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Cigarette smoking increases the risk of serious cardiovascular side effects from oral contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. Women who use oral contraceptives should be strongly advised not to smoke.
The use of oral contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia, and gallbladder disease, although the risk of serious morbidity or mortality is very small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly in the presence of other underlying risk factors such as hypertension, hyperlipidemias, obesity, and diabetes.
Practitioners prescribing oral contraceptives should be familiar with the following information relating to these risks.
The information contained in this package insert is principally based on studies carried out in patients who used oral contraceptives with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of the oral contraceptives with lower formulations of both estrogens and progestogens remains to be determined.
Throughout this labeling, epidemiological studies reported are of two types: retrospective or case control studies and prospective or cohort studies. Case control studies provide a measure of the relative risk of a disease, namely, a ratio of the incidence of a disease among oral contraceptive users to that among nonusers. The relative risk does not provide information on the actual clinical occurrence of a disease. Cohort studies provide a measure of attributable risk, which is the difference in the incidence of disease between oral contraceptive users and nonusers. The attributable risk does provide information about the actual occurrence of a disease in the population (adapted from References 8 and 9 with the author's permission). For further information, the reader is referred to a text on epidemiological methods.
Thromboembolic Disorders And Other Vascular Problems
An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six (10 to 16). The risk is very low under the age of 30.
Smoking in combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases (17). Mortality rates associated with circulatory disease have been shown to increase substantially in smokers over the age of 35 and non-smokers over the age of 40 (Table II) among women who use oral contraceptives.
Table II : Circulatory Disease Mortality Rates Per
100,000 Woman Years by Age, Smoking Status and oral Contraceptive Use
Adapted from, P.M. Layde and V. Beral, Reference 18
Oral contraceptives may compound the effects of well-known risk factors, such as hypertension, diabetes, hyperlipidemias, age and obesity (19). In particular, some progestogens are known to decrease HDL cholesterol and cause glucose intolerance, while estrogens may create a state of hyperinsulinism (20 to 24). Oral contraceptives have been shown to increase blood pressure among users (see section under Elevated Blood Pressure). Similar effects on risk factors have been associated with an increased risk of heart disease. Oral contraceptives must be used with caution in women with cardiovascular disease risk factors.
An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case control studies have found the relative risk of users compared to non-users to be 3 for the first episode of superficial venous thrombosis, 4 to 11 for deep vein thrombosis or pulmonary embolism, and 1.5 to 6 for women with predisposing conditions for venous thromboembolic disease (9,10,25 to 30). Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization (31). The risk of thromboembolic disease due to oral contraceptives is not related to length of use and disappears after pill use is stopped (8).
A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives (15,32). The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions (15,32). If feasible, oral contraceptives should be discontinued at least four weeks prior to and for two weeks after elective surgery of a type associated with an increase in risk of thromboembolism and during and following prolonged immobilization. Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four to six weeks after delivery in women who elect not to breast feed.
Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older ( > 35 years), hypertensive women who also smoke. Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, while smoking interacted to increase the risk for hemorrhagic strokes (33 to 35).
In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension (36). The relative risk of hemorrhagic stroke is reported to be 1.2 for non-smokers who used oral contraceptives, 2.6 for smokers who did not use oral contraceptives, 7.6 for smokers who used oral contraceptives, 1.8 for normotensive users, and 25.7 for users with severe hypertension (36). The attributable risk is also greater in older women (9).
Dose-Related Risk Of Vascular Disease From Oral Contraceptives
A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease (37 to 39). A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents (20 to 22). A decline in serum high-density lipoproteins has been associated with an increased incidence of ischemic heart disease. Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestin and the nature of the progestin used in the contraceptives. The amount and activity of both hormones should be considered in the choice of an oral contraceptive.
Minimizing exposure to estrogen and progestogen is in keeping with good principles of therapeutics. For any particular oral contraceptive, the dosage regimen prescribed should be one which contains the least amount of estrogen and progestogen that is compatible with the needs of the individual patient. New acceptors of oral contraceptive agents should be started on preparations containing the lowest dose of estrogen which produces satisfactory results for the patient.
Persistence Of Risk Of Vascular Disease
There are two studies which have shown persistence of risk of vascular disease for ever-users of oral contraceptives. In a study in the United States, the risk of developing myocardial infarction after discontinuing oral contraceptives persists for at least 9 years for women 40 to 49 years who had used oral contraceptives for 5 or more years, but this increased risk was not demonstrated in other age groups (14). In another study in Great Britain, the risk of developing cerebrovascular disease persisted for at least 6 years after discontinuation of oral contraceptives, although excess risk was very small (40). However, both studies were performed with oral contraceptive formulations containing 50 mcg or higher of estrogens.
