Pregnancy outcomes in healthy nulliparas who developed hypertension. Calcium for Preeclampsia Prevention Study Group.

OBJECTIVE: To determine maternal and perinatal outcomes in nulliparas with pregnancy-associated hypertension or preeclampsia. METHODS: We conducted (and reported elsewhere) a randomized, double-masked, placebo-controlled trial calcium supplementation of 4589 healthy nulliparas assigned at 13-21 weeks' gestation. This well-defined and characterized data set provided an opportunity to detail more precisely adverse maternal, fetal, and newborn outcomes in women who developed hypertension among a prospective series of healthy nulliparas. RESULTS: Of 4302 women observed to or beyond 20 weeks' gestation, 1073 (24.9%) developed mild or severe pregnancy-associated hypertension or preeclampsia. One hundred sixteen women of the 1073 with hypertension (10.8%) and 336 of the 3229 without hypertension (10.4%) were delivered before 37 weeks' gestation. Fetal and neonatal mortality were similar in those groups; however, selected maternal and newborn morbidities were significantly greater in women with hypertension. Significantly increased maternal morbidities included increased cesarean deliveries, abruptio placentae, and acute renal dysfunction; and significantly increased perinatal morbidities included respiratory distress syndrome, ventilatory support, and fetal growth restriction. Adverse outcomes were highest in women with severe pregnancy-associated hypertension or preeclampsia. CONCLUSION: Hypertension, especially severe hypertension, was associated with an appreciable increase in important maternal and perinatal morbidity but not perinatal mortality.

The relationship between abnormal glucose tolerance and hypertensive disorders of pregnancy in healthy nulliparous women. Calcium for Preeclampsia Prevention (CPEP) Study Group.

OBJECTIVE: The study's aim was to determine whether healthy nulliparous women with abnormal glucose tolerance during pregnancy are at increased risk for development of pregnancy-associated hypertension or preeclampsia. STUDY DESIGN: A series of 4589 healthy nulliparous women from 5 university centers were evaluated prospectively to determine whether calcium supplementation would prevent preeclampsia. Pregnancy-associated hypertension was a diastolic blood pressure > or = 90 mm Hg on 2 occasions 4 hours to 1 week apart. Pregnancy-associated proteinuria was proteinuria > or = 1+ by dipstick testing on 2 occasions 4 hours to 1 week apart, proteinuria > or = 300 mg/24 h, a protein to creatinine ratio of > or = 0.35, or a single dipstick measurement of > or = 2+. Preeclampsia was defined as pregnancy-associated hypertension and pregnancy-associated proteinuria documented within 7 days of each other. Normal glucose tolerance was a plasma glucose level < 140 mg/dL 1 hour after a 50-g oral glucose challenge. Abnormal glucose tolerance was a plasma glucose level > or = 140 mg/dL 1 hour after a 50-g oral glucose challenge followed by a 3-hour 100-g oral glucose tolerance test yielding < 2 abnormal values. Gestational diabetes mellitus was a plasma glucose level > or = 200 mg/dL 1 hour after a 50-g oral glucose challenge in the absence of an oral glucose tolerance test or > or = 2 abnormal plasma glucose values in a 3-hour 100-g oral glucose tolerance test (> or = 105 mg/dL fasting, > or = 190 mg/dL at 1 hour, > or = 165 mg/dL at 2 hours, or > or = 145 mg/dL at 3 hours). For purposes of this study women with preeclampsia were excluded from the category of pregnancy-associated hypertension. RESULTS: Calcium supplementation did not prevent pregnancy-associated hypertension or preeclampsia. Of 3689 women with complete glucose testing data, 227 (6%) had abnormal glucose tolerance and 81 (2%) had gestational diabetes mellitus. Compared with women with normal glucose tolerance, women with abnormal glucose tolerance were significantly older, had greater body mass index, and were more likely to be white non-Hispanic, to smoke, and to have private medical insurance. Among women with gestational diabetes mellitus, after adjustment for clinical center the relative risks of preeclampsia and of all hypertensive disorders were increased (relative risk 1.67, 95% confidence interval 0.92-3.05, and relative risk 1.54, 95% confidence interval 1.28-2.11, respectively). Risk ratios were not substantially reduced after further adjustment for race and body mass index (odds ratios 1.41 and 1.48, respectively). Even within the normal range, multivariate analysis demonstrated that the level of plasma glucose 1 hour after a 50-g oral glucose challenge was an important predictor of preeclampsia. CONCLUSION: Even within the normal range, the level of plasma glucose 1 hour after a 50-g oral glucose challenge was positively correlated with the likelihood of preeclampsia. Women with gestational diabetes mellitus were at increased risk for hypertensive disorders during pregnancy after adjustment for clinical center, race, and body mass index, although the increase was not statistically significant. These findings suggest that insulin resistance may play a role in the pathogenesis of the hypertensive disorders of pregnancy.

