oral contraceptives or hormone replacement therapy. Semin Thromb Hemost 1998;24(suppl 1):33–39.  ).
  • Hormonal Contraception and VTE  National Cohort Study in Denmark: 1995-2005  Full article available
  • Hormonal contraception and risk of venous thromboembolism: national follow-up study. Stud Healthy Danish women 15-49 years, from 1995-2005, 10.4 M woman – y years 7 VTE RISK RATIO / 10,000 WOMEN-YEARS 6.29 6 5 4 3.01 3 2 1 0 NON USERS OC USERS Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C., BMJ. 2009 Aug 13;339:b2890. doi: 10.1136/bmj.b2890. 71
  • Hormonal contraception and risk of venous thromboembolism: national follow-up study. Study Healthy Danish women 15-49 years, from 1995-2005, 10.4 M woman – years VTE RATE RATIO ACCDG TO DURATION OF USE IN YEARS 5 4 3 2 1 0 NON USER <1 1-4 >4 Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C., BMJ. 2009 Aug 13;339 72
  • Hormonal contraception and risk of venous thromboembolism: national follow-up study. Stud Healthy Danish women 15-49 years, from 1995-2005, 10.4 M woman – y years VTE RATE RATIO ACCDG TO TYPE OF PROGESTINS 3 2 1 0 LEVO NORETH NORGE DESO GST DRSP CPA Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C., BMJ. 2009 Aug 13;339 73
  • MEGA: Venous thromboembolism increased with OC use irrespective of progestin type Study 1524 Premenopausal women <50 years old vs 1760 controls Risk (OR, 95% CI) of VTE associated with type of progestogen in combined OCs 25 20 15 10 5 3.6 5.6 7.3 5.6 3.9 6.8 5.9 6.3 0 Levonorgestrel Gestodene Desogestrel Lynestrenol Norethisterone Cyproterone Norgestimate Drospirenone MEGA study: multiple environmental and genetic assessment of risk factors for venous thrombosis-study. van Hylckama Vlieg A, et al. BMJ. 2009 Aug 13;339:b2921. doi:0.1136/bmj.b2921. 74
  • Risk of venous thromboembolism* by population characteristics Non-OC users 8 OC users 35 Pregnant women 60 OC users with Factor V Leiden 230 0 50 100 150 200 250 300 350 400 Estimated average risk/100,000 women/year *Cases of non-fatal venous thromboembolism. FDA. FDA Talk Paper. 1995. Ridker PM, et al. JAMA. 1997 Apr 23-30;277(16):1305-7. 75
  • Prevalence in Asian women of Factor V Leiden mutation is low Study of the ethnic distribution of Factor V Leiden mutation in 4047 men and women Prevalence of Factor V Leiden mutation, % Native Americans 1.25 Hispanics 2.21 Asians 0.45 Blacks 1.23 White 4.85 0 1 2 3 4 5 6 Ridker PM, et al. J Am Med Assoc 1997;277:1305–7. 76
  • 4. WHICH OF THE FOLLOWING CONDITIONS HAS THE GREATEST ATTRIBUTABLE RISK TO AN ISCHEMIC CARDIOVASCULAR EVENT AMONG OCP USERS? A. Age > 35 but < 50 B. Controlled hypertension C. BMI > 30 D. 25 sticks of cigarettes/day
  • COC and Vascular events  Past use of OCs does not increase risk for subsequent myocardial infarction (123Stampfer MJ, Willett WC, Colditz GA, et al. A prospective study of past use of oral contraceptive agents and risk of cardiovascular diseases. N Engl J Med 1988;319:1313-1317.  Smokers taking OCs had seven times the risk of ischemic (thrombotic) stroke when compared with smokers who did not use OCs, and hypertensive women had 10-fold increased risk if they took OCs, but a fivefold risk if they did not (129World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ischaemic stroke and combined oral contraceptives: results of an international, multicenter, case control study. Lancet 1996;348:505- 510).
  • COC and MI  After adjusting for age, illness, smoking, ethnicity, and body mass index, risk for myocardial infarction was not increased by OC use (OR, 1.14; CI 95%, 0.27 to 4.72).  Of heart attack victims, 61% smoked; only 7.7% were current users of OCs.  In a later study, the same investigators pooled results from the California study with a similar study from Washington State.  The results were the same. Current users of low-dose OCs had no increased risk for myocardial infarction after adjustment for major risk factors and sociodemographic factors (122Sidney S, Siscovick DS, Petitti DB, et al. Myocardial infarction and use of low dose oral contraceptives: a pooled analysis of 2 U.S. studies. Circulation 1998;98:1058- 1063).