Estimates Of Mortality From Contraceptive Use
One study gathered data from a variety of sources which have estimated the mortality rate associated with different methods of contraception at different ages (Table III). These estimates include the combined risk of death associated with contraceptive methods plus the risk attributable to pregnancy in the event of method failure. Each method of contraception has its specific benefits and risks. The study concluded that with the exception of oral contraceptive users 35 and older who smoke and 40 and older who do not smoke, mortality associated with all methods of birth control is low and below that associated with childbirth. The observation of a possible increase in risk of mortality with age for oral contraceptive users is based on data gathered in the 1970's but not reported until 1983 (41). However, current clinical practice involves the use of lower estrogen dose formulations combined with careful restriction of oral contraceptive use to women who do not have the various risk factors listed in this labeling.
Because of these changes in practice and, also, because of some limited new data which suggest that the risk of cardiovascular disease with the use of oral contraceptives may now be less than previously observed (Porter JB, Hunter J, Jick H, et al. Oral contraceptives and nonfatal vascular disease. Obstet Gynecol 1985;66:1–4; and Porter JB, Hershel J, Walker AM. Mortality among oral contraceptive users. Obstet Gynecol 1987;70:29–32), the Fertility and Maternal Health Drugs Advisory Committee was asked to review the topic in 1989. The Committee concluded that although cardiovascular disease risks may be increased with oral contraceptive use after age 40 in healthy non-smoking women (even with the
newer low-dose formulations), there are greater potential health risks associated with pregnancy in older women and with the alternative surgical and medical procedures which may be necessary if such women do not have access to effective and acceptable means of contraception.
TABLE III : ANNUAL NUMBER OF BIRTH-RELATED OR METHOD-RELATED DEATHS ASSOCIATED WITH CONTROL OF FERTILITY PER 100,000 N0NSTERILE WOMEN BY FERTILITY CONTROL METHOD ACCORDING TO AGE
|Method of control and outcome||15-19||20-24||25-29||30-34||35-39||40-44|
|No fertility control methods*||7.0||7.4||9.1||14,8||25.7||28,2|
|Oral contraceptives non-smoker**||0.3||0.5||0.9||1,9||13,8||31.6|
|Oral contraceptives smoker**||2.2||3,4||6,6||13.5||51,1||117.2|
|D i aph rag m/sperm ici de*||1.9||1,2||1.2||1,3||2,2||2.8|
|* Deaths are birth related.
**Deaths are method related.
Adapted from H.W. Ory, Reference 41
Therefore, the Committee recommended that the benefits of oral contraceptive use by healthy nonsmoking women over age 40 may outweigh the possible risks. Of course, older women, as all women who take oral contraceptives, should take the lowest possible dose formulation that is effective.
Carcinoma Of The Reproductive Organs
Numerous epidemiological studies have been performed on the incidence of breast, endometrial, ovarian, and cervical cancer in women using oral contraceptives. Most of the studies on breast cancer and oral contraceptive use report that the use of oral contraceptives is not associated with an increase in the risk of developing breast cancer (42,44,89). Some studies have reported an increased risk of developing breast cancer in certain subgroups of oral contraceptive users, but the findings reported in these studies are not consistent (43,45 to 49,85 to 88).
Some studies suggest that oral contraceptive use has been associated with an increase in the risk of cervical intraepithelial neoplasia in some populations of women (51 to 54). However, there continues to be controversy about the extent to which such findings may be due to differences in sexual behavior and other factors.
In spite of many studies of the relationship between oral contraceptive use and breast and cervical cancers, a cause and effect relationship has not been established.
Benign hepatic adenomas are associated with oral contraceptive use, although the incidence of benign tumors is rare in the United States. Indirect calculations have estimated the attributable risk to be in the range of 3.3 cases/100,000 for users, a risk that increases after four or more years of use (55). Rupture of rare, benign, hepatic adenomas may cause death through intra-abdominal hemorrhage (56 to 57).
Studies from Britain have shown an increased risk of developing hepatocellular carcinoma (58 to 60) in long-term ( > 8 years) oral contraceptive users. However, these cancers are extremely rare in the U.S., and the attributable risk (the excess incidence) of liver cancers in oral contraceptive users approaches less than one per million users.
There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision; onset of proptosis or diplopia; papilledema; or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.
Oral Contraceptive Use Before And During Early Pregnancy
Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy (61 to 63). Studies also do not suggest a teratogenic effect, particularly insofar as cardiac anomalies and limb reduction defects are concerned (61,62,64,65) when taken inadvertently during early pregnancy.
