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OBJECTIVE: To test the hypothesis that high circulating concentrations of maternal anti-angiogenic factors are associated with increased risk of respiratory distress syndrome (RDS). STUDY DESIGN: This is a nested case-control study of nulliparous women who delivered less than 37 weeks of gestation within the Calcium for Preeclampsia Prevention (CPEP) trial. The study included 116 women with preeclampsia or gestational hypertension and 323 normotensive controls. Soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF) and soluble endoglin (sEng) in maternal serum were measured at 21-32 weeks of gestation. RESULTS: Preterm infants born to hypertensive mothers were more likely to develop RDS (22.5% vs. 20.9%, p = 0.03). After adjustment for gestational age at delivery, the odds ratio for the relationship between hypertension in pregnancy and RDS was 2.18 (95% CI 1.08-4.39). In hypertensive pregnancies women whose infants developed RDS had significantly higher circulating mean sFlt1 levels during midpregnancy (21-32 weeks of gestation) even after adjustment for gestational age at delivery (21,516 pg/mL vs. 7,000 pg/mL, p = 0.01). CONCLUSIONS: Preterm preeclampsia and gestational hypertension, characterized by high circulating levels of sFlt1, are associated with a twofold increased risk of RDS in infants delivered before 37 weeks. Among women with these hypertensive pregnancies circulating sFlt1 concentrations during midpregnancy were substantially higher in women whose infants developed RDS.

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BACKGROUND: We sought to assess the relationship between bacterial vaginosis (BV) assessed by Gram stain and incident trichomonal, gonococcal, and/or chlamydial genital infection. METHODS: This longitudinal study included 3620 nonpregnant women aged 15-44 years who presented for routine care at 12 clinics in Birmingham, Alabama. Participants were assessed quarterly for 1 year. Vaginal smears were categorized by the Nugent Gram stain score (0-3, normal; 4-6, intermediate state; 7-10, BV). Pooled logistic regression was used to estimate the hazard ratios for the comparison of trichomonal, gonococcal, and chlamydial infection incidence in participants by Nugent score at the prior visit. Participants were censored at their first visit with a positive test result for trichomonal, gonococcal, and/or chlamydial infection. RESULTS: Of the 10,606 eligible visits, 37.96% were classified by BV and 13.3% by positive detection of trichomonal, gonococcal, and/or chlamydial infection. An intermediate state or BV at the prior visit was associated with a 1.5-2-fold increased risk for incident trichomonal, gonococcal, and/or chlamydial infection (adjusted hazard ratio [AHR] for intermediate state, 1.41 [95% confidence interval {CI}, 1.12-1.76]; AHR for BV, 1.73 [95% CI, 1.42-2.11]; P= .058 for trend). Estimates were similar for trichomonal-only, gonococcal-only, and chlamydial-only infection outcomes. CONCLUSION: BV microbiota as gauged by Gram stain is associated with a significantly elevated risk for acquisition of trichomonal, gonococcal, and/or chlamydial genital infection.

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BACKGROUND: Large comparative clinical trials usually target a wide-range of patients population in which subgroups exist according to certain patients' characteristics. Often, scientific knowledge or existing empirical data support the assumption that patients' improvement is larger among certain subgroups than others. Such information can be used to design a more cost-effective clinical trial. PURPOSE: The goal of the article is to use such information to design a more cost-effective clinical trial. METHODS: A two-stage sample-enrichment design strategy is proposed that begins with enrollment from certain subgroup of patients and allows the trial to be terminated for futility in that subgroup. RESULTS: Simulation studies show that the two-stage sample-enrichment strategy is cost-effective if indeed the null hypothesis of no treatment improvement is true, as also so illustrated with data from a completed trial of calcium to prevent preeclampsia. LIMITATIONS: Feasibility of the proposed enrichment design relies on the knowledge prior to the start of the trial that certain patients can benefit more than others from the treatment. Prolonged accrual and longer-waited outcomes may hinder utilization of the proposed design. CONCLUSIONS: The two-stage sample-enrichment approach borrows strength from treatment heterogeneity among target patients in a large-scale comparative clinical trial, and is more cost-effective if the treatment arms are indeed of no difference.

