PIERS proteinuria: relationship with adverse maternal and perinatal outcome.

OBJECTIVE: To examine the ability of three different proteinuria assessment methods (urinary dipstick, spot urine protein:creatinine ratio [Pr/Cr], and 24-hour urine collection) to predict adverse pregnancy outcomes. METHODS: We performed a prospective multicentre cohort study, PIERS (Preeclampsia Integrated Estimate of RiSk), in seven academic tertiary maternity centres practising expectant management of preeclampsia remote from term in Canada, New Zealand, and Australia. Eligible women were those admitted with preeclampsia who had at least one antenatal proteinuria assessment by urinary dipstick, spot urine Pr/Cr ratio, and/or 24-hour urine collection. Proteinuria assessment was done either visually at the bedside (by dipstick) or by hospital clinical laboratories for spot urine Pr/Cr and 24-hour urine collection. We calculated receiver operating characteristic area under the curve (95% CI) for each proteinuria method and each of the combined adverse maternal outcomes (within 48 hours) or adverse perinatal outcomes (at any time). Models with AUC ≥ 0.70 were considered of interest. Analyses were run for all women who had each type of proteinuria assessment and for a cohort of women ("ALL measures") who had all three proteinuria assessments. RESULTS: More women were proteinuric by urinary dipstick (≥ 2+, 61.4%) than by spot urine Pr/Cr (≥ 30 g/mol, 50.4%) or 24-hour urine collection (≥ 0.3g/d, 34.7%). Each proteinuria measure evaluated had some discriminative power, and dipstick proteinuria (categorical) performed as well as other methods. No single method was predictive of adverse perinatal outcome. CONCLUSION: The measured amount of proteinuria should not be used in isolation for decision-making in women with preeclampsia. Dipstick proteinuria performs as well as other methods of assessing proteinuria for prediction of adverse events.

Methodological and technical issues related to the diagnosis, screening, prevention, and treatment of pre-eclampsia and eclampsia.

In contrast with advances made in treating or eliminating many other serious disorders, severe morbidity and mortality associated with pre-eclampsia/eclampsia remain among the leading problems that threaten safe motherhood, particularly in developing countries. This article reviews technical issues related to diagnosis, screening, prevention, and treatment of pre-eclampsia and identifies corresponding needs. The authors stress the lack of standardized definitions of pre-eclampsia and eclampsia and discuss problems in blood-pressure measurements and assessment of urinary protein. They summarize the evidence for prevention strategies and screening tests for early detection. For treatment, magnesium sulfate has been proven effective, but not widely used. The authors outline priorities for narrowing the identified gaps and emphasize the need for coordinated efforts to reduce the morbidity and mortality due to pre-eclampsia/eclampsia. They conclude that the mystery of this disease must be resolved to achieve primary prevention of it.

Glomerular heteroporous membrane modeling in third trimester and postpartum before and during amino acid infusion.

Human pregnancy is associated with substantial increments in glomerular filtration rate (GFR) and renal plasma flow (RPF). We have previously demonstrated that permselectivity to neutral dextrans is altered in pregnancy, theoretical analysis of the dextran sieving curves suggesting that elevated GFR is due to increased RPF and decreased glomerular oncotic pressure (pi(GC)) with no evidence of increased transglomerular hydrostatic pressure difference (DeltaP). These conclusions have been challenged, with claims that the rise in GFR is primarily a result of a decrement in pi(GC). With refined laboratory and infusion protocols, we have reexplored the determinants of ultrafiltration in a serial study of 11 healthy women in late pregnancy (LP) and 4 mo postpartum (PP), both in the baseline state and after increasing GFR and RPF by infusion of amino acids. Results were analyzed using two computer modeling programs. Increased GFR in LP (38%, P < 0.05) was due to a combination of elevated RPF (22%) and a decrement in pi(GC) and associated with an increased ultrafiltration coefficient, without evidence of increased DeltaP, and additional amino acid-provoked GFR increments (P < 0.05) produced similar findings. In addition, refined methodology permitted collection of sufficient data on excreted large-radii dextrans (>60 A) to better define the nondiscriminatory "shunt" pathway (omega(0)) and the standard deviation of pore size (S) about the mean radius of the distribution. Thus it was possible to demonstrate that the physiological increase in total protein excretion in LP is associated with a prominent shunt and an upward shift in breadth of distribution of pore sizes. This ability to quantify omega(0) and S will now permit better evaluation of the pathophysiological changes in the glomerulus associated with pregnancy in women with renal disease and in gravidas developing preeclampsia.

Antihypertensive therapy in pregnancy.