The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy. Oral contraceptives should not be used during pregnancy to treat threatened or habitual abortion.
It is recommended that for any patient who has missed two consecutive periods, pregnancy should be ruled out before continuing oral contraceptive use. If the patient has not adhered to the prescribed schedule, the possibility of pregnancy should be considered at the time of the first missed period. Oral contraceptive use should be discontinued if pregnancy is confirmed.
Earlier studies have reported an increased lifetime relative risk of gallbladder surgery in users of oral contraceptives and estrogens (66,67). More recent studies, however, have shown that the relative risk of developing gallbladder disease among oral contraceptive users may be minimal (68 to 70). The recent findings of minimal risk may be related to the use of oral contraceptive formulations containing lower hormonal doses of estrogens and progestogens.
Carbohydrate And Lipid Metabolic Effects
Oral contraceptives have shown to cause glucose intolerance in a significant percentage of users (23). Oral contraceptives containing greater than 75 mcg of estrogens cause hyperinsulinism, while lower doses of estrogen cause less glucose intolerance (71). Progestogens increase insulin secretion and create insulin resistance, this effect varying with different progestational agents (23,72). However, in the non-diabetic woman, oral contraceptives appear to have no effect on fasting blood glucose (73). Because of these demonstrated effects, prediabetic and diabetic women should be carefully observed while taking oral contraceptives.
A small proportion of women will have persistent hypertriglyceridemia while on the pill. As discussed earlier (see Myocardial Infarction and Dose-Related Risk of Vascular Disease from Oral Contraceptives), changes in serum triglycerides and lipoprotein levels have been reported in oral contraceptive users.
Elevated Blood Pressure
An increase in blood pressure has been reported in women taking oral contraceptives (74) and this increase is more likely in older oral contraceptive users (75) and with continued use (74). Data from the Royal College of General Practitioners (18) and subsequent randomized trials have shown that the incidence of hypertension increases with increasing concentrations of progestogens.
Women with a history of hypertension or hypertension-related diseases or renal disease (76) should be encouraged to use another method of contraception. If women elect to use oral contraceptives, they should be monitored closely, and if significant elevation of blood pressure occurs, oral contraceptives should be discontinued. For most women, elevated blood pressure will return to normal after stopping oral contraceptives (75), and there is no difference in the occurrence of hypertension among ever and never users (74,76,77).
The onset or exacerbation of migraine or development of headache with a new pattern which is recurrent, persistent, or severe requires discontinuation of oral contraceptives and evaluation of the cause.
Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use. Non-hormonal causes should be considered, and adequate diagnostic measures taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding. If pathology has been excluded, time or a change to another formulation may solve the problem. In the event of amenorrhea, pregnancy should be ruled out.
Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent.
Patients Should Be Counseled That This Product Does Not Protect Against HIV Infection (AIDS) And Other Sexually Transmitted Diseases.
Physical Examination And Follow-Up
It is good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination, however, may be deferred until after initiation of oral contraceptives if requested by the woman and judged appropriate by the clinician. The physical examination should include special reference to blood pressure, breasts, abdomen and pelvic organs, including cervical cytology, and relevant laboratory tests. In case of undiagnosed, persistent or recurrent abnormal vaginal bleeding, appropriate measures should be conducted to rule out malignancy. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care.
Women who are being treated for hyperlipidemia should be followed closely if they elect to use oral contraceptives. Some progestogens may elevate LDL levels and may render the control of hyperlipidemias more difficult.
Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution, and only with careful monitoring, in patients with conditions which might be aggravated by fluid retention.
Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.
Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist.
See WARNINGS section.
Pregnancy Category X
See CONTRAINDICATIONS and WARNINGS sections.
Small amounts of oral contraceptive steroids have been identified in the milk of nursing mothers, and a few adverse effects on the child have been reported, including jaundice and breast enlargement. In addition, oral contraceptives given in the postpartum period may interfere with lactation by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.
Safety and efficacy of norethindrone acetate and ethinyl estradiol tablets have been established in women of reproductive age. Safety and efficacy are expected to be the same for postpubertal adolescents under the age of 16 and for users 16 years and older. Use of this product before menarche is not indicated.
Information For The Patient
See patient labeling printed below.
7. Hatcher RA, et al. 1998. Contraceptive Technology, Seventeenth Edition. New York: Irvington Publishers.
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9. Stadel, B.V.: Oral contraceptives and cardiovascular disease. (Pt. 2). New England Journal of Medicine, 305:672–677, 1981.
