Maternal serum paraxanthine, a caffeine metabolite, and the risk of spontaneous abortion

BACKGROUND: Whether the consumption of caffeine during pregnancy increases the risk of spontaneous abortion is controversial. Prior studies have determined caffeine consumption by questionnaire. We used a biologic marker, such as serum paraxanthine, a metabolite of caffeine, to measure the dose of caffeine. METHODS: In a nested case-control study, we measured serum paraxanthine in 591 women who had spontaneous abortions at less than 140 days' gestation and in 2558 matched women from the same clinic who gave birth to live infants at 28 weeks' gestation or later and who had serum drawn on the same day of gestation as the women who had abortions. The women were enrolled in the Collaborative Perinatal Project during the period from 1959 to 1966, and serum paraxanthine was measured over 30 years later. RESULTS: A total of 487 women who had spontaneous abortions (82 percent) and 2087 controls (82 percent) had quantifiable serum paraxanthine concentrations. However, the mean serum paraxanthine concentration was higher in the women who had spontaneous abortions than in the controls (752 vs. 583 ng per milliliter, P<0.001). The odds ratio for spontaneous abortion was not significantly elevated in the women who had serum paraxanthine concentrations of 1845 ng per milliliter or lower, corresponding to the 95th percentile of the matched women. However, the adjusted odds ratio for spontaneous abortion among women with serum paraxanthine concentrations higher than 1845 ng per milliliter, as compared with women who had concentrations below 50 ng per milliliter, was 1.9 (95 percent confidence interval, 1.2 to 2.8). CONCLUSIONS: Only extremely high serum paraxanthine concentrations are associated with spontaneous abortion. This suggests that moderate consumption of caffeine is unlikely to increase the risk of spontaneous abortion.     

Does caffeine and alcohol intake before pregnancy predict the occurrence of spontaneous abortion?

BACKGROUND: Consumption of caffeine and alcohol is suspected to affect pregnancy outcome. Use of both stimulants is widespread and even minor effects on fetal viability are of public health interest. METHODS: We performed a nested case-control study using prospective data from a population-based cohort comprising 11088 women aged 20-29 years. From this cohort, women who experienced either a spontaneous abortion (n = 303) or who gave birth (n = 1381) during follow-up [mean time: 2.1 years (range: 1.6-3.4)] were selected. Associations between self-reported exposures to caffeine and/or alcohol at enrolment and spontaneous abortion were analysed by means of logistic regression. RESULTS: Compared with women with a pre-pregnancy intake of <75 mg caffeine per day, the adjusted odds ratio (95% confidence interval) for spontaneous abortion was 1.26 (0.77-2.06), 1.45 (0.87-2.41), 1.44 (0.87-2.37) and 1.72 (1.00-2.96) for a pre-pregnancy intake on 75-300, 301-500, 501-900 and >900 mg caffeine per day respectively (P = 0.05 for trend). A pre-pregnancy intake of alcohol was not a predictor for spontaneous abortion. CONCLUSIONS: A high intake of caffeine prior to pregnancy seems to be associated with an increased risk of spontaneous abortion, whereas a low-to-moderate alcohol intake does not influence the risk.     

Video display terminals and the risk of spontaneous abortion

BACKGROUND. The relation between spontaneous abortion and the use of video display terminals (VDTs) is of great public health concern. Previous investigators of this issue have reported inconsistent findings. METHODS. To determine whether electromagnetic fields emitted by VDTs are associated with an increased risk of spontaneous abortion, a cohort of female telephone operators who used VDTs at work was compared with a cohort of operators who did not use VDTs. To obtain reliable estimates of exposure, we determined the number of hours of VDT use per week from company records and measured electromagnetic fields at VDT workstations and, for purposes of comparison, at workstations without VDTs. Operators who used VDTs had higher abdominal exposure to very-low-frequency (15 kHz) electromagnetic fields (workstations without VDTs did not emit very-low-frequency energy). Abdominal exposure to extremely-low-frequency fields (45 to 60 Hz) was similar for both operators who used VDTs and those who did not. Among 2430 women interviewed, there were 882 pregnancies that met our criteria for inclusion in the study. RESULTS. We found no excess risk of spontaneous abortion among women who used VDTs during the first trimester of pregnancy (odds ratio = 0.93; 95 percent confidence interval, 0.63 to 1.38), and no dose-response relation was apparent when we examined the women's hours of VDT use per week (odds ratio for 1 to 25 hours per week = 1.04; 95 percent confidence interval, 0.61 to 1.79; odds ratio for greater than 25 hours per week = 1.00; 95 percent confidence interval, 0.61 to 1.64). There continued to be no risk associated with the use of VDTs when we accounted for multiple pregnancies, conducted separate analyses of early abortion, late abortion, and all fetal losses, or limited our analyses to spontaneous abortions for which a physician was consulted. CONCLUSIONS. The use of VDTs and exposure to the accompanying electromagnetic fields were not associated with an increased risk of spontaneous abortion in this study.     

Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception

Whether pregnant women with insulin-dependent diabetes mellitus have an increased risk of spontaneous abortion is controversial. To address this question, we enrolled 386 women with insulin-dependent diabetes and 432 women without diabetes before or within 21 days after conception and followed both groups prospectively. Sixty-two diabetic women (16.1 percent) and 70 control women (16.2 percent) had pregnancy losses (odds ratio, 0.99; 95 percent confidence interval, 0.67 to 1.46). After adjustment for known risk factors for spontaneous abortion, the rate was still not significantly higher in the diabetic group (odds ratio, 0.91; 95 percent confidence interval, 0.59 to 1.40). Nonetheless, among the diabetic women, most of whom had good metabolic control, those who had spontaneous abortions had higher fasting and postprandial glucose levels in the first trimester than those whose pregnancies continued to delivery (P = 0.01 for fasting glucose levels and P = 0.005 for postprandial levels). In the small subgroup of diabetic women with poor control, who had elevated values for glycosylated hemoglobin in the first trimester, each increase of 1 SD above the normal range was associated with an increase of 3.1 percent in the rate of pregnancy loss (95 percent confidence interval, 0.6 to 5.6). We conclude that diabetic women with good metabolic control are no more likely than nondiabetic women to lose a pregnancy, but that diabetic women with elevated blood glucose and glycosylated hemoglobin levels in the first trimester have a significantly increased risk of having a spontaneous abortion.     

The influence of gestational age and smoking habits on the risk of subsequent preterm deliveries.

BACKGROUND: Previous preterm delivery and maternal smoking are associated with increased risks of preterm delivery. It is not known whether gestational age at the time of a preterm delivery is correlated with gestational age in successive preterm deliveries and whether changes in smoking habits influence the subsequent risk of preterm delivery. METHODS: We studied the associations among smoking habits, previous very preterm or moderately preterm delivery (before 32 weeks and at 32 to 36 weeks, respectively), and the risk of a subsequent very preterm or moderately preterm delivery in a population-based cohort of 243,858 women in Sweden between 1983 and 1993. The results were adjusted for covariates known to be associated with preterm delivery. RESULTS: The odds ratios for very or moderately preterm delivery in a subsequent pregnancy among women with a previous very preterm delivery, as compared with women who had a previous term delivery, were 12.4 (95 percent confidence interval, 9.1 to 17.0) and 7.1 (95 percent confidence interval, 6.0 to 8.4), respectively. Among women with a previous moderately preterm delivery, the corresponding odds ratios were 2.3 (95 percent confidence interval, 1.9 to 3.0) and 5.9 (95 percent confidence interval, 5.5 to 6.3), respectively. The odds ratios for a very preterm second delivery among the women who smoked 1 to 9 cigarettes per day and those who smoked 10 or more cigarettes per day, as compared with nonsmokers, were 1.4 (95 percent confidence interval, 1.1 to 1.7) and 1.6 (95 percent confidence interval, 1.3 to 2.0), respectively. The corresponding odds ratios for moderate preterm delivery were 1.3 (95% confidence interval, 1.2 to 1.4) and 1.5 (95 percent confidence interval, 1.4 to 1.6). The women who quit smoking between pregnancies were not at increased risk for very or moderately preterm delivery, whereas the women who started to smoke in the second pregnancy had the same risk as those who continued to smoke. CONCLUSIONS: The risk of a very preterm delivery in successive pregnancies is increased primarily among women with a previous very preterm delivery. Changes in smoking habits influence the risk of preterm delivery as well.     