  • Ischemic Stroke Risk With Oral Contraceptives: A meta-analysis Study 73 Studies published from January 1960 through November 1999 RISK RATIO OF OC USERS 7 6 5 4 3 2 1 0 HPN NO HPN Hx OF HPN NO HX of HPN Leslie Allison Gillum, BA, JAMA, July 5, 2000—Vol 284, No. 1 81
  • Risk of Myocardial Infarction among women < 50 years old: effect of smoking Never smoked Past smoker Current smoker 30 Relative Risks 20 10 0 Non smoker1-24 sticks +25 sticks/day
  • COC and stroke  Similarly, a study from Denmark found that women with diabetes had a fivefold increase risk for stroke, which increased to 10-fold if they took OCs (132 Lidegaard O. Oral contraceptives, pregnancy and the risk of cerebral thromboembolism: the influence of diabetes, hypertension, migraine and previous thromboembolic disease. BJOG 1995;102:153-159).  Unfortunately, these data were not limited to low- estrogen OCs.  Oral estrogen alone has no adverse effect on glucose metabolism, but progestins exhibit insulin antagonism .
  • Risk of myocardial infarction in current OC users by smoking status Risk (RR, 95% CI) of MI with OC use and smoking status 301 251 201 151 101 87 51 20.8 30 4 11.1 0.9 3.3 8.7 1 -49 Current Never Current Current Never Current Never Current user, nonsmoker user, heavy user, heavy user, nonsmoker user, heavy user, heavy user, heavy user, heavy smoker smoker smoker smoker smoker smoker WHO (Europe). 1997* Croft P (RCGP). 1989** Rosenberg L. 1990*** Heavy smokers defined as: *10 cigarettes/day; **15 cigarettes/day; ***25 cigarettes/day. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1997 Apr 26;349(9060):1202-9. Croft P, Hannaford P. BMJ. 1989 Jan;298(6667):165-8. Rosenberg L, et al. Am J Epidemiol 1990 Jun;131(6):1009-16. 84
  • Low-dose OC use not associated with increased myocardial infarction risk Study 48,321 Swedish women, aged 30–49 years, followed for mean of 11 years Most current users were taking low-dose estrogen and second- or third-generation progestins Results Risk (RR, 95% CI) of fatal and nonfatal MI in OC users vs non-users 1.4 1 1 0.6 0.7 0.2 Former users Current users Margolis KL,et al. Fertil Steril 2007 Aug;88(2):310-6. 85
  • 5. WHICH OF THE FOLLOWING THYROID CONDITIONS IS COC CONTRAINDICATED? A. HYPERTHYROIDISM B. HYPOTHYROIDISM C. BOTH D. NEITHER
  • COC and thyroid function tests  The estrogen in OCs increases circulating thyroid-binding globulin, thereby affecting tests of thyroid function that are based on binding, increasing total thyroxine (T4) levels, and decreasing triiodothyronine (T3) resin uptake.  The results of actual thyroid function tests, as measured by free T4 and radioiodine tests, are normal (138Mishell DR Jr, Colodyn SZ, Swanson LA. The effect of an oral contraceptive on tests of thyroid function. Fertil Steril 1969;20:335-339).
  • 6. IN WHICH GROUP OF COC USERS HAS THE GREATEST RELATIVE RISK OF BREAST CANCER ? A. Positive family history of breast cancer B. > 4 year use prior to FFTP (first full term pregnancy) C. 35-40 years of age D. Caucasian pill users
  • COC and breast cancer  A meta-analysis of 54 studies of breast cancer and hormonal contraceptive use reanalyzed data on 53,297 women with breast cancer and 100,239 controls from 25 countries, representing about 90% of the epidemiologic data available worldwide at that time Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiologic studies. Lancet 1996;347:1713-1727.  Current use of OCs was associated with a very small but statistically stable 24% increased risk (RR, 1.24; 95% CI, 1.15-1.33).
