Origin of the immunological pregnancy test.

Promising innovations which enhance accuracy of laboratory testing and shorten turnaround time in the laboratory should receive timely recognition. Reporting a finding is more important than the apprehension that the finding might later prove to be an erroneous 'fluke'. Delay in reporting a finding until it is supported by more exacting and extensive testing may cause a clinically significant test to go undiscovered, whatever the reason. This article credits those who assisted the author in developing the world's first nonbiological pregnancy test. By serially injecting rabbits with human chorionic gonadotropin (HCG) mixed with Freund's adjuvant, the author induced antibodies to HCG. By our use of the latex particle fixation slide test, these antibodies could be detected and measured to a precision of within 10 IU.

Decline in incidence of endometrial cancer following increase in prescriptions for opposed conjugated estrogens in a prepaid health plan.

During the 1980s, the ecologic association of conjugated estrogens with endometrial cancer changed from positive to negative in a prepaid health plan. During the same period, use of progestins increased dramatically. We investigated whether the latter increase could explain the reversal of the estrogen-cancer association. Endometrial cancer incidence was estimated from cases recorded in the health plan registry divided by the number of women over age 45 years. Conjugated estrogens usage was measured as milligrams prescribed per woman per year and progestin was measured as tablets per woman per year, both based upon pharmacy records. Graphical and regression methods were used to analyze the resulting ecologic data. In a log-linear regression of incidence on conjugated estrogens and medroxyprogesterone usage, estrogen usage had a strong positive association with incidence, while medroxyprogesterone had a strong negative association with incidence. The change in the direction of the ecologic association between estrogen and endometrial cancer that occurred in 1984 continued until 1993, suggesting that the decline in endometrial cancer incidence and concomitant increase in conjugated estrogens usage since 1984 is explained by the increasing use of progestins. The data are entirely consistent with the hypothesis that progestins can protect against most of the excess risk conferred by conjugated estrogens, although the ecologic nature of the data prohibits drawing further inferences.

Myocardial infarction in users of low-dose oral contraceptives.

OBJECTIVE: To determine the relationship between the use of low-dose (less than 50 micrograms estrogen) oral contraceptives (OC) and myocardial infarction. METHODS: In this population-based case-control study, all incident myocardial infarctions in women, ages 15-44 years who were members of the Kaiser Permanente Medical Care Program, Northern and Southern California regions were ascertained during a 39-month period from 1991 through 1994. For each woman with myocardial infarction, up to three age- and facility-matched controls were chosen at random from female members. Information about OC use (predominantly low-dose preparations) was obtained in face-to-face interviews. RESULTS: There were 187 incident cases of myocardial infarction during 3.6 million woman-years of observation (incidence rate, 5.2 per 100,000 woman-years). The prevalence of several risk factors for myocardial infarction was lower in controls who were current users of OCs than in controls who were noncurrent (past and never) users. The odds ratio for myocardial infarction in current OC users compared with noncurrent users was 1.65 (95% confidence interval 0.45, 6.06) after adjustment for major risk factors and for race and ethnicity, corresponding to an excess risk of less than one case per 100,000 woman-years. The study had 80% power to detect a relative risk of 2.3 (one-sided test, alpha = .05). The odds ratio of myocardial infarction in past OC users was not elevated. CONCLUSION: With respect to myocardial infarction, low-dose oral contraceptives can be used safely by women who lack risk factors for coronary heart disease.

Stroke in users of low-dose oral contraceptives.

BACKGROUND: Previous studies have linked the use of oral contraceptive agents to an increased risk of stroke, but those studies have been limited to oral contraceptives containing more estrogen than is now generally used. METHODS: In a population-based, case-control study, we identified fatal and nonfatal strokes in female members of the California Kaiser Permanente Medical Care Program and who were 15 through 44 years of age. Matched controls were randomly selected from female members who had not had strokes. Information about the use of oral contraceptives (essentially limited to low-estrogen preparations) was obtained in interviews. RESULTS: A total of 408 confirmed strokes occurred in a total of 1.1 million women during 3.6 million woman-years of observation. The incidence of stroke was thus 11.3 per 100,000 woman-years. On the basis of data from 295 women with stroke who were interviewed and their controls, the odds ratio for ischemic stroke among current users of oral contraceptives, as compared with former users and women who had never used such drugs, was 1.18 (95 percent confidence interval, 0.54 to 2.59) after adjustment for other risk factors for stroke. The adjusted odds ratio for hemorrhagic stroke was 1.14 (95 percent confidence interval, 0.60 to 2.16). With respect to the risk of hemorrhagic stroke, there was a positive interaction between the current use of oral contraceptives and smoking (odds ratio for women with both these factors, 3.64; 95 percent confidence interval, 0.95 to 13.87). CONCLUSIONS: Stroke is rare among women of childbearing age. Low-estrogen oral-contraceptive preparations do not appear to increase the risk of stroke.

