Dennis Slone

VENOUS THROMBOEMBOLIC DISEASE AND ABO BLOOD TYPE: A Cooperative Study

Abstract A prospective drug-surveillance programme revealed a deficit of patients with bloodgroup O among those who received anticoagulants for venous thromboembolism. This observation led to a cooperative study in the United States of America, Sweden, and the United Kingdom to obtain the blood types of young white women developing venous thromboembolism while taking oral contraceptives, during pregnancy or the puerperium, or at other times. There was a deficit of patients with blood type O in all the groups studied. This deficit was particularly prominent when the thromboembolism was associated with the use of oral contraceptives or with pregnancy.

Diphenylhydantoin and Selected Congenital Malformations

Abstract In a cohort of 50,897 pregnancies, frequencies of malformations, selected on the basis of reports in the literature, were compared between four groups of children born to epileptic mothers and those born to nonepileptic mothers. The highest malformation rate (61 per 1000) was observed in 98 children exposed during the early months of pregnancy to daily diphenylhydantoin (phenytoin) use. The rate was lowest in 50,591 children born to nonepileptic women (25 per 1000). It was intermediate in children of epileptic mothers exposed before delivery to sporadic or late use of diphenylhydantoin, and in children of such mothers who were not exposed to the drug. Among epileptic women with varying or no exposure to diphenylhydantoin, the malformation rates did not differ significantly. The difference in the malformation rates between children exposed regularly to diphenylhydantoin during early gestation and children born to nonepileptic mothers could reflect the teratogenic effect of the drug, of epilepsy it...

ORAL-CONTRACEPTIVE USE IN RELATION TO MYOCARDIAL INFARCTION

The effect of oral-contraceptive use on the risk of myocardial infarction and, in particular, the possible accentuation of that effect by cigarette smoking, was investigated in 234 premenopausal women with a first infarction and 1742 hospital controls. The overall rate ratio estimate of acute myocardial infarction for women who had used oral contraceptives in the preceding month was 4.0 (95% confidence interval, 2.5--6.3). Women who smoked heavily and used oral contraceptives had a point estimate of 39 (lower two-sided 95% confidence limit, 22) compared with those who did neither. This value was appreciably larger than could be accounted for by the separate effects of cigarettes and oral contraceptives, and this suggests a considerable accentuation by cigarette smoking of the effect of oral contraceptive use on myocardial infarction.

Coffee and Myocardial Infarction

Abstract A positive association between coffee consumption and acute myocardial infarction was confirmed by analyses of data from a multipurpose survey of 12,759 hospitalized patients, including 440 with a diagnosis of acute myocardial infarction. As compared with those who drink no coffee, the risks of infarction among those drinking one to five and six or more cups of coffee per day are estimated to be increased by 60 and 120 per cent, respectively. This association could not be attributed to confounding by age, sex, past coronary heart disease, hypertension, congestive heart failure, obesity, diabetes, smoking or occupation, nor could it be explained by the use of sugar with coffee. There was no positive association between tea drinking and acute myocardial infarction. (N Engl J Med 289:63–67, 1973)

Efficacy and Toxicity of Heparin in Relation to Age and Sex

Abstract In 97 consecutive patients who received heparin, efficacy, as assessed by a clinically satisfactory response, was not related to sex or age. Adverse reactions occurred in 18 out of 56 women (32 per cent) and six out of 41 men (15 per cent). Average age of patients with reactions was 66 years versus 55 years for the remainder. The p values for association by sex and age were respectively less than 0.05 and 0.02. The increased toxicity in women appeared to be limited to those over the age of 60. In these, the risk was 50 per cent. Corresponding figures for men over 60, women under 60 and men under 60 were 19 per cent, 14 per cent and 10 per cent, respectively. All but one of the reactions were due to bleeding. Death from massive intrapulmonary hemorrhage was attributed to heparin in one case. There appears to be a higher risk of bleeding, without a corresponding improvement in efficacy, in women over the age of 60 who receive heparin.

Risk of Myocardial Infarction in Relation to Current and Discontinued Use of Oral Contraceptives

In a hospital-based case-control study, we evaluated the rate of myocardial infarction in relation to discontinued as well as current use of oral contraceptives. We compared 556 women with infarction, 25 to 49 years old, with 2036 age-matched control subjects. For current users, the rate-ratio estimate was 3.5 (95 per cent confidence limits, 2.2 to 5.5). For past users 40 to 49 years of age, the magnitude of the rate ratio was related to the duration of use: for total durations of past use of less than five years, five to nine years, and 10 or more years, respectively, the rate-ratio estimates (with 95 per cent confidence limits) were 1.0 (0.8 and 1.4), 1.6 (1.1 and 2.5), and 2.5 (1.5 and 4.1). This trend was statistically significant (P less than 0.01). The findings suggest that an effect on the risk of myocardial infarction persists after the discontinuation of long-term use of oral contraceptives.

Cardiovascular birth defects and antenatal exposure to female sex hormones.

In a cohort of 50,282 pregnancies 19 children with cardiovascular defects were born to 1042 women who received female hormones during early pregnancy (18.2 per 1000). Among 49,240 children not exposed in utero to these agents there were 385 with cardiovascular malformations (7.8 per 1000). Six children with cardiovascular defects were born to a sub-group of 278 women who used oral contraceptives during early pregnancy (21.5 per 1000). After the data were controlled for a wide variety of potentially confounding factors by multivariate methods, the association between in utero exposure to female hormones and cardiovascular birth defects was statistically significant.

Cigarette smoking and age at natural menopause.

In a cohort of 656 naturally postmenopausal women who were interviewed at age 60 to 69 years, and was had reached their menopause between the ages of 35 and 59 years, the mean age at menopause declined with increasing number of cigarettes smoked, from 49.4 years of age among women who had never smoked to 47.6 years of age among women who smoked at least 15 cigarettes per day (p less than 0.02). The relationship was not attributable to the onset of menopause inducing women to take up smoking.

Antenatal exposure to the phenothiazines in relation to congenital malformations, perinatal mortality rate, birth weight, and intelligence quotient score

In a prospective cohort study of 50,282 gravidas and their offspring, over-all rates of congenital malformations were similar in 1,309 children of women exposed to phenothiazine drugs during the first four lunar months of pregnancy and in 48,973 children of women who were not exposed. There was a suspicion of association between phenothiazine exposure and cardiovascular malformations. In a cohort reduced to 41,337 mother-child pairs for technical reasons, perinatal mortality rates and mean birth weight were similar according to phenothiazine exposure or nonexposure, as were intelligence quotient scores measured at four years of age in 28,358 of the children. Control of potential confounding factors with a variety of multivariate techniques did not materially alter the findings.

Recent and Past Use of Conjugated Estrogens in Relation to Adenocarcinoma of the Endometrium

It has been suggested that the reported association between estrogen use and endometrial cancer may have been biased because estrogens provoke uterine bleeding in women with otherwise asymptomatic disease. To evaluate this hypothesis we compared 149 patients with endometrial cancer and 402 control subjects with other conditions with reference to the time when they had last used conjugated estrogens. In women who had last used conjugated estrogens two or more years previously and who had taken them for at least five years, the rate-ratio estimate was 3.3 (95 per cent confidence interval, 1.4 to 8.0) relative to women who had never used them. Uterine bleeding, and hence the diagnosis of otherwise asymptomatic cancer, cannot be attributed to estrogen use that ceased in the distant past. Our results suggest that such use has a residual effect on the risk of endometrial cancer; this effect is not accounted for by biased selection of cases according to estrogen use.