Lupus anticoagulants, anticardiolipin antibodies, and fetal loss. A case-control study

BACKGROUND. Lupus anticoagulants and anticardiolipin antibodies are antiphospholipid antibodies that have been associated with fetal loss, but they have not been shown unequivocally to be a risk factor for this event. METHODS. To estimate the risk of fetal loss in association with these antibodies, we conducted a hospital-based case-control study of 331 women with spontaneous abortion or fetal death (case patients) and 993 controls. The subjects were included in the study only if they reported that they had had no previous spontaneous fetal loss. Each control was a pregnant woman who, in the same period of pregnancy as a case patient, had not had a fetal loss. Lupus anticoagulants were identified in blood samples through a series of coagulation tests, and IgG anticardiolipins by an enzyme-linked immunosorbent assay. Each subject was interviewed in person to obtain information on potential confounding variables, such as sociodemographic characteristics and medical conditions. RESULTS. Lupus anticoagulants were found in blood from 17 case patients (5.1 percent) and 38 controls (3.8 percent). The crude odds ratio for the association between lupus anticoagulants and fetal loss was 1.36 (95 percent confidence interval, 0.75 to 2.43); the odds ratio adjusted for confounders was 1.42 (95 percent confidence interval, 0.72 to 2.80). An IgG anticardiolipin level of 5 units or more was found in 4 case patients (1.2 percent) and 15 controls (1.5 percent). The crude and adjusted odds ratios for fetal loss were 0.80 (95 percent confidence interval, 0.26 to 2.41) and 1.28 (95 percent confidence interval, 0.38 to 4.21), respectively. CONCLUSIONS. There is not apparent justification for considering lupus anticoagulants or IgG anticardiolipins to be risk factors for fetal loss among women who present with spontaneous abortion or fetal death and have had no previous spontaneous fetal loss.     

Risk factors for adenomyosis

In order to analyse risk factors for adenomyosis, 707 consecutive women who underwent hysterectomy between January 1993 and June 1994 at the Clinica Luigi Mangiagalli, Milan, Italy, were interviewed before surgery by trained physicians. Information on the presence of adenomyosis was obtained from pathologic records. Out of the 707 women, adenomyosis was identified in 150 subjects (21.2%). Women who smoked tended to be at decreased risk of the condition: in comparison with women who had never smoked, the risk for current smokers was 0.7 (0.3- 1.3) and the risk decreased with number of cigarettes smoked per day, the odds ratios being 0.8 and 0.6 respectively in women reporting fewer than 10 and more than 10 cigarette smoked per day (chi2 trend 3.57, P = 0.06). The frequency of adenomyosis was higher in parous women: in comparison with nulliparae, the odds ratio of the disease were 1.8 [95% confidence interval (CI) 0.9-3.4] and 3.1 (95% CI 1.7-5.5) respectively in women reporting one and two or more births (chi2 trend 20.71, P < 0.01). Likewise, women reporting one or more spontaneous abortions had an odds ratio of 1.7 (95% CI 1.1-2.6) for adenomyosis, in comparison with those reporting no spontaneous abortion.      

Risk of uterine rupture during labor among women with a prior cesarean delivery.

BACKGROUND: Each year in the United States, approximately 60 percent of women with a prior cesarean delivery who become pregnant again attempt labor. Concern persists that a trial of labor may increase the risk of uterine rupture, an uncommon but serious obstetrical complication. METHODS: We conducted a population-based, retrospective cohort analysis using data from all primiparous women who gave birth to live singleton infants by cesarean section in civilian hospitals in Washington State from 1987 through 1996 and who delivered a second singleton child during the same period (a total of 20,095 women). We assessed the risk of uterine rupture for deliveries with spontaneous onset of labor, those with labor induced by prostaglandins, and those in which labor was induced by other means; these three groups of deliveries were compared with repeated cesarean delivery without labor. RESULTS: Uterine rupture occurred at a rate of 1.6 per 1000 among women with repeated cesarean delivery without labor (11 women), 5.2 per 1000 among women with spontaneous onset of labor (56 women), 7.7 per 1000 among women whose labor was induced without prostaglandins (15 women), and 24.5 per 1000 among women with prostaglandin-induced labor (9 women). As compared with the risk in women with repeated cesarean delivery without labor, uterine rupture was more likely among women with spontaneous onset of labor (relative risk, 3.3; 95 percent confidence interval, 1.8 to 6.0), induction of labor without prostaglandins (relative risk, 4.9; 95 percent confidence interval, 2.4 to 9.7), and induction with prostaglandins (relative risk, 15.6; 95 percent confidence interval, 8.1 to 30.0). CONCLUSIONS: For women with one prior cesarean delivery, the risk of uterine rupture is higher among those whose labor is induced than among those with repeated cesarean delivery without labor. Labor induced with a prostaglandin confers the highest risk.     