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For comparison of multiple outcomes commonly encountered in biomedical research, Huang et al. (2005) improved O'Brien's (1984) rank-sum tests through the replacement of the ad hoc variance by the asymptotic variance of the test statistics. The improved tests control the Type I error rate at the desired level and gain power when the differences between the two comparison groups in each outcome variable fall into the same direction. However, they may lose power when the differences are in different directions (e.g., some are positive and some are negative). These tests and the popular Bonferroni correction failed to show important significant difference when applied to compare heart rates from a clinical trial to evaluate the effect of a procedure to remove the cardioprotective solution HTK. We propose an alternative test statistic, taking the maximum of the individual rank-sum statistics, which controls the type I error and maintains satisfactory power regardless of the directions of the differences. Simulation studies show the proposed test to be of higher power than other tests in certain alternative parameter space of interest. Furthermore, when used to analyze the heart rates data the proposed test yields more satisfactory results.

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OBJECTIVE: To determine if pre-eclampsia is associated with reduced thyroid function during and after pregnancy. DESIGN: Nested case-control study during pregnancy and population based follow-up study after pregnancy. SETTING: Calcium for Pre-eclampsia Prevention trial of healthy pregnant nulliparous women in the United States during 1992-5, and a Norwegian population based study (Nord-Trondelag Health Study or HUNT-2) during 1995-7 with linkage to the medical birth registry of Norway. PARTICIPANTS: All 141 women (cases) in the Calcium for Pre-eclampsia Prevention trial with serum measurements before 21 weeks' gestation (baseline) and after onset of pre-eclampsia (before delivery), 141 normotensive controls with serum measurements at similar gestational ages, and 7121 women in the Nord-Trondelag Health Study whose first birth had occurred in 1967 or later and in whom serum levels of thyroid stimulating hormone had been subsequently measured. MAIN OUTCOME MEASURES: Thyroid function tests and human chorionic gonadotrophin and soluble fms-like tyrosine kinase 1 concentrations in the Calcium for Pre-eclampsia Prevention cohort and odds ratios for levels of thyroid stimulating hormone above the reference range, according to pre-eclampsia status in singleton pregnancies before the Nord-Trondelag Health Study. RESULTS: In predelivery specimens of the Calcium for Pre-eclampsia Prevention cohort after the onset of pre-eclampsia, thyroid stimulating hormone levels increased 2.42 times above baseline compared with a 1.48 times increase in controls. The ratio of the predelivery to baseline ratio of cases to that of the controls was 1.64 (95% confidence interval 1.29 to 2.08). Free triiodothyronine decreased more in the women with pre-eclampsia than in the controls (case ratio to control ratio 0.96, 95% confidence interval 0.92 to 0.99). The predelivery specimens but not baseline samples from women with pre-eclampsia were significantly more likely than those from controls to have concentrations of thyroid stimulating hormone above the reference range (adjusted odds ratio 2.2, 95% confidence interval 1.1 to 4.4). Both in women who developed pre-eclampsia and in normotensive controls the increase in thyroid stimulating hormone concentration between baseline and predelivery specimens was strongly associated with increasing quarters of predelivery soluble fms-like tyrosine kinase 1 (P for trend 0.002 and <0.001, respectively). In the Nord-Trondelag Health Study, women with a history of pre-eclampsia in their first pregnancy were more likely than other women (adjusted odds ratio 1.7, 95% confidence interval 1.1 to 2.5) to have concentrations of thyroid stimulating hormone above the reference range (>3.5 mIU/l). In particular, they were more likely to have high concentrations of thyroid stimulating hormone without thyroid peroxidase antibodies (adjusted odds ratio 2.6, 95% confidence interval 1.3 to 5.0), suggesting hypothyroid function in the absence of an autoimmune process. This association was especially strong (5.8, 1.3 to 25.5) if pre-eclampsia had occurred in both the first and the second pregnancies. CONCLUSION: Increased serum concentration of soluble fms-like tyrosine kinase 1 during pre-eclampsia is associated with subclinical hypothyroidism during pregnancy. Pre-eclampsia may also predispose to reduced thyroid function in later years.

