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Although past studies have shown that oral contraceptives with 50 microg or more of estrogen reduce the risk of ovarian cancer, it is not clear whether newer, lower-dose formulations do as well. We conducted a population-based, case-control study in the Delaware Valley to assess the impact of dose of oral contraception on risk of ovarian cancer. Cases aged 20-69 years with a diagnosis of epithelial ovarian cancer ascertained between May 1994 and July 1999 (n = 767) were compared with community controls (n = 1,367). Compared with never users, the adjusted risk of ovarian cancer was reduced by 40% for oral contraceptive users overall, with longer duration of use affording greater protection. The ovarian cancer risk reduction was similar for women who initiated oral contraception before 1972, when high-dose pills dominated the market; between 1972 and 1980; and after 1980, when newer, lower-dose pills dominated. Oral contraceptive estrogen and progestin content were compared for cases and controls after adjustment for current age, number of pregnancies, race, and family history of ovarian cancer. Use of low-estrogen/low-progestin pills afforded an estimated risk reduction (odds ratio = 0.5, 95% confidence interval: 0.3, 0.6) that was identical to that for high-estrogen/high-progestin pills (odds ratio = 0.5, 95% confidence interval: 0.3, 0.7).

Approximately 25% of patients with stage I (node negative) breast cancer relapse at a rate similar to those with stage II disease. Inadvertent pathologic "understaging" of lymph node status is one plausible explanation for this phenomenon. While many studies have shown that additional sectioning +/- immunohistochemical staining for epithelial markers increases the rate of detection of small deposits of metastatic carcinoma, few have had sufficient statistical power to examine the impact of "occult" metastasis on clinical outcome. This provocative update by the International Ludwig Breast Cancer Study Group provides support for considering going "the extra mile" to detect lymph node metastasis in postmenopausal patients and those with the lobular subtype of invasive breast cancer.

Objective: To understand physician concerns about litigation and beliefs regarding vaccine safety., Design: A stratified random sample of family physicians, pediatricians, and general practitioners younger than 65 years who were in office-based practices across the United States was selected from the American Medical Association list that includes nonmembers. A standardized telephone survey was conducted by trained interviewers in 1995., Participants: Physicians seeing 5 or more patients per week younger than 6 years and having 50% or more primary care patients were eligible for the study., Results: Of the 1236 physicians who were surveyed, 32% and 13% overestimated the risk for serious adverse effects related to pertussis and measles vaccines, respectively. Among physicians who thought that serious adverse effects from diphtheria and tetanus toxoids and pertussis vaccine (DTP) were unlikely, 15% were highly concerned about litigation; however, among those with higher ratings of the likelihood of serious adverse effects, 38% were highly concerned about vaccine litigation (P < .01). Of those aware of the Vaccine Injury Compensation Program, only 41% believed that it afforded a high level of liability protection; 22% believed that it gives little protection, and 37% gave an intermediate answer. Among physicians highly concerned about vaccine litigation, 22% were unlikely to recommend the third dose of DTP for a child with a fever of 39.4 degrees C and no other symptoms after the second dose of DTP, whereas among those expressing little concern about litigation, only 12% were unlikely to vaccinate (P < .05). Although some physicians were concerned about litigation, most (86%) encouraged vaccination even if a parent was argumentative about possible adverse effects., Conclusion: Physicians' perceptions about the risk for adverse effects and protection afforded by the Vaccine Injury Compensation Program influence their concern about litigation and, to a lesser extent, their reported likelihood to administer immunizations.

Objective: To determine the causes of low childhood immunization rates based on physicians' knowledge, attitudes, and self-reported practices concerning childhood immunization., Design: A standardized telephone survey conducted by trained interviewers., Setting: Primary care physicians across the United States., Participants: A stratified random sample of office-based family physicians, pediatricians, and general practitioners younger than 65 years was selected from the American Medical Association master file list that includes nonmembers. Physicians seeing 5 or more patients per week younger than 6 years and having 50% or more primary care patients were eligible for study. Of 1769 eligible physicians who spoke directly with the interviewers, 70% (N = 1241) completed the questionnaire., Interventions: The interview was designed to determine physicians' likelihood of recommending vaccination in common clinical scenarios and to probe reasons behind these decisions., Results: Only 4% of physicians who thought the risk for side effects was increased by upper respiratory tract infection (URI) were likely to vaccinate a child with URI vs 55% of physicians who thought there would be no increased risk (P < .001). Eighty-three percent of those who thought the efficacy of measles, mumps, and rubella vaccine would not be affected by a URI recommended vaccination vs only 8% of physicians who thought efficacy would decrease (P < .001). Some respondents (11%) would not administer 3 injectable vaccines simultaneously based on beliefs about side effects, parental objections, and vaccine efficacy. Physicians' likelihood of vaccination also varied by type of visit: 47% were less likely to vaccinate a child with a URI in an acute care as opposed to a well-child setting., Conclusion: Physicians' beliefs and practice policies materially influence their likelihood of recommending vaccinations.