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12. Mann, J.I., M.P. Vessey, M. Thorogood, and R. Doll: Myocardial infarction in young women with special reference to oral contraceptive practice. Brit. Med. J., 2(5956):241–245, 1975.
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14. Slone, D., S. Shapiro, D.W. Kaufman, L. Rosenberg, O.S. Miettinen, and P.D. Stolley: Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. N.E.J.M., 05:420–424, 1981.
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19. Knopp, R.H.: Arteriosclerosis risk: The roles of oral contraceptives and postmenopausal estrogens. J. of Reprod. Med., 31(9)(Supplement): 913–921, 1986.
20. Krauss, R.M., S. Roy, D.R. Mishell, J. Casagrande, and M.C. Pike: Effects of two low-dose oral contraceptives on serum lipids and lipoproteins: Differential changes in high-density lipoproteins subclasses. Am. J. Obstet. Gyn., 145:446–452, 1983.
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26. Maguire, M.G., J. Tonascia, P.E. Sartwell, P.D. Stolley, and M.S. Tockman: Increased risk of thrombosis due to oral contraceptives: A further report. Am. J. Epidemiology, 110(2): 188–195, 1979.
27. Pettiti, D.B., J. Wingerd, F. Pelligrin, and S. Ramacharan: Risk of vascular disease in women: Smoking, oral contraceptives, noncontraceptive estrogens, and other factors. J.A.M.A., 242:1150–1154, 1979.
28. Vessey, M.P., and R. Doll: Investigation of relation between use of oral contraceptives and thromboembolic disease. Brit. Med. J., 2(5599): 199–205, 1968.
29. Vessey, M.P., and R. Doll: Investigation of relation between use of oral contraceptives and thromboembolic disease: A further report. Brit. Med. J., 2(5658): 651–657, 1969.
30. Porter, J.B., J.R. Hunter, D.A. Danielson, H. Jick, and A. Stergachis: Oral contraceptives and nonfatal vascular disease: Recent experience. Obstet. and Gyn., 59(3):299–302, 1982.
31. Vessey, M., R. Doll, R. Peto, B. Johnson, and P. Wiggins: A long-term follow-up study of women using different methods of contraception: An interim report. J. Biosocial. Sci., 8:375–427, 1976.
32. Royal College of General Practitioners: Oral contraceptives, venous thrombosis, and varicose veins. J. of Royal College of General Practitioners, 28:393–399, 1978.
33. Collaborative Group for the study of stroke in young women: Oral contraception and increased risk of cerebral ischemia or thrombosis. N.E.J.M., 288:871–878, 1973.
34. Petitti, D.B., and J. Wingerd: Use of oral contraceptives, cigarette smoking, and risk of subarachnoid hemorrhage. Lancet, 2:234–236, 1978.
35. Inman, W.H.: Oral contraceptives and fatal subarachnoid hemorrhage. Brit. Med. J., 2(6203): 1468– 70, 1979.
36. Collaborative Group for the study of stroke in young women: Oral contraceptives and stroke in young women: Associated risk factors. J.A.M.A., 231:718–722, 1975.
37. Inman, W.H., M.P. Vessey, B. Westerholm, and A. Engelund: Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs. Brit. Med. J., 2:203–209, 1970.
38. Meade, T.W., G. Greenberg, and S.G. Thompson: Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 35-mcg oestrogen preparations. Brit. Med. J., 280(6224): 1157–1161, 1980.
39. Kay, C.R.: Progestogens and arterial disease: Evidence from the Royal College of General Practitioners' study. Amer. J. Obstet. Gyn., 142:762–765, 1982.
40. Royal College of General Practitioners: Incidence of arterial disease among oral contraceptive users. J. Coll. Gen. Pract., 33:75–82, 1983.
41. Ory, H.W.: Mortality associated with fertility and fertility control:1983. Family Planning Perspectives, 15:50–56, 1983.
42. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development: Oral-contraceptive use and the risk of breast cancer. N.E.J.M., 315: 405–411, 1986.
43. Pike, M.C., B.E. Henderson, M.D. Krailo, A. Duke, and S. Roy: Breast cancer in young women and use of oral contraceptives: Possible modifying effect of formulation and age at use. Lancet, 2:926– 929, 1983.
44. Paul, C., D.G. Skegg, G.F.S. Spears, and J.M. Kaldor: Oral contraceptives and breast cancer: A national study. Brit. Med. J., 293:723–725, 1986.