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For comparing the distribution of two samples with multiple endpoints, O'Brien (1984) proposed rank-sum-type test statistics. Huang et al. (2005) extended these statistics to the general nonparametric Behrens-Fisher hypothesis problem and obtained improved test statistics by replacing the ad hoc variance with the asymptotic variance of the rank-sum statistics. In this paper we generalize the work of O'Brien (1984) and Huang et al. (2005) and propose a weighted rank-sum statistic. We show that the weighted rank-sum statistic is asymptotically normally distributed, permitting the computation of power, p-values and confidence intervals. We further demonstrate via simulation that the weighted rank-sum statistic is efficient in controlling the type I error rate and under certain alternatives, is more powerful than the statistics of O'Brien (1984) and Huang et al.(2005).

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OBJECTIVE: Our goal was to determine whether obstetric outcomes and serum angiogenic factors are altered in women with gestational proteinuria without hypertension. STUDY DESIGN: We performed a nested case-control study of 108 women with gestational proteinuria and compared them with 1564 randomly selected women with normotension without proteinuria during pregnancy (control subjects) and with 319 women who experienced preeclampsia. RESULTS: Women with gestational proteinuria had greater body-mass index and higher blood pressure at study enrollment. Adverse obstetric outcomes were infrequent. Levels of free placental growth factor were lower than control levels beginning early in gestation. Compared with gestational-age matched control subjects, free placental growth factor was reduced beginning 6-8 weeks before proteinuria. Although soluble fms-like tyrosine kinase 1 and soluble endoglin concentrations were elevated 1-2 weeks before proteinuria, these elevations were modest and transient. After the onset of proteinuria, angiogenic factor levels generally did not differ significantly from control levels. CONCLUSION: Gestational proteinuria in healthy nulliparous women appears to be a mild variant of preeclampsia.

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Intraclass correlation models with missing data at random are considered. With a properly reduced model, a general method, which allows repeated observations with missing in non-monotone pattern, is proposed to construct exact test statistics and simultaneous confidence intervals for linear contrasts in the means. Simulation results are given to compare exact and asymptotic simultaneous confidence intervals. A real example is provided for illustration of the proposed method.

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OBJECTIVE: Our objective was to investigate whether serum concentrations of a novel anti-angiogenic factor, soluble endoglin (sEng), could predict placental abruption. METHODS: In a nested case-control study of nulliparous pregnancies, we examined levels of sEng in serum collected prospectively from 31 women who later developed placental abruption and from 31 normal controls. All serum specimens were collected before the onset of hypertension or abruption and before labor or delivery. Serum sEng was compared within three gestational age intervals: early- (<20 weeks), mid- (21-32 weeks), and late (>or=33 weeks) pregnancy. RESULTS: There was no significant difference in sEng between abruption cases and controls in early pregnancy. sEng was significantly elevated among abruption cases at 21-32 weeks (10.7 vs 5.9 ng/mL, P < 0.01). Subgroup analyses revealed no differences in sEng concentrations at any gestational age interval between cases with abruption without hypertension and healthy controls. Among women who developed hypertension and placental abruption, sEng was not significantly increased in early pregnancy, but was in mid-pregnancy (19.3 vs 5.5 ng/mL, P = 0.002) and in late pregnancy (15.6 vs 9.5 ng/mL, P = 0.04). CONCLUSIONS: Serum levels of the anti-angiogenic factor sEng are elevated prior to the development of hypertension and placental abruption. These elevations are not apparent until the late second trimester (26-27 weeks, on average), but they persist from this time in gestation onward. sEng may be useful for identifying pregnant women at risk for abruption and hypertension.

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The etiology of bacterial vaginosis is unknown, and there are no long-term therapies for preventing this frequently recurring condition. Vaginal douching has been reported to be associated with bacterial vaginosis in observational studies. However, this association may be due to confounding by indication--that is, confounding by women douching in response to vaginal symptoms associated with bacterial vaginosis. The authors used marginal structural modeling to estimate the causal effect of douching on bacterial vaginosis risk while controlling for this confounding effect. In 1999-2002, nonpregnant women (n = 3,620) were recruited into a prospective study when they visited one of 12 public health clinics in Birmingham, Alabama, for routine care. Participants were assessed quarterly for 1 year. Bacterial vaginosis was based on a Nugent's Gram stain score of 7 or higher. Thirty-two percent of participants douched in every study interval, and 43.0% never douched. Of the 12,349 study visits, 40.2% were classified as involving bacterial vaginosis. The relative risk for regular douching as compared with no douching was 1.21 (95% confidence interval: 1.08, 1.38). These findings indicate that douching confers increased risk of disruption of vaginal flora. In the absence of a large randomized trial, these findings provide the best evidence to date for a risk of bacterial vaginosis associated with douching.