Objective: To estimate by meta-analysis the risk of developing cancer of the breast, uterine cervix, endometrium, ovary, and liver from age 20-54 years in the United States in women using oral contraceptives (OCs) for 4, 8, or 12 years., Data Sources: Using pairs of terms (such as oral contraception and breast neoplasms), I searched for English-language literature on OC use and cancer published since 1980 and cited through July 1994 in the MEDLINE data base., Methods of Study Selection: I analyzed all epidemiologic studies reporting estimates of relative risk (RR) by duration and recency of OC use (79 independent studies in total)., Data Extraction and Synthesis: Reported duration-specific and recency-specific estimates of RR, with the corresponding numbers of cases and controls or person-time at risk for cohort studies, were abstracted from each article. Relative risk of cancer as a function of both duration and recency of OC use was then estimated by weighted regression and applied, using life-table methods, to United States population-based data on age-specific mortality and cancer incidence., Conclusions: For every 100,000 women in the United States who never use OCs, the number developing cancer from age 20-54 years is estimated to be 2782 (breast), 425 (cervix), 438 (endometrium), 369 (ovary), and 20 (liver). For women using OCs for 8 years, the estimated number of additional or fewer cases per 100,000 users is +151 (breast), +125 (cervix), -197 (endometrium), -193 (ovary), and +41 (liver). Therefore, from a population perspective, there are only small cancer-related risks and benefits associated with OC use and, on balance, the net effect is negligible.

Objective: To determine the effect of oral contraceptive (OC) use on the cumulative incidence of epithelial ovarian cancer from ages 20-40, 20-50, and 20-55 years among four groups of women: positive family history, negative family history, parous, and nulliparous., Methods: Cancer and Steroid Hormone Study data were combined with data from the Surveillance, Epidemiology, and End Results Network to provide estimates of the age-specific incidence rates of epithelial ovarian cancer among never-users of OCs in the four specified groups of women. These rates provided the basis for calculating cumulative incidences. The rates in women using OCs were estimated from meta-analyses of the epidemiologic literature, using regression equations expressing the log-relative rate of epithelial ovarian cancer as a function of duration of use and recency., Results: In all four groups, the cumulative number of epithelial ovarian cancer cases estimated to occur per 100,000 OC users, compared to never-users, decreased with increasing duration of OC use. Our results suggest that 5 years of OC use by nulliparous women can reduce their ovarian cancer risk to the level seen in parous women who never use OCs, and that 10 years of OC use by women with a positive family history can reduce their risk to a level below that for women whose family history is negative and who never use OCs., Conclusion: These data represent the first published estimates of the effect of OC use on the cumulative incidence of epithelial ovarian cancer by family history and by parity. The demonstrated substantial noncontraceptive benefit from OCs justifies their judicious use as a potentially powerful resource for primary prevention in women at high risk of ovarian cancer.

Analyses of tumor size and breast cancer stage were used to determine whether biased detection of breast cancer could have materially influenced estimates of risk associated with use of oral contraceptives. In a population-based case-control study conducted from 1980-1982, surveillance for breast cancer by breast exams, but not mammography, was found to be strongly linked to use of oral contraceptives. Tumors were slightly smaller and less likely to be late-stage (TNM stage III or IV) in patients who had used oral contraceptives. The net effect of any diagnostic bias on advancing the date of cancer diagnosis, whether from breast exams or other sources, was estimated to be less than 8 weeks. This corresponds to spuriously increasing the risk of early-occurring breast cancer in oral contraceptive users by at most 2.4% (relative risk = 1.024).