A clinical trial of estrogen-replacement therapy after ischemic stroke.

BACKGROUND: Observational studies have suggested that estrogen-replacement therapy may reduce a woman's risk of stroke and death. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of estrogen therapy (1 mg of estradiol-17beta per day) in 664 postmenopausal women (mean age, 71 years) who had recently had an ischemic stroke or transient ischemic attack. Women were recruited from 21 hospitals in the United States and were followed for the occurrence of stroke or death. RESULTS: During a mean follow-up period of 2.8 years, there were 99 strokes or deaths among the women in the estradiol group, and 93 among those in the placebo group (relative risk in the estradiol group, 1.1; 95 percent confidence interval, 0.8 to 1.4). Estrogen therapy did not reduce the risk of death alone (relative risk, 1.2; 95 percent confidence interval, 0.8 to 1.8) or the risk of nonfatal stroke (relative risk, 1.0; 95 percent confidence interval, 0.7 to 1.4). The women who were randomly assigned to receive estrogen therapy had a higher risk of fatal stroke (relative risk, 2.9; 95 percent confidence interval, 0.9 to 9.0), and their nonfatal strokes were associated with slightly worse neurologic and functional deficits. CONCLUSIONS: Estradiol does not reduce mortality orthe recurrence of stroke in postmenopausal women with cerebrovascular disease. This therapy should not be prescribed for the secondary prevention of cerebrovascular disease.     

Oral contraceptives and the risk of myocardial infarction.

BACKGROUND: An association between the use of oral contraceptives and the risk of myocardial infarction has been found in some, but not all, studies. We investigated this association, according to the type of progestagen included in third-generation (i.e., desogestrel or gestodene) and second-generation (i.e., levonorgestrel) oral contraceptives, the dose of estrogen, and the presence or absence of prothrombotic mutations METHODS: In a nationwide, population-based, case-control study, we identified and enrolled 248 women 18 through 49 years of age who had had a first myocardial infarction between 1990 and 1995 and 925 control women who had not had a myocardial infarction and who were matched for age, calendar year of the index event, and area of residence. Subjects supplied information on oral-contraceptive use and major cardiovascular risk factors. An analysis for factor V Leiden and the G20210A mutation in the prothrombin gene was conducted in 217 patients and 763 controls RESULTS: The odds ratio for myocardial infarction among women who used any type of combined oral contraceptive, as compared with nonusers, was 2.0 (95 percent confidence interval, 1.5 to 2.8). The adjusted odds ratio was 2.5 (95 percent confidence interval, 1.5 to 4.1) among women who used second-generation oral contraceptives and 1.3 (95 percent confidence interval, 0.7 to 2.5) among those who used third-generation oral contraceptives. Among women who used oral contraceptives, the odds ratio was 2.1 (95 percent confidence interval, 1.5 to 3.0) for those without a prothrombotic mutation and 1.9 (95 percent confidence interval, 0.6 to 5.5) for those with a mutation CONCLUSIONS: The risk of myocardial infarction was increased among women who used second-generation oral contraceptives. The results with respect to the use of third-generation oral contraceptives were inconclusive but suggested that the risk was lower than the risk associated with second-generation oral contraceptives. The risk of myocardial infarction was similar among women who used oral contraceptives whether or not they had a prothrombotic mutation.     