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Considered in the paper is the problem of selecting a diagnostic biomarker that has the highest classification rate among several candidate markers with dichotomous outcomes. The probability of correct selection depends on a number of nuisance parameters from the joint distribution of the biomarkers and thus can be substantially affected if these nuisance parameters are misspecified. A two-stage procedure is proposed to compute the needed sample size that achieves the desired level of correct selection, as so confirmed by simulation results.

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Investigated in this paper is the point estimation and confidence intervals of the treatment efficacy parameter and related secondary parameters in a two-stage adaptive trial. Based on the minimal sufficient statistics, several alternative estimators to the sample averages are proposed to reduce the bias and to improve the precision of estimation. Confidence intervals are constructed using Woodroofe's pivot method. Numerical studies are conducted to evaluate the bias and mean squared error of the estimators and the coverage probability of the confidence intervals.

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Bone development, casein-free diet use, supplements, and medications were assessed for 75 boys with autism or autism spectrum disorder, ages 4-8 years. Second metacarpal bone cortical thickness (BCT), measured on hand-wrist radiographs, and % deviations in BCT from reference medians were derived. BCT increased with age, but % deviations evidenced a progressive fall-off (p = .02): +3.1 +/- 4.7%, -6.5 +/- 4.0%, -16.6 +/- 3.4%, -19.4 +/- 3.7%,-24.1 +/- 4.4%, at ages 4-8, respectively, adjusting for height. The 12% of the boys on casein-free diets had an overall % deviation of -18.9 +/- 3.7%, nearly twice that of boys on minimally restricted or unrestricted diets (-10.5 +/- 1.3%, p < .04), although even for boys on minimally restricted or unrestricted diets the % deviation was highly significant (p < .001). Our data suggest that the bone development of autistic boys should be monitored as part of routine care, especially if they are on casein-free diets.

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Comparative diagnostic studies usually involve comparison of the area under receiver operating characteristic curves when biomarkers are measured on a continuous or ordinal scales. In designing such studies, specification of a number of nuisance parameters is often required to compute sample sizes. When these parameters are incorrectly specified, statistical power to detect a meaningful difference in area can be substantially adversely affected. We propose an adaptive method to calculate the sample size and show these procedures to be effective in controlling error rates.

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PURPOSE: Although vaginal douching is associated with several adverse outcomes, the reasons why women douche have not been studied prospectively. METHODS: Non-pregnant (N = 3620) women aged 15 to 44 years presenting for routine care at 12 clinics in Birmingham, Alabama, participated in a longitudinal study of vaginal flora (1999-2003). Participants were assessed quarterly for 1 year. The authors applied conditional logistic regression in a case-crossover analysis to determine the individual-level factors that vary between a woman's douching and non-douching intervals. Findings were compared to a population-level analysis utilizing generalized estimating equations. RESULTS: Thirty percent of participants douched in every interval; 28% douched in some but not all intervals. The case-crossover analysis indicated a woman was more likely to douche when reporting "fishy" vaginal odor (odds ratio [OR]:2.74; 95% confidence interval [CI]: 1.55, 1.84), vaginal irritation (OR: 1.52; 95% CI: 1.10, 2.11), summer month (OR: 1.37, 95% CI: 1.13, 1.67), or increase in number of sex partners (> or = 3, OR: 2.42, 95% CI: 1.11, 5.26). Bacterial vaginosis/trichomoniasis treatment (OR: 0.72, 95% CL: 0.59, 0.89) and absent menses (OR: 0.37, 95% CI: 0.28, 0.50) were negatively associated with douching. These ORs were farther from the null than comparable population-level estimates. CONCLUSIONS: Programs targeting these predictors may decrease the untoward sequelae associated with douching. Furthermore, a case-crossover analysis applied to prospective studies can provide insights into time-varying factors.