Trial of calcium to prevent preeclampsia.

BACKGROUND: Previous trials have suggested that calcium supplementation during pregnancy may reduce the risk of preeclampsia. However, differences in study design and a low dietary calcium intake in the populations studied limit acceptance of the data. METHODS: We randomly assigned 4589 healthy nulliparous women who were 13 to 21 weeks pregnant to receive daily treatment with either 2 g of elemental calcium or placebo for the remainder of their pregnancies. Surveillance for preeclampsia was conducted by personnel unaware of treatment-group assignments, using standardized measurements of blood pressure and urinary protein excretion at uniformly scheduled prenatal visits, protocols for monitoring these measurements during the hospitalization for delivery, and reviews of medical records of unscheduled outpatient visits and all hospitalizations. RESULTS: Calcium supplementation did not significantly reduce the incidence or severity of preeclampsia or delay its onset. Preeclampsia occurred in 158 of the 2295 women in the calcium group (6.9 percent) and 168 of the 2294 women in the placebo group (7.3 percent) (relative risk, 0.94; 95 percent confidence interval, 0.76 to 1.16). There were no significant differences between the two groups in the prevalence of pregnancy-associated hypertension without preeclampsia (15.3 percent vs. 17.3 percent) or of all hypertensive disorders (22.2 percent vs. 24.6 percent). The mean systolic and diastolic blood pressures during pregnancy were similar in both groups. Calcium did not reduce the numbers of preterm deliveries, small-for-gestational-age births, or fetal and neonatal deaths; nor did it increase urolithiasis during pregnancy. CONCLUSIONS: Calcium supplementation during pregnancy did not prevent preeclampsia, pregnancy-associated hypertension, or adverse perinatal outcomes in healthy nulliparous women.

Trial of Calcium for Preeclampsia Prevention (CPEP): rationale, design, and methods.

The results of ten clinical trials suggest that supplemental calcium may prevent preeclampsia. However, methodologic problems and differences in study design limit the acceptance of the results and their relevance to other patient populations. Many of the trials were conducted in countries where, unlike the United States, the usual daily diet contained little calcium. Moreover, none of the trials has reported the outcome of systematic surveillance for urolithiasis, a potential complication of calcium supplementation. In response to the need for a thorough evaluation of the effects of calcium supplementation for the prevention of preeclampsia in the United States, the trial of Calcium for Preeclampsia Prevention (CPEP) was undertaken at five university medical centers. Healthy nulliparous patients were randomly assigned to receive either 2 g supplemental calcium daily (n = 2295) or placebo (n = 2294) in a double-blind study. Study tablets were administered beginning from 13 to 21 completed weeks of gestation and continued until the termination of pregnancy. CPEP employed detailed diagnostic criteria, standardized techniques of measurement, and systematic surveillance for the major study endpoints and for urolithiasis. The nutrient intake of each patient was assessed at randomization and at 32-33 weeks gestation. This report describes the study rationale, design, and methods.

Safety and immunogenicity of a candidate HIV-1 vaccine in healthy adults: recombinant glycoprotein (rgp) 120. A randomized, double-blind trial. NIAID AIDS Vaccine Evaluation Group.