Caffeine intake, CYP1A2 polymorphism and the risk of recurrent pregnancy loss

Some case-control studies have demonstrated that caffeine intake and high CYP1A2 activity increase risks of recurrent pregnancy loss (RPL) but the multifactorial effect is obscure. To investigate whether susceptible women who have more caffeine intake are at high risk of RPL, a case-control study of 58 cases with two or more RPL and fertile 147 controls was performed. The association between daily caffeine intake together with CYP1A21F (AA versus CA and CC) genotype and RPL was assessed. Without consideration of the genotype, there were no significant differences of the RPL risk in proportion to daily caffeine intake [less than 100 mg (reference); 100-299 mg: odds ratio (OR), 1.29; 95% confidence interval (CI), 0.66-2.50; 300 mg or more: OR, 1.82; 95% CI, 0.72-4.58; P for trend, 0.20]. However, the RPL risk significantly increased only among women who had homozygous CYP1A21F alleles with a dosage effect of daily caffeine intake [less than 100 mg (reference); 100-299 mg: OR, 1.94; 95% CI, 0.57-6.66; 300 mg or more: OR, 5.23; 95% CI, 1.05-25.9; P for trend, 0.03]. It was demonstrated for the first time that an increase in caffeine intake deteriorates the fecundity among susceptible women.     

The risk of menstrual abnormalities after tubal sterilization. U.S. Collaborative Review of Sterilization Working Group

BACKGROUND: The existence of a post-tubal-ligation syndrome of menstrual abnormalities has been debated for decades. We used data from the U.S. Collaborative Review of Sterilization to determine whether the likelihood of persistent menstrual abnormalities was greater among women who had undergone tubal sterilization than among women who had not. METHODS: A total of 9514 women who underwent tubal sterilization and 573 women whose partners underwent vasectomy were followed in a multicenter, prospective cohort study for up to five years by means of annual telephone interviews. All women were asked the same questions about six characteristics of their menstrual cycles in the presterilization and follow-up interviews. Multiple logistic-regression analysis was used to assess the risk of persistent menstrual changes. RESULTS: The women who had undergone sterilization were no more likely than those who had not undergone the procedure to report persistent changes in intermenstrual bleeding or the length of the menstrual cycle. They were more likely to have decreases in the number of days of bleeding (odds ratio, 2.4; 95 percent confidence interval, 1.1 to 5.2), the amount of bleeding (odds ratio, 1.5; 95 percent confidence interval, 1.1 to 2.0), and menstrual pain (odds ratio, 1.3; 95 percent confidence interval, 1.0 to 1.8) and to have an increase in cycle irregularity (odds ratio, 1.6; 95 percent confidence interval, 1.1 to 2.3). Among women who had had very heavy bleeding at base line, women who had undergone sterilization were more likely than women who had not undergone the procedure to report decreased bleeding (45 percent vs. 33 percent, P=0.03). CONCLUSIONS: Women who have undergone tubal sterilization are no more likely than other women to have menstrual abnormalities.     

Weight, diet, and the risk of symptomatic gallstones in middle-aged women

To assess the risk factors for symptomatic gallstones, 88,837 women in the Nurses' Health Study cohort (age range, 34 to 59 years) were followed for four years after completing a detailed questionnaire about food and alcohol intake in 1980. A total of 433 cholecystectomies and 179 cases of newly symptomatic, unremoved gallstones, diagnosed by ultrasonographic examination or x-ray films, were reported during the four-year follow-up. The age-adjusted relative risk for very obese women, who had a Quetelet index of relative weight (weight in kilograms divided by the square of the height in meters) of more than 32 kg per square meter, was 6.0 (95 percent confidence interval, 4.0 to 9.0), as compared with women whose relative weight was less than 20 kg per square meter. For slightly overweight women (relative weight, 24 to 24.9 kg per square meter), the relative risk was 1.7 (95 percent confidence interval, 1.1 to 2.7). Overall, we observed a roughly linear relation between relative weight and the risk of gallstones. Among the 59,306 women whose relative weight was less than 25 kg per square meter, a high energy intake (greater than 8200 J per day), as compared with a low energy intake (less than 4730 J per day), was associated with an increased incidence of symptomatic gallstones (relative risk, 2.1; 95 percent confidence interval, 1.4 to 3.3), and an alcohol intake of at least 5 g per day was associated with a decreased incidence as compared with abstention (relative risk, 0.6; 95 percent confidence interval, 0.4 to 0.8). Parity did not appear to be an important risk factor after an adjustment was made for relative weight. These data support a strong association between obesity and symptomatic gallstones and suggest that even moderate overweight may increase the risk.     