  • COC and breast cancer  The risk fell rapidly after discontinuation, to 16% 1 to 4 years after stopping and to 7% 5 to 9 years after stopping.  Risk disappeared 10 years after cessation (RR, 1.01; 95% CI, 0.96-1.05).  Results did not differ in any important way by ethnic group, reproductive history, or family history.  Since the meta-analysis was published, subsequent studies have found no increased risk. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and risk of breast cancer. N Engl J Med 2002;346:2025-2032
  • Use of oral contraceptive pills does not lead to an increased risk of breast cancer OCP None 4000 number of cases 3000 2000 OR = 0.91 (95%CI 0.90-0.91) 1000 0 Breast Cancer Normal Marchbanks, PA, et al. Oral contraceptive and the risk of breast cancer. NEJM 2002 June, 346(26):2025-2032
  • Odd’s Ratio for invasive Breast cancer for OCP user accdg to duration of use Study 907 cases with incident invasive breast cancer and 1,711 controls from 1993 to 2007 ODD.’S RATIO ACCDG TO DURATION OF USE 3.5 3 2.5 2 1.5 1 0.5 0 NON USER 1-4 5-9 10-14 >15 Lynn Rosenberg, et al, Amer J Epid Vol 169, No. 4, Dec 2008 92
  • Odd’s Ratio for Premenopausal invasive Breast cancer among OCP user Study Meta-Analysis: 34 studies after 1980, < 50 years old ODD.’S RATIO 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 NON USER OVERALL B4FFTP AFFTP CHRIS KAHLENBORN, MD; et al, Mayo Clin Proc. 2006;81(10):1290-1302 93
  • 7. WHICH OF THE FOLLOWING RELATIONSHIP BETWEEN HORMONAL CONTRACEPTION AND CERVICAL CANCER HAS NO EVIDENCE? A. OCP has a causal relationship to cervical cancer B. Increasing risk of cervical cancer according to duration of use of OCP among HPV positive women C. HPV maybe a confounder
  • COC and other genital cancer  Combination OCs reduce the risk of subsequent endometrial cancer and ovarian cancer (139,140).  Two-year use of OCs reduces the risk of endometrial cancer by 40%, and 4 or more years of use reduces the risk by 60%.  Another study found a 50% reduction in ovarian cancer risk for women who took OCs for 3 to 4 years and an 80% reduction with 10 or more years of use (141).  There was some benefit from as little as 3 to 11 months of use. Benefit continues for at least 15 years from last use (125,127,142).
  • COC and cervical cancer  A systematic review of 28 epidemiologic studies of cervical cancer in OC users compared with those who never used OCs reported summary relative risks of 1.1 (95% CI 1.1-1.2) at less than 5 years of pill use, 1.6 (1.4-1.7) at 5 to 9 years, and 2.2 (1.9-2.4) at 10 or more years (146 Smith JS, Green J, Berrington de Gonzales A, et al. Cervical cancer and use of hormonal contraceptives: a systematic review. Lancet 2003;363:1159-1167).  A critique of this study argued that causation is not proved because few of the studies cited adequately control for the key behavioral factors of partners, use of barrier contraception, and adequacy of cervical cancer screening (147 Miller K, Blumenthal P, Blanchard K. Oral contraceptives and cervical cancer: critique of a recent review. Contraception 2004;69:347-351).
  • OCP use and Cervical Cancer Study Meta-Analysis: 28 studies, 12531 cases RELATIVE RISKS ACCDG TO DURATION OF USE 3 2.5 2 1.5 1 0.5 0 NON USER <5 5-9 >10 Smith JS, et al,, Lancet. 2003 Apr 5;361(9364):1159-67. 97
  • OCP use and Cervical Cancer: HPV POSITIVE Study Meta-Analysis: 28 studies, 12531 cases RELATIVE RISKS ACCDG TO DURATION OF USE 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 NON USER <5 5-9 >10 Smith JS, et al,, Lancet. 2003 Apr 5;361(9364):1159-67. 98
  • COC and Cervical Cancer  Individual data for 16,573 women with cervical cancer and 35,509 without cervical cancer were reanalysed centrally  The relative risk of cervical cancer is increased in current users of oral contraceptives and declines after use ceases
  • Cancer and COC  No additional cancer risk in a cohort of UK women  oral contraception was not associated with an overall increased risk of cancer
  • COC and Liver Cancer  There are case reports of hepatocellular carcinoma in young women with no risk factors other than long-term OC use (157).  However, a large study from six countries in Europe found no association between use of OCs and subsequent liver cancer (158Oral contraceptives and liver cancer: results from the Multicentre International Liver Tumor Study (MILTS). Contraception 1997;56:275–284.).