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Reliance on self-reported smoking status among pregnant women can result in exposure misclassification. We used data from the Calcium for Preeclampsia Prevention trial, a randomized study of nulliparous women conducted from 1992 to 1995, to characterize tobacco exposure misclassification among women who reported at study enrollment that they had quit smoking. Urinary cotinine concentration was used to validate quit status, and factors associated with exposure misclassification and the effects of misclassification on associations between smoking and pregnancy outcomes were evaluated using logistic regression. Of 4,289 women enrolled, 508 were self-reported smokers and 771 were self-reported quitters. Of 737 self-reported quitters with a valid cotinine measurement, 21.6% had evidence of active smoking and were reclassified as smokers. Women who reported having quit smoking during pregnancy were more likely to be reclassified than women who reported quitting before pregnancy (p<.001). Among smokers, factors independently associated with misclassification of smoking status included fewer cigarettes smoked per day and fewer years smoked. After reclassification the odds ratio for a small-for-gestational-age birth among smokers decreased by 14%, and the smoking-related reduction in birth weight decreased by 15%. Effects of misclassification on the association with hypertensive disorders of pregnancy were present but less dramatic. In conclusion, use of self-reported smoking status collected at the time of study enrollment resulted in the introduction of bias into our study of smoking and pregnancy outcomes. The potential for this type of bias should be considered when conducting and interpreting epidemiologic studies of smoking and pregnancy outcomes.

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OBJECTIVE: The objective of the study was to examine whether blood pressure in early pregnancy and its rise in the second half of gestation are associated with spontaneous preterm birth in healthy, normotensive, nulliparous women. STUDY DESIGN: We included 5167 women with singleton gestation who participated in the World Health Organization Calcium Supplementation for the Prevention of Preeclampsia Trial. Systolic, diastolic, and mean arterial blood pressure and pulse pressure at baseline (12-19 weeks of gestation) and at the midthird trimester (30-34 weeks) were calculated. Rise in blood pressure was the difference between the midthird trimester and baseline. Preterm birth was defined as early preterm (less than 34 completed weeks) and late preterm birth (34-36 weeks). RESULTS: Women experiencing early or late preterm birth had over 10 mm Hg and 3 mm Hg higher rise, respectively, in systolic, diastolic, and mean arterial blood pressure than women delivering at term. A rise in systolic pressure over 30 mm Hg or diastolic pressure over 15 mm Hg was associated with a statistically significant 2- to 3-fold increase in risk of spontaneous preterm birth. CONCLUSION: An excessive rise in either systolic or diastolic blood pressures from early pregnancy to the midthird trimester is associated with spontaneous preterm birth in a dose-response pattern.

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OBJECTIVE: Children with autism are known to have larger head circumferences; whether they are above average in height and weight is less clear. Moreover, little is known about growth-related hormone levels in children with autism. We investigated whether children with autism were taller and heavier, and whether they had higher levels of growth-related hormones than control children did. DESIGN: A case-control study design was employed. PATIENTS: Boys with autism spectrum disorder (ASD) or autism (n = 71) and age-matched control boys (n = 59) were evaluated at Cincinnati Children's Hospital. MEASUREMENTS: Height, weight and head circumference were measured. Blood samples were assayed for IGF-1 and 2, IGFBP-3, growth hormone binding protein (GHBP) and for dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEAS). RESULTS: Subjects with autism/ASD had significantly (P = 0.03) greater head circumferences (mean z-score 1.24, SD 1.35) than controls (mean z-score 0.78, SD 0.93). Subjects with autism also had significantly (P = 0.01) greater weights (mean z-score 0.91, SD 1.13) than controls (mean z-score 0.41, SD 1.11). Height did not differ significantly between groups (P = 0.65); subjects with autism/ASD had significantly (P = 0.003) higher body mass indices (BMI) (mean z-score 0.85, SD 1.19) than controls (mean z-score 0.24, SD 1.17). Levels of IGF-1, IGF-2, IGFBP-3 and GHBP in the group with autism/ASD were all significantly higher (all P < or = 0.0001) than in controls. CONCLUSIONS: Children with autism/ASD had significantly higher levels of many growth-related hormones: IGF-1, IGF-2, IGFBP-3 and GHBP. These findings could help explain the significantly larger head circumferences and higher weights and BMIs seen in these subjects. Future studies should examine the potential role of growth-related hormones in the pathophysiology of autism.