Pregnancy: Alcohol and risk of spontaneous abortion

The objective of this study was to assess the association betweenalcohol drinking before and during pregnancy and the risk ofspontaneous abortion using data from a case-control study conductedin Milan, Italy. A total of 462 women (median age 30 years)were admitted for spontaneous abortion (within the 12th weekof gestation) to a network of obstetrics departments in thegreater Milan area. Of these, 148 (32%) were between the fourthand the eighth week of gestation and 314 (68%) between the ninthand the 12th week. A control group was made up of 814 women(median age 29 years) who gave birth at term (>37 weeks gestation)to healthy infants (Apgar 5th minute 8, weight 3000 g) on randomlyselected days at the same hospitals where cases had been identified.A total of 212 cases (46%) and 355 controls (47%) reported alcoholdrinking before conception. Considering non-drinkers as thereference category, the relative risks (RR) of spontaneous abortionwere 1.2 (95% confidence interval (CI), 0.9–1.6] and 0.8(95% CI, 0.6–1.1), respectively, in drinkers of one toseven and more than seven drinks per week before conception.No association emerged between the duration of alcohol drinkingand the risk of spontaneous abortion. A total of 166 cases (35.9%)and 263 (32.3%) controls reported any alcohol drinking duringthe first trimester of pregnancy. The corresponding relativerisk was 1.1 (95% CI, 0.9–1.4) and no relationship emergedbetween the number of drinks per week and the risk of abortion.Likewise, maternal wine and beer drinking in the first trimesterof pregnancy was not associated with the risk of spontaneousabortion. Evidence available from this and previous studies,although partially controversial, indicates that moderate (oneor two drinks per day) alcohol consumption does not increasemarkedly the risk of miscarriage.     

Light-to-moderate alcohol consumption and risk of stroke among U.S. male physicians

BACKGROUND: Several studies have shown U- or J-shaped relations between alcohol consumption and the risk of stroke. We evaluated the effect of light-to-moderate alcohol intake on the risk of stroke, with separate analyses of ischemic stroke and hemorrhagic stroke. METHODS: Our analyses were based on a prospective cohort study of 22,071 male physicians, 40 to 84 years old, who were participating in the Physicians' Health Study. At base line, the participants reported that they had no history of stroke, transient ischemic attack, or myocardial infarction and were free of cancer. Alcohol intake, reported by 21,870 participants at base line, ranged from none or almost none to two or more drinks per day. RESULTS: During an average of 12.2 years of follow-up, 679 strokes were reported. As compared with participants who had less than one drink per week, those who drank more had a reduced overall risk of stroke (relative risk, 0.79; 95 percent confidence interval, 0.66 to 0.94) and a reduced risk of ischemic stroke (relative risk, 0.77; 95 percent confidence interval, 0.63 to 0.94). There was no statistically significant association between alcohol consumption and hemorrhagic stroke. The overall relative risks of stroke for the men who had one drink per week, two to four drinks per week, five or six drinks per week, or one or more drinks per day were 0.78 (95 percent confidence interval, 0.59 to 1.04), 0.75 (95 percent confidence interval, 0.58 to 0.96), 0.83 (95 percent confidence interval, 0.62 to 1.11), and 0.80 (95 percent confidence interval, 0.64 to 0.99), respectively, in an analysis in which we controlled for major risk factors for stroke. CONCLUSIONS: Light-to-moderate alcohol consumption reduced the overall risk of stroke and the risk of ischemic stroke in men. The benefit is apparent with as little as one drink per week. Greater consumption, up to one drink per day, does not increase the observed benefit.     

Alcohol consumption and withdrawal in new-onset seizures

We studied alcohol use before the onset of a first seizure in 308 patients with seizures and 294 controls. The risk of seizures increased with increasing current alcohol use. For unprovoked seizures (i.e., seizures occurring without an antecedent event, such as a recent stroke), the adjusted odds ratios rose from 3-fold at intakes of 51 to 100 g of ethanol per day (95 percent confidence limits, 1.3 and 6.3), to 8-fold at 101 to 200 g per day (95 percent confidence limits, 3.3 and 18.7), and to almost 20-fold at 201 to 300 g per day (95 percent confidence limits, 6.1 and 6.2). For provoked seizures, the odds ratios were lower and statistically significant only above 200 g per day (odds ratio, 10.1; 95 percent confidence limits, 2.3 and 43.8 at 201 to 300 g per day; odds ratio, 7.4; 95 percent confidence limits, 1.8 and 30.5 above 300 g per day). Among ex-drinkers (abstention greater than or equal to 1 year), no increased risk was detected. Alcohol withdrawal was not associated with the onset of seizures in this study; 16 percent of first seizures in drinkers fell outside the conventionally defined withdrawal period, and the remainder exhibited a seemingly random timing after the last drink. We conclude that the relation of seizures to alcohol use is dose dependent and appears to be causal, and that seizures can be interpreted as a disorder induced by the ingestion of alcohol, independently of alcohol withdrawal.     

Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins

BACKGROUND. Postmenopausal estrogen-replacement therapy may reduce the risk of cardiovascular disease, and this beneficial effect may be mediated in part by favorable changes in plasma lipid levels. However, the effects on plasma lipoprotein levels of postmenopausal estrogens in the low doses currently used have not been precisely quantified, and the mechanism of these effects is unknown. METHODS. We conducted two randomized, double-blind crossover studies in healthy postmenopausal women who had normal lipid values at base line. In study 1, 31 women received placebo and conjugated estrogens at two doses (0.625 mg and 1.25 mg per day), each treatment for three months. In study 2, nine women received placebo, oral micronized estradiol (2 mg per day), and transdermal estradiol (0.1 mg twice a week), each treatment for six weeks. The metabolism of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) was measured by endogenously labeling their protein component, apolipoprotein B. RESULTS. In study 1, the conjugated estrogens at doses of 0.625 mg per day and 1.25 mg per day decreased the mean LDL cholesterol level by 15 percent (95 percent confidence interval, 11 to 19 percent; P less than 0.0001) and 19 percent (95 percent confidence interval, 15 to 23 percent; P less than 0.0001), respectively; increased the HDL cholesterol level by 16 percent (95 percent confidence interval, 12 to 20 percent; P less than 0.0001) and 18 percent (95 percent confidence interval, 14 to 22 percent; P less than 0.0001), respectively; and increased VLDL triglyceride levels by 24 percent (95 percent confidence interval, 8 to 40 percent; P less than 0.003) and 42 percent (95 percent confidence interval, 26 to 58 percent; P less than 0.0001), respectively. In study 2, oral estradiol increased the mean concentration of large VLDL apolipoprotein B by 30 +/- 10 percent (P = 0.05) by increasing its production rate by 82 +/- 18 percent (P less than 0.01). Most of this additional large VLDL was cleared directly from the circulation and was not converted to small VLDL or LDL. Oral estradiol reduced LDL cholesterol concentrations by 14 +/- 3 percent (P less than 0.005), because LDL catabolism increased by 36 +/- 7 percent (P less than 0.005). The oral estradiol increased the HDL cholesterol level by 15 +/- 2 percent (P less than 0.0001). Transdermal estradiol had no effect. CONCLUSIONS. The postmenopausal use of oral estrogens in low doses favorably alters LDL and HDL levels that may protect women against atherosclerosis, while minimizing potentially adverse effects on triglyceride levels. The decrease in LDL levels results from accelerated LDL catabolism; the increase in triglyceride levels results from increased production of large, triglyceride-rich VLDL.     

Passive smoking and the risk of coronary heart disease--a meta-analysis of epidemiologic studies

BACKGROUND: The effect of passive smoking on the risk of coronary heart disease is controversial. We conducted a meta-analysis of the risk of coronary heart disease associated with passive smoking among nonsmokers. METHODS: We searched the Medline and Dissertation Abstracts Online data bases and reviewed citations in relevant articles to identify 18 epidemiologic (10 cohort and 8 case-control) studies that met prestated inclusion criteria. Information on the designs of the studies, the characteristics of the study subjects, exposure and outcome measures, control for potential confounding factors, and risk estimates was abstracted independently by three investigators using a standardized protocol. RESULTS: Overall, nonsmokers exposed to environmental smoke had a relative risk of coronary heart disease of 1.25 (95 percent confidence interval, 1.17 to 1.32) as compared with nonsmokers not exposed to smoke. Passive smoking was consistently associated with an increased relative risk of coronary heart disease in cohort studies (relative risk, 1.21; 95 percent confidence interval, 1.14 to 1.30), in case-control studies (relative risk, 1.51; 95 percent confidence interval, 1.26 to 1.81), in men (relative risk, 1.22; 95 percent confidence interval, 1.10 to 1.35), in women (relative risk, 1.24; 95 percent confidence interval, 1.15 to 1.34), and in those exposed to smoking at home (relative risk, 1.17; 95 percent confidence interval, 1.11 to 1.24) or in the workplace (relative risk, 1.11; 95 percent confidence interval, 1.00 to 1.23). A significant dose-response relation was identified, with respective relative risks of 1.23 and 1.31 for nonsmokers who were exposed to the smoke of 1 to 19 cigarettes per day and those who were exposed to the smoke of 20 or more cigarettes per day, as compared with nonsmokers not exposed to smoke (P=0.006 for linear trend). CONCLUSIONS: Passive smoking is associated with a small increase in the risk of coronary heart disease. Given the high prevalence of cigarette smoking, the public health consequences of passive smoking with regard to coronary heart disease may be important.     