Effects of oral contraception on neoplasia of the uterine corpus are reviewed on the basis of epidemiologic studies reported to date. A duration-related protective effect against endometrial cancer occurs from use of combined oral contraceptives, those in which each active pill contains both estrogen and progestogen. The risk before age 60 years is reduced by about 38% with two years of use; use of combined OCs for 4, 8, and 12 years, respectively, confers an estimated 51%, 64%, and 70% reduction in endometrial cancer risk. The protective effect appears not to be diminished by discontinued use, even 15 or more years after stopping. Whether protection continues throughout the entire postmenopausal period, even in the presence of long-term hormone replacement therapy, remains to be seen. Use of combined OCs may protect against uterine leiomyomas ("fibroids"), but the evidence is not conclusive. The few findings about effects of oral contraception on the risk of adenomatous hyperplasia are of uncertain validity. Only one study, with few patients, has considered oral contraception in relation to uterine sarcomas.

Among women in general the risk of breast cancer through 59 years of age does not appear to be affected appreciably by the use of oral contraceptives. Nonetheless, concern continues to be expressed about the effects of early age at first use, long-term duration of use, formulation, and a variety of other factors thought to influence breast cancer risk in the presence of oral contraception. A number of recent studies restricted to young women suggest that long-term use may increase the risk of disease occurring very early, but the present lack of consistent findings in well-conducted epidemiologic studies prevents any certain conclusion with regard to cause-and-effect. However, if an increased risk were indeed present, the most plausible interpretation is that long-term oral contraception promotes earlier clinical manifestation of breast cancer in some women while having no net impact on their lifetime risk of the disease.

Consistency and plausibility are fundamental criteria for judging cause and effect from observational studies. They are applied here to the interpretation of data from a population-based case-control study of oral contraceptives and breast cancer. A preliminary analysis of oral contraceptive use in young nulliparous women, who had no family history of either breast cancer or benign breast disease, showed a statistically significant dose-response, with long-term users (49 months or more) having an apparent 4-fold elevation in risk of early breast cancer. Further analyses, however, revealed striking inconsistencies which were biologically implausible. These effectively undermine cause and effect as an explanation for the initial finding.

In case-control studies, exposure to a risk factor often occurs at several levels, so the attributable risk at each level is of interest. In this paper, estimation for the 2 X 2 table (case-control status versus dichotomous exposure) and the 2 X k table (case-control status versus exposure at several levels) are reviewed along with an example. A method for finding confidence intervals for attributable risk in the 2 X k table is proposed, and its application to estimates adjusted across strata (the 2 X k X s case) is indicated. The results of a Monte Carlo study of the procedure demonstrate that the nominal and actual coverage probabilities agree satisfactorily for practical applications.

Effects of oral contraception on cancers of the female breast and reproductive tract are critically reviewed from human studies reported since 1980. The cumulative risk of breast cancer through 59 years of age appears to bear no relationship to oral contraceptive (OC) use whatsoever. Studies restricted to women under age 45, however, raise concern about a possible adverse effect from OC use before a first-term pregnancy. A duration-related protective effect against endometrial cancer occurs from use of combined OCs. The risk is reduced by about 40% with 2 years of use, and by about 60% with 4 or more years of oral contraception. Oral contraception in excess of 3 years protects against ovarian cancer. Four years of use confers a 50% reduction in risk and 7 or more years of use confers a 60%-80% reduction in ovarian cancer risk. Studies of cervical dysplasia and carcinoma in situ suggest elevated risks with 2 or more years of OC use, although results are difficult to interpret in view of numerous factors that might distort the findings. The risk of invasive cervical cancer appear to be unaffected by up to 5 years of oral contraception. Beyond this, there is evidence suggesting an elevated risk which approaches a 2-fold increase at 10 years of use. Cancers of the vagina and fallopian tube are extremely rare. Their risks have yet to be characterized in relation to oral contraception.

Characteristics of women with potential for modifying the relationship between use of oral contraceptives (OCs) and the risk of premenopausal breast cancer were investigated using data from the Cancer and Steroid Hormone study, a population-based, case-control study conducted in eight geographic areas of the United States. Cases consisted of 2945 women who were premenopausal and 20-54 years of age when breast cancer was diagnosed between December 1, 1980, and December 31, 1982; controls consisted of 2646 women with no history of breast cancer who were also premenopausal and 20-54 years of age when selected during the same period. Results are presented with the cases and controls divided into eight groups on the basis of age at diagnosis on selection (20-44, 45-54), parity (0, greater than or equal to 1), and age at menarche (less than 13, greater than or equal to 13). Among nulliparous women who experienced menarche before age 13, the relative risk of developing breast cancer in the age interval 20-44 years is estimated to be 1.0 for never-users of OCs (reference), 1.3 for greater than 0-3 years of use (95% confidence intervals 0.7-2.4), 1.3 for 4-7 years (95% CI 0.7-2.6), 2.7 for 8-11 years (95% CI 1.2-6.3), and 11.8 for 12 years or longer (95% CI 1.4-95.7). OC use is not significantly related to the risk of breast cancer among women in any of the other seven groups. These findings suggest that prolonged OC use may accelerate the onset of breast cancer for a small group of susceptible women while having no appreciable impact on overall risk. The findings should be regarded as tentative, however, since they are based upon numerous comparisons and because age of menarche was stratified at 13 years to highlight the concentration of breast cancer risk apparent in our data.