Human pregnancy, normally characterized by systemic vasodilation and modest hypotension, can be complicated by underlying maternal hypertension and several unique hypertensive disorders, including pre-eclampsia. Although well-designed and adequately powered clinical trials are critically needed, there have been several recent meta-analyses of this large literature, along with consensus statements and treatment guidelines from three distinct multidisciplinary groups of clinicians and investigators. In this paper we review recent analyses and guidelines, advising on our current approach to antihypertensive therapy in pregnant women.

Antiphospholipid antibodies in women at risk for preeclampsia.

OBJECTIVE: The aim of this study was to determine whether positive results of tests for any of 5 antiphospholipid antibodies are associated with recurrent preeclampsia among women with a history of preeclampsia in a previous pregnancy. STUDY DESIGN: Second-trimester serum samples were obtained from 317 women with preeclampsia in a previous pregnancy who were being followed up in a prospective treatment trial. The serum samples were measured by enzyme-linked immunoassay for immunoglobulin G and immunoglobulin M antibodies against 5 phospholipids. Positive results were analyzed with regard to preeclampsia, severe preeclampsia, intrauterine growth restriction, and preterm delivery. RESULTS: Sixty-two of the 317 women (20%) had recurrent preeclampsia develop, 19 (6%) had severe preeclampsia, and 18 (5.8%) were delivered of infants with growth restriction. Positive results of tests for immunoglobulin G or immunoglobulin M antiphospholipid antibodies were not associated with recurrent preeclampsia. Positive results for immunoglobulin G or immunoglobulin M antibodies at the 99th percentile were also not associated with preterm delivery. Positive results at the 99th percentile for immunoglobulin G antiphosphatidylserine antibody were associated with severe preeclampsia, and positive results at the 99th percentile for immunoglobulin G anticardiolipin, antiphosphatidylinositol, and antiphosphatidylglycerol antibodies were associated with intrauterine growth restriction. The positive predictive values for these outcomes all were approximately 30%. CONCLUSION: Positive results of testing for antiphospholipid antibodies in the second trimester were not associated with recurrent preeclampsia among women at risk because of a history of preeclampsia. Positive results for immunoglobulin G antiphosphatidylserine antibody were associated with severe preeclampsia, and positive results for immunoglobulin G anticardiolipin, antiphosphatidylinositol, and antiphosphatidylglycerol antibodies were associated with intrauterine growth restriction. However, the positive predictive values for all these associations were modest. Testing for antiphospholipid antibodies during pregnancy is of little prognostic value in the assessment of the risk for recurrent preeclampsia among women with a history of preeclampsia.

The kidney and hypertension in pregnancy: twenty exciting years.

Before 1980 research on the kidney and hypertension during pregnancy was neglected, although these diseases, especially hypertension, are major causes of morbidity to mother and child. The past 20 years, however, has witnessed a striking reversal of this neglect. This review focuses on recent progress in renal physiology, kidney disease, and hypertension as relates to pregnancy. Why do renal hemodynamics increase markedly in pregnancy? Studies have suggested roles for nitric oxide synthase, prostaglandins, endothelin and relaxin. This area of research is exciting, as unraveling why glomerular filtration rate and renal plasma flow increase in pregnancy may eventually help all patients with acute and chronic renal function loss. Concerning other advances: Micropuncture studies in rats, and the interpretation of fractional dextran clearances in humans show that the hyperfiltration that occurs during normal gestation is not associated with increased glomerular capillary pressure. Finally, description of changes in osmoregulation and in the metabolic disposal of arginine vasopressin in human pregnancy led to identification and appropriate treatment of a new group of disorders termed "transient diabetes insipidus of pregnancy." Chronic renal disease of any severity once led to proscription or interrupting of pregnancy. Clinical-pathological correlation studies and long-term follow-up of the mothers have revealed that most of these gestations succeed with little risk of worsening the natural history of the kidney disorder. This is also true in allograft recipients, and we now have guidelines to counsel both groups of patients. Progress relating to hypertension in pregnancy has been in 2 broad areas; systematic attempts to accurately define and differentiate the various disorders and population studies to predict, prevent, and improve the management of preeclampsia. There has also been considerable progress in unraveling the pathophysiology and identifying the cause of preeclampsia.

A study of the adsorption of bile salts onto model lecithin membranes.