PIP: Previous studies have linked the use of oral contraceptive agents to an increased risk of stroke, but those studies have been limited to oral contraceptives containing more estrogen than is now generally used. In a population-based, case-control study, the authors identified fatal and nonfatal strokes in female members of the California Kaiser Permanente Medical Care Program who were 15-44 years of age. Matched controls were randomly selected from female members who had not had strokes. Information about the use of oral contraceptives (essentially limited to low-estrogen preparations) was obtained in interviews. A total of 408 confirmed strokes occurred in a total of 1.1 million women during 3.6 million woman-years of observation. The incidence of stroke was thus 11.3 per 100,000 woman-years. On the basis of data from 295 women with stroke who were interviewed and their controls, the odds ratio for ischemic stroke among current users of oral contraceptives, as compared with former users and women who had never used such drugs, was 1.18 (95% confidence interval [CI], 0.54-2.59) after adjustment for other risk factors for stroke. The adjusted odds ratio for hemorrhagic stroke was 1.14 (95% CI, 0.60-2.16). With respect to the risk of hemorrhagic stroke, there was a positive interaction between the current use of oral contraceptives and smoking (odds ratio for women with both these factors, 3.64; 95% CI, 0.95-13.87). The authors conclude that stroke is rare among women of childbearing age and that low-estrogen oral contraceptive preparations do not appear to increase the risk of stroke.

The relation of gastroesophageal reflux disease and its treatment to adenocarcinomas of the esophagus and gastric cardia.

OBJECTIVE: To examine the relationship of gastrointestinal disorders and their treatment to the risk of adenocarcinomas of the esophagus and gastric cardia (AEC). DESIGN: A medical record-based case-control study, with data collected on a standardized form by a trained abstractor, blind to the case-control status. SETTING: A large prepaid health plan. SUBJECTS: Case patients were plan members newly diagnosed with histologically confirmed AEC from 1986 to 1992. For each of the 196 eligible case patients, one control was selected who matched for membership at time of diagnosis, sex, year of birth, and duration of membership. MAIN OUTCOME MEASURES: Association between AEC and history of gastroesophageal conditions and their treatment. Conditional logistic regression procedures were used for calculation of odds ratios (ORs) and corresponding 95% confidence intervals (Cls), with adjustment for race, smoking status, and body mass index. Medications were grouped into H2 antagonists (cimetidine, ranitidine, famotidine, and nizatidine) and anticholinergics (propantheline bromide, dicyclomine hydrochloride, Donnatal [combination of atropine sulfate, hyoscyamine sulfate, phenobarbital, and scopolamine hydrobromide], and Librax [combination of chlordiazepoxide hydrochloride and clidinium bromide]). RESULTS: Significant twofold or greater risks of AEC were associated with a history of esophageal reflux, hiatal hernia, esophagitis/esophageal ulcer, and difficulty swallowing. The ORs increased with increasing number of these conditions. Although a fourfold risk was linked to four or more prescriptions for H2 antagonists, the risk was reduced to 1.5 (95% Cl, 0.4 to 5.4) after adjusting for the predisposing conditions. Further analysis revealed that the excess risk was restricted to persons with a history of gastroesophageal reflux and related conditions. No association was observed for overall use of anticholinergics. However, after adjustment for predisposing conditions, ORs decreased with increasing number of prescriptions for anticholinergics (P for trend = .08) CONCLUSIONS: This study provides reassuring findings that use of H2 antagonists and anticholinergics does not increase AEC risk. It also quantifies the elevated risk of AEC associated with gastroesophageal reflux disease. Further research into reflux disease and the production of premalignant epithelial changes may help elucidate carcinogenic mechanisms and measures aimed at early detection and prevention of AEC.