OBJECTIVE: To evaluate the safety and immunogenicity of recombinant glycoprotein (rgp) 120, a candidate vaccine for the human immunodeficiency virus (HIV), formulated with a novel adjuvant, MF59, with or without a biological response modifier, MTP-PE. DESIGN: Multicenter, double-blind, randomized trial. SETTING: University medical centers. PARTICIPANTS: 49 healthy, HIV-seronegative volunteers 18 to 60 years of age who were at low risk for HIV type 1 (HIV-1) infection. INTERVENTIONS: In part A of the study, 32 participants were randomly assigned to receive either 15 micrograms of rgp 120 in MF59, 15 micrograms of rgp 120 in MF59 plus 50 micrograms of MTP-PE, 50 micrograms of rgp 120 in MF59, or 50 micrograms of rgp 120 in MF59 plus 50 micrograms of MTP-PE. Participants were vaccinated at 0, 1, 6, and 12 to 18 months. In part B, 17 participants were randomly assigned to receive five monthly injections of either 50 micrograms of rgp 120 in MF59 or MF59 alone followed by a booster injection at 12 to 18 months. MAIN OUTCOME MEASURES: Local and systemic reactions; laboratory measures of hepatic, renal, immunologic, and bone marrow toxicity; and HIV-specific serologic and cell-mediated immune responses. RESULTS: 13 patients in part A received 50-micrograms doses of rgp 120; type-specific neutralizing antibody responses against the SF-2 strain of HIV-1 (HIV-1/SF-2) were induced in all 13. Nine of the 13 had crossreactive neutralizing activity against the MN strain of HIV-1 (HIV-1/MN), and 2 had crossreactive neutralizing activity against the IIIB strain of HIV-1 (HIV-1/IIIB). Twelve patients had typespecific fusion inhibition activity; only 1 had crossreactive fusion inhibition activity against HIV-1/MN. The monthly vaccination schedule used in part B resulted in decreased antibody titers, indicating that a rest period in the schedule is necessary for maximal immunogenicity. Lymphoproliferative responses against gp120 were induced in all vaccine recipients. The stimulation index to gp120 was persistently greater than 15 for 6 months after the last booster vaccination was given. CD8+ cytotoxic T-lymphocyte activity was detected in 1 of the 11 participants tested. Vaccine that contained MTP-PE caused a greater number of moderate or severe local and systemic reactions (of 16 participants, 4 had local reactions and 13 had systemic reactions) than did vaccine formulated with MF59 alone (of 16 participants, 7 had local reactions [P < 0.01] and 0 had systemic reactions [P < 0.001]). CONCLUSIONS: The SF-2 rgp120 vaccine is safe and immunogenic. Three vaccinations with rgp120 in MF59 can induce type-specific and crossreactive neutralizing antibody against B-subtype laboratory strains of HIV-1. Human immunodeficiency virus-specific lymphoproliferative responses were induced in all vaccinated participants, and CD8+ cytotoxic T-lymphocyte activity was shown in one participant. A trend toward the augmentation of lymphoproliferative and humoral responses by MTP-PE was seen in the participants receiving 15 micrograms of rgp120. However, MTP-PE caused a statistically significant increase in the incidence of local and systemic side effects, which was felt to outweigh the small increase in immunogenicity provided by this biological response modifier in an otherwise well-tolerated vaccine.

Relative risk of death from ejection by crash type and crash mode.

In virtually all circumstances, the chance of survival in a crash is much greater if the occupant is not ejected from the vehicle. Several estimates of the increased risk of death as a result of ejection (ranging from 2.5 to 25) have been made, but none were specific to the crash mode and most did not control for crash severity. The current study examined the relative risk of fatality due to ejection, by crash type and crash mode, using the Fatal Accident Reporting System data from the years 1982 through 1986. Crash type was defined as either single vehicle or multivehicle and crash mode included rollover, nonrollover, and/or direction of impact. Crash severity was controlled for using a paired comparison method of analysis. Both crash type and crash mode were found to have substantial effects on the relative risk of death due to ejection. In addition, risk differences across seating position exist. Depending on crash mode or type, the risks ranged from about 1.5 to 8. Single-vehicle rollover crashes have the highest increased risk of death due to ejection: about eightfold for the driver and sevenfold for the right front passenger.