Sérgio Martins-Costa

Antioxidant Therapy to Prevent Preeclampsia A Randomized Controlled Trial

OBJECTIVE: To study whether antioxidant supplementation will reduce the incidence of preeclampsia among patients at increased risk. METHODS: A randomized, placebo-controlled, double-blind clinical trial was conducted at four Brazilian sites. Women between 12 0/7 weeks and 19 6/7 weeks of gestation and diagnosed to have chronic hypertension or a prior history of preeclampsia were randomly assigned to daily treatment with both vitamin C (1,000 mg) and vitamin E (400 International Units) or placebo. Analyses were adjusted for clinical site and risk group (prior preeclampsia, chronic hypertension, or both). A sample size of 734 would provide 80% power to detect a 40% reduction in the risk of preeclampsia, assuming a placebo group rate of 21% and &agr;=.05. The &agr; level for the final analysis, adjusted for interim looks, was 0.0458. RESULTS: Outcome data for 707 of 739 randomly assigned patients revealed no significant reduction in the rate of preeclampsia (study drug, 13.8% [49 of 355] compared with placebo, 15.6% [55 of 352], adjusted risk ratio 0.87 [95.42% confidence interval 0.61–1.25]). There were no differences in mean gestational age at delivery or rates of perinatal mortality, abruptio placentae, preterm delivery, and small for gestational age or low birth weight infants. Among patients without chronic hypertension, there was a slightly higher rate of severe preeclampsia in the study group (study drug, 6.5% [11 of 170] compared with placebo, 2.4% [4 of 168], exact P=.11, odds ratio 2.78, 95% confidence interval 0.79–12.62). CONCLUSION: This trial failed to demonstrate a benefit of antioxidant supplementation in reducing the rate of preeclampsia among patients with chronic hypertension and/or prior preeclampsia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.ClinicalTrials.gov, NCT00097110 LEVEL OF EVIDENCE: I

Serum inhibin A and angiogenic factor levels in pregnancies with previous preeclampsia and/or chronic hypertension: are they useful markers for prediction of subsequent preeclampsia?

OBJECTIVE Our objective was to determine whether measurement of placenta growth factor (PLGF), inhibin A, or soluble fms-like tyrosine kinase-1 (sFlt-1) at 2 times during pregnancy would usefully predict subsequent preeclampsia (PE) in women at high risk. STUDY DESIGN We analyzed serum obtained at enrollment (12(0/7) to 19(6/7) weeks) and follow-up (24-28 weeks) from 704 patients with previous PE and/or chronic hypertension (CHTN) enrolled in a randomized trial for the prevention of PE. Logistic regression analysis assessed the association of log-transformed markers with subsequent PE; receiver operating characteristic analysis assessed predictive value. RESULTS One hundred four developed preeclampsia: 27 at 37 weeks or longer and 77 at less than 37 weeks (9 at less than 27 weeks). None of the markers was associated with PE at 37 weeks or longer. Significant associations were observed between PE at less than 37 weeks and reduced PLGF levels at baseline (P = .022) and follow-up (P < .0001) and elevated inhibin A (P < .0001) and sFlt-1 (P = .0002) levels at follow-up; at 75% specificity, sensitivities ranged from 38% to 52%. Using changes in markers from baseline to follow-up, sensitivities were 52-55%. Associations were observed between baseline markers and PE less than 27 weeks (P < or = .0004 for all); sensitivities were 67-89%, but positive predictive values (PPVs) were only 3.4-4.5%. CONCLUSION Inhibin A and circulating angiogenic factors levels obtained at 12(0/7) to 19(6/7) weeks have significant associations with onset of PE at less than 27 weeks, as do levels obtained at 24-28 weeks with onset of PE at less than 37 weeks. However, because the corresponding sensitivities and/or PPVs were low, these markers might not be clinically useful to predict PE in women with previous PE and/or CHTN.

Urinary protein/creatinine ratio in hypertensive pregnant women.