Endometrial cancer risk after discontinuing use of unopposed conjugated estrogens (California, United States).

To examine the decline in risk of endometrial cancer after discontinuation of use of conjugated estrogens, we conducted a case-control study in a prepaid health plan. We identified 318 patients who had endometrial cancer but had no history of bilateral oophorectomy and had been in the Southern California (United States) Kaiser Foundation Health Plan for more than 10 years. For each patient, one or two control members were selected, 599 in all, matched for age and duration of membership at the time of cancer detection and who had had neither hysterectomy nor bilateral oophorectomy. A history of prescriptions for conjugated estrogens and of potential confounders was obtained for each subject by reviewing outpatient medical records. Rate ratios (RR) contrasting users with nonusers were estimated by time of latest prescription. We found that estrogen-induced risk of endometrial cancer decreases rapidly as the estrogen-free interval increases. The RR estimates, adjusted for duration of use and potential confounding factors, declined from 5.0 for those receiving their latest prescription within 24 months (95 percent confidence limits [CL] = 2.6-9.8), to 1.8 for those receiving their latest prescription within 24 to 48 months (CL = 0.9-3.7), to values near one for each latest prescription interval earlier than 48 months ago (P for trend = 0.00004). For those who used conjugated estrogens extensively (five or more prescriptions, five to 10 years ago), the RR estimate declined from 5.1 for those whose latest prescription was within two years to 0.6 yr for those whose latest prescription was four to five years previously (P for trend = 0.05).

Estrogen's role in endometrial cancer.

Data reported since 1975 indicate that the natural hormone estrogen may act as a carcinogen when unopposed by an adequate amount of progesterone. Carcinogenesis may proceed when it is present at a high level for a short time. It is generally accepted that 3 groups of women have been at risk of developing cancer from exogenous estrogen exposure: 1) women who took sequential oral contraceptives; 2) post-menopausal women who received estrogen replacement therapy; 3) girls with ovarian dysgenesis who received unopposed estrogen therapy at puberty. Similarly, 4 groups of women appear to be at risk of developing cancer form endogenous estrogen sources: 1) women with granulosa-cell or theca-cell ovarian tumors; 2) anovulatory women; 3) obese postmenopausal women; 4) women with liver disease. The falling incidence of endometrial cancer associated with diminished estrogen sales is the final proof of an association of estrogen exposure with development of disease.

False-negative cytology rates in patients in whom invasive cervical cancer subsequently developed.

The 3-year screening interval recommended by the American Cancer Society would appear to decrease the detection of premalignant and malignant disease. The authors have shown that 20% of study patients in whom subsequently invasive cervical cancer developed had at least 2 negative Papanicolaou smears within 3 years of the diagnosis of cancer. Moreover, the majority of false-negative results in the series could be attributed to sample error. The authors recommend yearly or at least biennial cervical cytologic screening.

Reduction of Rh0(D) sensitization: a cost-effective analysis.

The first American study on the incidence of gestational Rh0(D) sensitization is reported. The authors studied 3995 Rh0(D)-negative pregnancies from a population of 40,319 deliveries at Los Angeles-area Kaiser hospitals between 1976 and 1978. Among these were 61 Rh0(D)-sensitized pregnancies: 38 in women with prior sensitizations, 21 with gestational sensitizations, and 2 postpartum Rh0(D antigen) immune globulin (RhoGAM) failures. The incidence of gestational sensitization was 1.0% (21/2098). Cost-effectiveness of prophylactic RhoGAM post partum, prophylactic RhoGAM at 28 weeks' gestation, and Fetaldex testing post partum was analyzed. Prophylactic RhoGAM at 28 weeks' gestation was the most cost-effective method of further reduction of the Rh0(D) sensitization. All nonsensitized Rh0(D)-negative mothers who delivered Rh0(D)-positive fetuses received RhoGAM.

Pseudo Meigs' syndrome. A case report.