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BACKGROUND: Alterations in circulating soluble fms-like tyrosine kinase 1 (sFlt1), an antiangiogenic protein, and placental growth factor (PlGF), a proangiogenic protein, appear to be involved in the pathogenesis of preeclampsia. Since soluble endoglin, another antiangiogenic protein, acts together with sFlt1 to induce a severe preeclampsia-like syndrome in pregnant rats, we examined whether it is associated with preeclampsia in women. METHODS: We performed a nested case-control study of healthy nulliparous women within the Calcium for Preeclampsia Prevention trial. The study included all 72 women who had preterm preeclampsia (<37 weeks), as well as 480 randomly selected women--120 women with preeclampsia at term (at > or =37 weeks), 120 women with gestational hypertension, 120 normotensive women who delivered infants who were small for gestational age, and 120 normotensive controls who delivered infants who were not small for gestational age. RESULTS: Circulating soluble endoglin levels increased markedly beginning 2 to 3 months before the onset of preeclampsia. After the onset of clinical disease, the mean serum level in women with preterm preeclampsia was 46.4 ng per milliliter, as compared with 9.8 ng per milliliter in controls (P<0.001). The mean serum level in women with preeclampsia at term was 31.0 ng per milliliter, as compared with 13.3 ng per milliliter in controls (P<0.001). Beginning at 17 weeks through 20 weeks of gestation, soluble endoglin levels were significantly higher in women in whom preterm preeclampsia later developed than in controls (10.2 ng per milliliter vs. 5.8 ng per milliliter, P<0.001), and at 25 through 28 weeks of gestation, the levels were significantly higher in women in whom term preeclampsia developed than in controls (8.5 ng per milliliter vs. 5.9 ng per milliliter, P<0.001). An increased level of soluble endoglin was usually accompanied by an increased ratio of sFlt1:PlGF. The risk of preeclampsia was greatest among women in the highest quartile of the control distributions for both biomarkers but not for either biomarker alone. CONCLUSIONS: Rising circulating levels of soluble endoglin and ratios of sFlt1:PlGF herald the onset of preeclampsia.

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OBJECTIVE: The purpose of this study was to determine whether serum fms-like tyrosine kinase 1 (sFlt1) concentration during preeclampsia were associated with mid trimester blood pressure, other maternal characteristics, or pregnancy outcomes. STUDY DESIGN: We performed a nested case-control study within the Calcium for Preeclampsia Prevention study cohort. Each woman with preeclampsia (case) was matched to 1 normotensive control. A total of 120 pairs of women was chosen randomly. Serum concentrations of sFlt1 and placental growth factor were measured throughout pregnancy, but before labor and delivery. We focused on data from 40 women with blood specimens that were obtained after the onset of preeclampsia. After logarithmic transformation, we determined mean serum sFlt1 concentrations of all control specimens within gestational age windows during which case specimens had been obtained after the onset of preeclampsia. Within each of these gestational age windows, we computed an upper bound for the control specimens equal to 2 standard deviations above the mean. After the onset of preeclampsia, 16 women with log-transformed serum sFlt1 values greater than the upper bound of the control specimens were considered to have high preeclampsia serum sFlt1 levels. The 24 other women were considered to have low preeclampsia serum sFlt1 levels. RESULTS: Women with high or low concentrations of serum sFlt1 during preeclampsia (arithmetic means, 5746 and 3007 pg/mL, respectively) had similar pregnancy outcomes and similar maternal characteristics, except for blood pressure at Calcium for Preeclampsia Prevention study enrollment. Systolic and diastolic blood pressure at enrollment at 13 to 21 weeks of gestation were significantly higher in the 24 women with low serum sFlt1 concentrations during preeclampsia (systolic blood pressure, 114 mm Hg; diastolic blood pressure, 65 mm Hg) than in the 16 women who had preeclampsia at high serum sFlt1 concentrations (systolic blood pressure, 106 mm Hg; diastolic blood pressure, 59 mm Hg). Blood pressure at 13 to 21 weeks among the women with high preeclampsia serum sFlt1 concentrations was identical to the blood pressure among normotensive control subjects. In linear regression analyses of data from all 40 women, both systolic (P < .0001) and diastolic (P = .014) blood pressures at enrollment were correlated negatively with natural logarithm serum sFlt1 concentration after onset of preeclampsia. CONCLUSION: Women with higher mid trimester blood pressure had preeclampsia at lower serum sFlt1 concentrations. Because higher blood pressure may reflect occult endothelial damage, these observations may explain increased susceptibility to preeclampsia among women with pre-existing vascular disease.

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