Five study centers enrolled 1,311 women seeking postcoital contraception methods. Ethinyl estradiol was administered at 5 mg/day and conjugated estrogens at 30 mg/day for five consecutive days starting within 72 hours of unprotected coitus. Eleven pregnancies occurred in the 976 women who had a single unprotected coitus at midcycle. Based on published information, 69 pregnancies would have been expected if no contraceptives were used. Although both treatments were effective in preventing pregnancy, ethinyl estradiol seemed to be more effective. At the two centers alternately prescribing both drugs, none of 137 women treated with ethinyl estradiol became pregnant, while six of the 132 given conjugated estrogens became pregnant. Women whose treatment commenced on the first postcoital day seemed to have lower pregnancy rates than those whose medication was delayed to the second or third postcoital day regardless of which drug was used. Side effects were mainly limited to nausea that occurred in 70% and vomiting that was experienced by 33% of all women treated.

The consequences of a factory closure on future employment, disability and death were investigated in a 10-year prospective follow-up study in a general practice setting. The study population consisted of 85 persons who lost their jobs when a brisling sardine factory close to Bergen in Norway was shut down in 1975. The employees of a nearby "sister factory" within the same company were chosen as a control population, consisting of 87 persons. After the factory closure, the annual employment rate of the study group showed a steady rise to a maximum level of 44% within 6 years, but even after 10 years never matched the employment rate of the controls. The cumulative rates of disability pension, granted for medical conditions only, was more than three times higher in the study group than among controls from the second through the fourth year of follow-up. This excess of disabilities then stayed relatively constant at approximately 17 per 100 persons from 5 to 10 years after the shut-down. Given present days' unemployment, the results of this investigation point to the importance of acknowledging a long-term effect of job-loss on health and social readjustment.

The procedure of in vitro fertilization, including ova collection and embryo culture and transfer, raises concern about the risk of abnormalities arising from the technique. In vitro versus in vivo comparison might be made in the study of preimplantation embryos and spontaneous abortions, the results of amniocentesis, and the findings among fetal deaths and live births. In vivo, 40% to 50% of implantation blastocysts are estimated to have a chromosomal abnormality, over 99% of which are estimated to be eliminated during the course of pregnancy. In principle, the use of early spontaneous abortions can be more efficient than amniocentesis for detecting an increased risk of chromosomal abnormalities at birth. Unless in vitro fertilization in humans strongly contradicts the experience in domestic animal reproduction, which suggests no increased risk of abnormalities at birth, a large number of births would be required to provide a definitive assessment of risk.

The effect of a factory shut-down on sick leave and disability pensions was investigated in a four-year controlled follow-up study in a general practice setting. The study population consisted of 85 people, 72 women and 13 men, who lost their jobs when a sardine factory near Bergen in Norway was shut down in 1975. The employees of a nearby sister factory' within the same company were chosen as a control population, consisting of 87 people, 66 women and 21 men. The average amount of sick leave for the study group within the first year of follow-up showed a twofold increase compared to the controls. The rate of disability pensions, estimated by the life table method with appropriate adjustments, was more than three times higher in the study group than in the control group from the second through the fourth year of follow-up. The results of this investigation provide further evidence in support of a causal relationship between job loss and illness.

Optimal allocation strategies for the comparison of proportions, p1 and p2, in two groups are discussed. Allocations which (i) maximize the precision in the estimation of the difference p1-p2, (ii) maximize the precision in the estimation of the ratio p1/p2, (iii) maximize the power to detect a group difference, and (iv) minimize the total cost of a study are compared. The recommended allocation varies markedly with the desired objective. Furthermore, there is a wide range of allocation schemes which are effectively optimal with regard to each criterion considered. A study of congenital malformations occurring in pregnancies of diabetic women is used to illustrate how these considerations apply to the planning of a study.