OBJECTIVES To determine the correlation between the protein/creatinine ratio and 24-h proteinuria; to estimate the sensitivity and specificity of this ratio for the diagnosis of significant proteinuria; to establish its cutoff point with the best predictive value for the diagnosis of significant proteinuria in patients with systemic arterial hypertension. STUDY DESIGN A cross-sectional study of 47 hypertensive patients who had been pregnant for 20 weeks or more seen at the Maternity of the University Hospital of Porto Alegre. The studied factor was the protein/creatinine ratio measured in a single random urine sample and the outcome was protein determination in 24-h urine. The level of significance was set at 0.05. RESULTS The correlation coefficient between the protein/creatinine ratio and 24-h proteinuria was 0.94 when urine was properly collected. A receiver-operator characteristic curve was constructed to determine the sensitivity and specificity of the ratio for the diagnosis of significant proteinuria (> or = 300 mg in 24 h). Specificity and predictive positive value were 100% for a ratio > or = 0.8. The best values for sensitivity, specificity, positive predictive value, and negative predictive value in the diagnosis of proteinuria > or = 300 mg in 24 h were obtained when the protein/creatinine ratio was 0.5 (0.96, 0.96, 0.96, and 0.96, respectively). CONCLUSION The protein/creatinine ratio measured in a single urine sample taken at random from hypertensive pregnant women showed good sensitivity and specificity for the diagnosis of 24-h proteinuria > or = 300 mg and was strongly correlated with 24-h proteinuria. A ratio of 0.5 mg/mg is predictive of significant proteinuria and can be used for the diagnosis and follow-up of hypertensive pregnant women.

Antioxidant Supplementation and Premature Rupture of the Membranes: A Planned Secondary Analysis

OBJECTIVE The purpose of this study was to determine if antioxidant supplementation during pregnancy reduces the incidence of premature rupture of the membranes (PROM). STUDY DESIGN A placebo-controlled, double-blind trial was conducted. PROM and preterm PROM (PPROM) were planned secondary outcomes of the trial. Women between 12(0/7) and 19(6/7) weeks of gestation and diagnosed to have chronic hypertension or a prior history of preeclampsia were randomized to daily treatment with both vitamin C (1000 mg) and E (400 IU) or placebo. RESULTS Outcome data for PROM were available for 697 of 739 patients. The rates of PROM (37/349 [10.6%] vs 19/348 [5.5%]; adjusted risk ratio [RR] 1.89 [95.42% CI, 1.11-3.23]; P = .015), and PPROM (16/349 [4.6%] vs 6/348 [1.7%]; RR 2.68 [1.07-6.71]; P = .025) were increased in the antioxidant group. CONCLUSION Contrary to expectations, vitamins C and E supplementation in this dose combination may be associated with an increased risk of PROM and PPROM.

The impact of prior preeclampsia on the risk of superimposed preeclampsia and other adverse pregnancy outcomes in patients with chronic hypertension

OBJECTIVE We sought to compare the rates of superimposed preeclampsia and adverse outcomes in women with chronic hypertension with or without prior preeclampsia. STUDY DESIGN We conducted secondary analysis of 369 women with chronic hypertension (104 with prior preeclampsia) enrolled at 12-19 weeks as part of a multisite trial of antioxidants to prevent preeclampsia (no reduction was found). Outcome measures were rates of superimposed preeclampsia and other adverse perinatal outcomes. RESULTS Prepregnancy body mass index, blood pressure, and smoking status at enrollment were similar between groups. The rates of superimposed preeclampsia (17.3% vs 17.7%), abruptio placentae (1.0% vs 3.1%), perinatal death (6.7% vs 8.7%), and small for gestational age (18.4% vs 14.3%) were similar between groups, but preterm delivery <37 weeks was higher in the prior preeclampsia group (36.9% vs 27.1%; adjusted risk ratio, 1.46; 95% confidence interval, 1.05-2.03; P = .032). CONCLUSION In women with chronic hypertension, a history of preeclampsia does not increase the rate of superimposed preeclampsia, but is associated with an increased rate of delivery at <37 weeks.

Variation in the urinary protein/creatinine ratio at four different periods of the day in hypertensive pregnant women.

Objective. To assess the urine protein/creatinine ratio in urine samples of pregnant women with hypertension in regard to: 1) the presence of significant variation at different periods of the day; 2) the differences if they exist, to identify the most reliable period of the day for sampling; and 3) whether the first sample, obtained when the patient arrives at the clinic, correlates with the same accuracy, with the 24-hour proteinuria. Design. Cross-sectional study. Place. Obstetrics Emergency Department, Hospital de Clínicas de Porto Alegre, a teaching hospital in Porto Alegre, Brazil. Population. Seventy-five women with hypertension with 20-week gestation or over. Methods. Urine samples for determination of the protein/creatinine ratio were obtained on arrival (first specimen) and every 6 hours thereafter, totaling four samples in 24 hours. Four sampling periods were established: 1) from 8 am to 2 pm, 2) from 2 pm to 8 pm, 3) from 8 pm to 2 am, and 4) from 2 am to 8 am. The protein/creatinine ratio in the four different day periods were compared with the 24-hour proteinuria obtained simultaneously. The results were analyzed by the Spearman correlation and the receiver-operator characteristic (ROC) curve. Results. The urine protein/creatinine ratio is strongly correlated (Spearman correlation equal to 0.8 or greater) with the 24-hour proteinuria at all four periods of the day (p < 0.001), as well as the first sample obtained on arrival (p = 0.003). These findings were corroborated by the ROC curve in which the values of four day periods and that of the first sample were equal to or greater than 0.930. Conclusion. In hypertensive pregnant women, the single voided urine sample protein/creatinine ratio, irrespective of sampling time, is strongly correlated with the 24-hour proteinuria, as is the sample obtained on arrival.