The association of ascites, hydrothorax and struma ovarii has been previously reported in the literature. This case is added to the literature describing a variant of Meigs' syndrome, or pseudo Meigs' syndrome. A discussion of the origin of ascitic fluid illustrates how little is known about these conditions as well as the importance of their careful differential diagnosis.

Leiomyomatosis peritonealis disseminata associated with pregnancy.

The first reported case in the English literature involving leiomyomatosis peritonealis disseminata (LPD) and a subsequent pregnancy is presented. A review of the literature revealed only 8 previous cases-all of which were treated by tubal ligation or surgical castration. The patient in this report was 22 years of age at the time of diagnosis, the youngest age at which LPD is known to have occurred. The LPD was first noted at primary cesarean section, and 20 months later at a second cesarean section performed at 35 1/2 weeks' gestation, the LPD had advanced to a stage that suggested possible malignancy. All biopsy specimens were subsequently reported as benign LPD.

Macrosomia. A proposed indication for primary cesarean section.

Fetal macrosomia (birthweight equal to or in excess of 4500 g) in a study of 110 affected infants was associated with excessive maternal weight, prolonged gestation, white race, multiparity, maternal diabetes, male fetus, and a previous macrosomic infant. The two most common obstetric complications associated with fetal macrosomia were postpartum hemorrhage and shoulder dystocia. One-minute Apgar score was less than 7 in 10.9% of the macrosomic infants, in contrast to 6.3% for the smaller infants studied as controls. The low fetal mortality rate (1.8%) was attributed to a 22.5% cesarean rate for the macrosomia group. Even more frequent use of abdominal delivery might further reduce obstetric and neonatal complications for macrosomic infants.

Estrogen and endometrial carcinoma. An independent pathology review supporting original risk estimate.

Initial evidence suggested that estrogen therapy increases the risk of endometrial carcinoma. It was then suggested that some studies may have exaggerated the hazard of estrogen therapy by including patients with atypical endometrial hyperplasia among those having endometrial carcinoma. Three internationally recognized pathologists reviewed the histology slides available from the Ziel and Finkle study, which originally reported a risk ratio of 7.6 for estrogen users. At least one of the pathologists concurred with the original diagnosis in all but one case. Furthermore, all pathologists aggreed that 74 per cent (66/89) were correctly diagnosed. In the 66 patients with unanimous diagnosis, 61 per cent (40/66) had used conjugated estrogens, versus 57 per cent (54/94) in the original study. On the basis of 66 patients and 132 matched controls, the revised risk-ratio estimate is 8.1 (with a one-sided 95 per cent lower confidence limit of 4.5), validating the original estimate.

Association of estrone with the development of endometrial carcinoma.

Although few clinicians suspect estrogen as the prime cause of endometrial carcinoma, a retrospective study showed the following among postmenopausal women: 70 per cent of those with endometrial carcinoma and only 23 per cent of matched control subjects used estrogen systemically. Endometrial cancer developed an average of five years earlier in those taking than in those not receiving estrogen. Forty-two per cent of those with endometrial cancer had received estrogen three years or more. Most significantly, conjugated estrogens were used by 89 per cent of postmenopausal cancer patients who had received any estrogenic substance. The increased risk of endometrial cancer for all patients receiving conjugated estrogen (the risk ratio) was 7.4. This risk ratio increased with duration of conjugated estrogen exposure, from 4.6 in patients with less than three years' exposure to 9.2 in patients with three or more years' exposure.

Increased risk of endometrial carcinoma among users of conjugated estrogens.

The possibility that the use of conjugated estrogens increases the risk of endometrial carcinoma was investigated in patients and a twofold age-matched control series from the same population. Conjugated estrogens (principally sodium estrone sulfate) use was recorded for 57 per cent of 94 patients with endometrial carcinoma, and for 15 per cent of controls. The corresponding point estimate of the (instantaneous) risk ratio was 7.6 with a one-sided 95 per cent lower confidence limit of 4.7. The risk-ratio estimate increased with duration of exposure: from 5.6 for 1 to 4.9 years exposure to 13.9 for seven or more years. The estimated proportion of cases related to conjugated estrogens, the etiologic fraction, was 50 per cent with a one-sided 95 per cent lower confidence limit of 41 per cent. These data suggest that conjugated estrogens have an etiologic role in endometrial carcinoma.