Second-trimester serum chorionic gonadotropin concentrations and complications and outcome of pregnancy

BACKGROUND: Maternal serum chorionic gonadotropin is measured to screen for fetal chromosomal abnormalities. Whether the results can also be used to predict the risk of complications or an adverse outcome of pregnancy is not known. METHODS: We reviewed the medical records of 28,743 girls and women in whom chorionic gonadotropin was measured during the second trimester of pregnancy (between July 1, 1995, and January 31, 1997), seeking information about the complications and outcome of their pregnancies. We excluded girls and women who had preexisting risk factors for complications or an adverse outcome of pregnancy. RESULTS: Higher serum chorionic gonadotropin concentrations were associated with higher rates of stillbirth (odds ratio for every increase in chorionic gonadotropin of 1 multiple of the median, 1.4; 95 percent confidence interval, 1.1 to 1.9). There was no relation between higher serum chorionic gonadotropin concentrations and the risk of gestational diabetes, premature rupture of membranes or intrauterine growth retardation or small size for gestational age (odds ratio, 1.1; 95 percent confidence interval, 0.9 to 1.2). Higher serum chorionic gonadotropin concentrations were associated with a risk of placental abnormalities (odds ratio, 1.5; 95 percent confidence interval, 1.3 to 1.7), pregnancy-induced hypertension (odds ratio, 1.4; 95 percent confidence interval, 1.3 to 1.5), and preterm delivery without pregnancy-induced hypertension (odds ratio, 1.1; 95 percent confidence interval, 1.0 to 1.2). Inclusion in certain racial or ethnic categories (black, Filipino or Pacific Islander, unknown race or ethnic group, and "other," which included those of Middle Eastern descent and Native Americans) was a better predictor of the risk of an adverse outcome than serum chorionic gonadotropin values. CONCLUSIONS: Measurements of serum chorionic gonadotropin are of little clinical value for predicting the risk of complications and the outcome of pregnancy.     

Cigarette smoking and risk of stroke in middle-aged women

It is known that cigarette smoking is associated with increased risk of both thrombotic and hemorrhagic stroke among men. To test for such an association among women, we examined the incidence of stroke in relation to cigarette smoking in a prospective cohort study of 118,539 women 30 to 55 years of age and free from coronary heart disease, stroke, and cancer in 1976. During eight years of follow-up (908,447 person-years), we identified 274 strokes, comprising 71 subarachnoid hemorrhages, 26 intracerebral hemorrhages, 122 thromboembolic strokes, and 55 strokes about which information was insufficient to permit classification. The number of cigarettes smoked per day was associated positively with the risk of stroke. Compared with the women who had never smoked, those who smoked 1 to 14 cigarettes per day had an age-adjusted relative risk of 2.2 (95 percent confidence interval, 1.5 to 3.3), whereas those who smoked 25 or more cigarettes per day had a relative risk of 3.7 (95 percent confidence interval, 2.7 to 5.1). For women in this latter group, the relative risk of subarachnoid hemorrhage was 9.8 (95 percent confidence interval, 5.3 to 17.9), as compared with those who had never smoked. Adjustment for the effects of relative weight, hypertension, diabetes, history of high cholesterol, previous use of oral contraceptives, postmenopausal estrogen therapy, and alcohol intake did not appreciably alter the association between cigarette use and incidence of stroke. These prospective data support a strong causal relation between cigarette smoking and stroke among young and middle-aged women.