  • 8. WHO WILL BENEFIT MOST FROM LACTATION AMENORRHEA METHOD IN THE PREVENTION OF BREAST CANCER? A. Positive history of breast cancer B. Asians C. Obese women D. Breast feeding for 24 months
  • Lactation Amenorrhea:  Ovulation is suppressed during lactation.  The suckling of the infant elevates prolactin levels and reduces gonadotropin-releasing hormone (GnRH) from the hypothalamus, reducing luteinizing hormone (LH) release and thus inhibiting follicular maturation (10 Knobil E, Neil JD, Ewing LI, et al (eds). The physiology of reproduction. New York, NY: Raven Press, 1988:2323-2349.  Breastfeeding reduces the mother's lifetime risk of breast cancer.  In a very large study in Korea, 13 to 24 months of lactation reduced the risk of breast cancer by 30%, and there was a clear trend of decreasing breast cancer risk with increasing duration of lactation (14 Lee SY, Kim MT, Kim SW, et al. Effect of lifetime lactation on breast cancer risk: a Korean women's cohort study. Int J Cancer 2003;105:390-393).
  • Lactational Amenorrhea Method and Reduction in Breast Cancer Risk Study Cohort Study: 110,604 premenopausal Korean Women, 57,440 breast fed, 4,584 breast fed > 24 months, 6 years follow-up RELATIVE RISKS ACCDG TO DURATION OF USE 1.2 1 0.8 0.6 0.4 0.2 0 NON USER 1-2 years > 2 years Lee SY,, et al, Int J Cancer. 2003 Jun 20;105(3):390-3. 111
  • LAM and Breast Cancer  Risk of breast cancer is reduced only in patients with family history of breast cancer  No reduction in the general population
  • Lactational Amenorrhea Method and Reduction in Breast Cancer Risk Study Cohort Study: 60,075 women, 608 incident cases, 357,556 person- years of follow-up HAZARD RATIO 1.2 1 0.8 0.6 0.4 0.2 0 NON USER BREASTFED 1ST DEGREE Stuebe AM, Arch Intern Med. 2009 Aug 10;169(15):1364-71. 113
  • 9. IS THERE A RELATIONSHIP BETWEEN THE CALENDAR METHOD AND ABORTION? A. Of course NOT! B. Yes, it is directly proportional to the remoteness of coitus to ovulation day C. Yes, it is highest when sex is consummated 3 days after ovulation day D. Yes, the fear of pregnancy creates a hostile intra-uterine environment
  • Timing of intercourse and Abortion  Conceptions resulting from intercourse remote from the time of ovulation more often lead to spontaneous abortion than conceptions from midcycle intercourse However, malformations are not more common Guerrero R, Rojas OI. Spontaneous abortion and aging of human ova and spermatozoa. N Engl J Med 1975;293
  • INJECTABLE HORMONAL CONTRACEPTION  Depomedroxyprogesterone acetate (DMPA), a suspension of micro crystals of a synthetic progestin, was approved for contraception in 1992. A single 150-mg intramuscular dose will suppress ovulation in most women for 14 weeks or longer (188).  Persistent irregular bleeding can be treated by adding low- dose estrogen temporarily; for example, conjugated estrogens, 1.25 mg per day, can be given for 10 to 21 days at a time.  Irregular bleeding with DMPA may be related to the down regulation of endometrial estrogen receptors it produces.
  •  The FDA has issued a black box warning proposing that DMPA treatment be limited to 2 years at a time unless the patient has no other good options for contraception.
  • 10. IS DMPA CARCINOGENIC? A. No, it is not carcinogenic B. It can cause breast cancer C. It can cause ovarian cancer D. It can cause both breast and ovarian cancer
  • DMPA and Breast Cancer  The risk of breast cancer during the first 4 years of use appears to be slightly increased, but there is no relation to long- term use and no overall increase in breast cancer risk; hence, any causal relationship between DMPA and breast cancer is unlikely Chilvers C. Breast cancer and depot-medroxyprogesterone acetate: a review. Contraception 1994;49:211-222). Breast cancer and depot-medroxyprogesterone acetate: a multinational study. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Lancet. 1991 Oct 5;338(8771):833-8.
  • BONUS: WHAT IS MAIN DRAWBACK OF A MALE HORMONAL CONTRACEPTIVE? A. Negative feedback is not complete B. Poor metabolic results C. Risk of liver cancer D. All of the above
  • MALE HORMONAL CONTRACEPTION  The same negative feedback of sex steroids that can block ovulation in women will also suppress spermatogenesis in men, but it will produce loss of libido and potentially extinguish sexual performance  Asian men virtually always achieve azospermia or oligospermia when treated with testosterone undecanoate, 500 to 1,000 mg monthly, whereas only 86% of white men achieved oligospermia or azospermia with similar testosterone regimens (218Wang C, Swerdloff RS. Male hormonal contraception. Am J Obstet Gynecol 2004;190:S60-S68.  However, pregnancy has occurred in partners of androgen-treated oligospermic men with sperm counts as low as 3 million/mL (219 Wallace EM, Aitken RJ, Wu FC. Residual sperm function in oligozoospermia induced by testosterone enanthate administered as a potential steroid male contraceptive. Int J Androl 1992;15:416-424.