45. Miller, D.R., L. Rosenberg, D.W. Kaufman, D. Schottenfeld, P.D. Stolley, and S. Shapiro: Breast cancer risk in relation to early oral contraceptive use. Obstet. Gynec., 68:863–868, 1986. cancer risk in relation to early oral contraceptive use. Obstet. Gynec., 68:863–868, 1986.
46. Olson, H., K.L. Olson, T.R. Moller, J. Ranstam, P. Holm: Oral contraceptive use and breast cancer in young women in Sweden (letter). Lancet, 2:748–749, 1985.
47. McPherson, K., M. Vessey, A. Neil, R. Doll, L. Jones, and M. Roberts: Early contraceptive use and breast cancer: Results of another case-control study. Brit. J. Cancer, 56: 653–660, 1987.
48. Huggins, G.R., and P.F. Zucker: Oral contraceptives and neoplasia: 1987 update. Fertil. Steril., 47:733–761, 1987.
49. McPherson, K., and J.O. Drife: The pill and breast cancer: Why the uncertainty? Brit. Med. J., 293:709–710, 1986.
50. Shapiro, S.: Oral contraceptives: Time to take stock. N.E.J.M., 315:450–451, 1987.
51. Ory, H., Z. Naib, S.B. Conger, R.A. Hatcher, and C.W. Tyler: Contraceptive choice and prevalence of cervical dysplasia and carcinoma in situ. Am. J. Obstet. Gynec., 124:573–577, 1976.
52. Vessey, M.P., M. Lawless, K. McPherson, D. Yeates: Neoplasia of the cervix uteri and contraception: A possible adverse effect of the pill. Lancet, 2:930, 1983.
53. Brinton, L.A., G.R. Huggins, H.F. Lehman, K. Malli, D.A. Savitz, E. Trapido, J. Rosenthal, and R. Hoover: Long-term use of oral contraceptives and risk of invasive cervical cancer. Int. J. Cancer, 38:339–344, 1986.
54. WHO Collaborative Study of Neoplasia and Steroid Contraceptives: Invasive cervical cancer and combined oral contraceptives. Brit. Med. J., 290:961–965, 1985.
55. Rooks, J.B., H.W. Ory, K.G. Ishak, L.T. Strauss, J.R. Greenspan, A.P. Hill, and C.W. Tyler: Epidemiology of hepatocellular adenoma: The role of oral contraceptive use. J.A.M.A., 242:644– 648, 1979.
56. Bein, N.N., and H.S. Goldsmith: Recurrent massive hemorrhage from benign hepatic tumors secondary to oral contraceptives. Brit. J. Surg., 64:433–435, 1977.
57. Klatskin, G.: Hepatic tumors: Possible relationship to use of oral contraceptives. Gastroenterology, 73:386–394, 1977.
58. Henderson, B.E., S. Preston-Martin, H.A. Edmondson, R.L. Peters, and M.C. Pike: Hepatocellular carcinoma and oral contraceptives. Brit. J. Cancer, 48:437–440. 1983.
59. Neuberger, J., D. Forman, R. Doll, and R. Williams: Oral contraceptives and hepatocellular carcinoma. Brit. Med. J., 292:1355–1357, 1986.
60. Forman, D., T.J. Vincent, and R. Doll: Cancer of the liver and oral contraceptives. Brit. Med. J., 292: 1357–1361, 1986.
61. Harlap, S., and J. Eldor: Births following oral contraceptive failures. Obstet. Gynec., 55:447–452, 1980.
62. Savolainen, E., E. Saksela, and L. Saxen: Teratogenic hazards of oral contraceptives analyzed in a national malformation register. Amer. J. Obstet. Gynec., 140:521–524, 1981.
63. Janerich, D.T., J.M. Piper, and D.M. Glebatis: Oral contraceptives and birth defects. Am. J. Epidemiology, 112:73–79, 1980.
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70. Strom, B.L., R.T. Tamragouri, M.L. Morse, E.L. Lazar, S.L. West, P. D. Stolley, and J.K. Jones: Oral contraceptives and other risk factors for gallbladder disease. Clin. Pharmacol. Ther., 39:335– 341, 1986.
71. Wynn, V., P.W. Adams, I.F. Godsland, J. Melrose, R. Niththyananthan, N.W. Oakley, and A. Seedj: Comparison of effects of different combined oral-contraceptive formulations on carbohydrate and lipid metabolism. Lancet, 1:1045–1049, 1979.
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73. Perlman, J.A., R.G. Roussell-Briefel, T.M. Ezzati, and G. Lieberknecht: Oral glucose tolerance and the potency of oral contraceptive progestogens. J. Chronic. Dis., 38:857–864, 1985.
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