Reported Calcium Intake is Reduced in Women with Preeclampsia

Objective: The purpose of this trial is to investigate the relationship between dietary calcium content and incidence of preeclampsia, comparing diet calcium content in normotensive and preeclampsia patients. Dietary calcium was measured by a dietary interview conducted at the day after delivery. Methods: This is a prospective cross-sectional study involving 1092 patients who delivered at Hospital de Clínicas de Porto Alegre – Brazil. Results: The average diet calcium content in the studied population was 1038 mg. The average calcium intake in the normotensive group was 1057 mg, in chronic hypertension group was 962 mg, in transient hypertension group was 963 mg, in mild preeclampsia was 902 mg and in severe preeclampsia group was 755 mg. The results of this study show that pregnant women who develop severe preeclampsia have a significant lower diet calcium intake when compared to normotensive women (P = 0.018). Conclusion: The results of the present study can provide the foundations for prospective trials, including randomised clinical trials involving only patients with a low content of calcium in their diet.

Translabial ultrasonography in the assessment of urethral diameter and intrinsic urethral sphincter deficiency.

Objective. The purpose of this study was to determine the role of translabial ultrasonography in the investigation of intrinsic urethral sphincter deficiency (ISD), assessing bladder neck hypermobility and urethral diameter in continent and incontinent patients. Methods. A case‐control study evaluated 94 women with the diagnosis of urinary incontinence and 96 continent women. Both groups underwent translabial ultrasonography to assess bladder neck hypermobility by means of the x‐y coordinate system and urethral diameter. The study was performed at Hospital de Clínicas de Porto Alegre. Results. Women with urinary stress incontinence showed significantly greater bladder neck descent than continent women and women with urge and mixed incontinence (P = .05). Women with ISD showed significantly larger urethral diameters than control subjects and incontinent women without ISD (P = .05). Of women with urinary incontinence, 78.7% had descent of greater than 10 mm, and 91.7% of the women with ISD had urethral diameters of greater than 6 mm. A urethral diameter of greater than 6 mm showed sensitivity of 91.7% and specificity of 75.6% for ISD. Conclusions. Translabial ultra‐sonography has an important role in the assessment of women with urinary stress incontinence and intrinsic urethral sphincter deficiency.

Calciuria and preeclampsia: a case-control study.

Aim:  Calciuria has been reported to decrease in preeclampsia. We compared calciuria among groups of normal, hypertensive and preeclamptic pregnant women, and assessed its correlation with the severity of the disease.

Natriuria and calciuria levels in preeclampsia : a cross-sectional study

CONTEXT AND OBJECTIVE Sodium excretion abnormalities in preeclampsia have been studied in relation to several factors. The objective of this study was to compare natriuria (mEq/24 h) and calciuria levels (mg/24 h) in preeclamptic patients. DESIGN AND SETTING An analytical cross-sectional study with a control group was conducted in the obstetric center and the high-risk pregnancy outpatient clinic at a university hospital in southern Brazil, and in a primary healthcare unit in the same city, including pregnant women with mild preeclampsia, severe preeclampsia or chronic hypertension, and women with normal pregnancies (14 patients in each group). METHOD Natriuria was measured using an ion-selective electrode in an automated clinical chemistry analyzer (Hitache 917, Roche). All the patients collected 24-hour urine, at home or at the hospital, for analysis of proteins, creatinine, calcium, sodium and uric acid. Quantitative variables with asymmetrical distribution were described using the median, minimum and maximum, and were compared using the Kruskal-Wallis test. The results were logarithmically transformed, with one-way analysis of variance (ANOVA) by ranks and then the post-hoc Tukey test, and were analyzed by means of the Spearman correlation and receiver operating characteristic (ROC) curve. The significance level used was 0.05. RESULTS There were significant differences between the groups in comparing severe preeclampsia with chronic hypertension and severe preeclampsia with controls (P < 0.0001 for both measurements). CONCLUSION Natriuria levels may be lower in preeclampsia when associated with calciuria. Natriuria assessment is an additional test for differential diagnosis of hypertensive diseases in pregnancy, but is a poor predictor when used alone.