  • Male Hormonal Contraception  Combining testosterone with a progestin allows a lower dose of the androgen with efficacy comparable to use of testosterone alone.  One promising regimen combined injections of testosterone undecanoate with norethindrone enanthate given at 6-week intervals.  This regimen produced azospermia in 90% of subjects (220). Adverse lipid changes have been noted with DMPA and androgen combinations, raising concern about vascular disease with prolonged use.  Liver cancer is also a concern with long-term androgen therapy (221).
  • WHO MEC 2009
  • WHO Categories for Temporary Methods WHO 1 Can use the method. No restriction on use WHO 2 Can use the method. Advantages outweigh theoretical or proven harm WHO 3 Should not use the method unless a doctor or nurse makes a clinical judgement that the client can safely use it WHO 4 Should not use the method. Condition represents an unacceptable health risk.
  • Simplified 2-Category System WHO With Clinical Judgement With Limited Category Clinical Judgement 1 Use the method in any Use the circumstances method 2 Generally use the method 3 Use of the method not Do not use usually recommended unless other, more appropriate the method methods are not available or acceptable 4 Method not to be used
  • Importance of Selected Procedures for Providing Family Planning Methods A. Essential and mandatory B. Contributes substantially to safe and effective use, but implementation maybe considered within the public health and / or service context C.Does not contribute substantially to safe and effective use D.No materially related to either good routine preventive health or to the safe and effective use of the method
  • Procedures before COC use PELVIC EXAM C BLOOD PRESSURE READING 2 BREAST EXAM BY PROVIDER C HEMOGLOBIN TEST C STD risk assessment C STD screening by lab test C CERVICAL CANCER SCREENING C Routine, mandatory lab tests (eg. Cholesterol, FBS, LFT) C Proper infection-prevention procedures C Specific COUNSELLING points for FP methods A COUNSELLING about change in menses A
  • CASES
  • Case 1:  32 year old G1P1 sought consult for contraception. Her mother is a breast cancer survivor. Menses are irregular but no dysmenorrhea. BP 120/80, Uterus is slightly enlarged due to 3x3 cms myoma found on ultrasound. What can be given to address her concerns?
  • Case 2:  V.N. is 42 years old, G5P4 with on and off BP elevations. No antihypertensive drugs taken. Non –smoker. Her blood sugar is controlled with regular medications. Menstruation is regular at 28-30 days cycle. She wants to take the pills. What is your advise?
  • Case 3:  24 year old, G2P2, DMPA user for 1 year before her husband left abroad for work sough consult for contraceptive advise. She used to have vaginal spotting while on DMPA. Her husband would be coming home for just 2 months. What is your recommendation?
  • Case 4  19 year old, nulligravida, with an OFW partner, comes come for 2 weeks. She, however, has vaginal discharge. What is her recommended method of contraception?
  • Case 5  42 years old, G3P3 is on COC for the past 4 years. Her vital signs are normal. She is concerned about VTE because of her varicose veins. Can she continue the COC? If not, what method is recommended?
  • Case 6  38 years old, G5P5, had just delivered by forceps delivery under epidural anesthesia. She had requested for BTL during the prenatal check-up. Her pregnancies were complicated by pre-eclampsia, severe. What will be your course of action?
  • Case 7  32 year old, G1P1, s/p partum 2 weeks, asks for contraceptive advise. She wants to go back to work but would want to continue breast feeding. What would be your advise?
  • Case 8  21 years old, nulligravida, had an unprotected intercourse 2 days ago. She requested for emergency contraception. She had tried EC 2x. What will be your advise?
  • Case 9  24 year old, G1P1, sought consult in a health center, manned by a midwife. She had controlled hypertension. Can she take the pills? If NO, what would you recommend?
  • Case 10  34 year old, G1P1, is diagnosed case of mental retardation. Her parents requested that she be ligated. She would usually leaves the house for days without information on her whereabouts. She does not remember the father of her child. What is your recommendation?
  • Learning Objectives: Strategies  Learning objective 1: Lecture – 1 hr  Learning objective 2 & 3: Interactive lecturettes – 1 hr  Learning objective 4: Problem solving, Case discussion – 2 hours  Learning objective 5: small group  Writeshop: course content of a FP method class