Bile salts play a central role in the promotion of cytotoxicity or cytoprotection. In this study, we examined the interaction of different bile salts with egg lecithin vesicles using 31P NMR spectroscopy. The effects of taurochenodeoxycholate (TCDC or 3alpha,7alpha,-dihydroxy-5beta-cholanoyl taurine, of tauroursodeoxycholate (TUDC) or 3alpha,7beta,-dihydroxy-5beta-cholanoyl taurine) and of taurobetamuricholate (TbetaMC or 3alpha,6beta,7beta,-trihydroxy-5beta-cholanoyl taurine), at various bile salt/lecithin ratios, were evaluated. From the percent 31P present in vesicles, the micellar capacity of bile salts to dissolve lecithin was determined. TCDC was incorporated into vesicles for bile salt/lecithin molar ratios lower than 0.62 while for TUDC and TbetaMC, the critical ratios were 0.94 and 1.1, respectively. The 31P chemical shift change was markedly larger with TCDC than that found with TUDC and TbetaMC. In order to specify the low interactions observed between hydrophilic bile salts and lecithin, we determined the intermixed micellar/vesicular bile salt concentrations (IMVC) of bile salt/lecithin solutions using rapid ultrafiltration-centrifugation for TUDC and lecithin solubility measurements for TUDC, TbetaMC and TCDC. The low IMVC obtained indicate that even hydrophilic bile salts were bound mostly to the mixed aggregates. In conclusion, the low disturbance in the arrangement of lecithin induced by TUDC and TbetaMC appears to be due to the interfacial location of these bile salts. TCDC (7alpha OH) penetrates more deeply in the membrane than the 7beta hydroxylated bile salts that may partly explain the distinct damaging effects of these bile salts.

Connexin expression is not altered in omental resistance vessels from women with preeclampsia.

OBJECTIVE: To compare connexin expression in omental resistance arteries from preeclamptic women and normal gravidas. METHODS: Small arteries (approximately 200-400 microm i.d.) were dissected from omental fat biopsies, taken at cesarean delivery from normotensive and preeclamptic women. Vessels were frozen and homogenized, then connexin-43 protein was detected by Western blot and quantitated by comparison with alpha-actin. RESULTS: Connexin-43 was detected in all specimens, primarily in its phosphorylated form. Abundance did not differ between vessels from preeclamptic and normotensive gravidas. CONCLUSIONS: Phasic activity in omental resistance vessels from preeclamptic women likely depends on abnormal genesis of an oscillatory signal rather than on more extensive gap junctional communication between vascular cells.

On the Behavior of Nonionic Surfactants at the N-Heptane/Silica Gel Interface: Influence of the Presence of Interfacial Water Inferred from Adsorption Isotherms and Calorimetric Data.

The behavior of two polydisperse nonionic surfactants, poly (oxyethylene) glycol alkylphenyl ether TX-35 and TX-100, at the prewetted silica gel/n-heptane and dried silica gel/n-heptane interfaces has been compared by the determination of the average adsorption isotherms of the polydisperse surfactants and of displacement enthalpies. From HPLC experiments, we could also separately quantify the adsorption of each ethyleneoxide (EO) fractions for silica gel from the polydisperse surfactant solution. The adsorption isotherms clearly indicate an incomplete preferential adsorption of the large (EO) chains over the small ones, as well on dried silica gel as on a prehydrated sample. This preferential adsorption and its driving force follow the solubility rules of the poly(oxyethylene) glycol alkylphenyl ether in an apolar solvent and support the idea of a solubility-limited adsorption: solubility in organic solvents of the smaller (EO) chains is much more significant than that of the longer ones and hence prevents adsorption of the smaller species. Consequently, it is observed that the presence of interfacial water decreases the affinity of TX-35 molecules for the hydrophilic silica surface due to the hydration of (EO) chains. In contrast, for TX-100 adsorption after the prewetting treatment the clearest trend is a drastic increase of the adsorption ascribed to the additional solubilization (and micellization) of the TX-100 molecules in the interfacial aqueous phase. The differential molar enthalpies of displacement show a change in the adsorption mechanism, depending on the presence of molecular water on the surface. In the initial part of the adsorption isotherm, a prevailing exothermic process is obtained with prehydrated silica and suggests that hydration of the polar heads of TX-35 and the solubilization of the TX-35 in interfacial water are occurring. For higher equilibrium concentrations, the enthalpies of displacement observed with the prehydrated adsorbent become slightly lower than those obtained with dry silica gel. It may be that this difference is due to the micellization phenomenon of the surfactant species with longer EO chains in interfacial water. These features emphasize the influence of interfacial water on the adsorption of EO fractions from organic solvent. Copyright 2000 Academic Press.

Hypertensive disorders in twin versus singleton gestations. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.

OBJECTIVE: This study was undertaken to compare rates and severity of gestational hypertension and preeclampsia, as well as perinatal outcomes when these complications develop, between women with twin gestations and those with singleton gestations. STUDY DESIGN: This was a secondary analysis of prospective data from women with twin (n = 684) and singleton (n = 2946) gestations enrolled in two separate multicenter trials of low-dose aspirin for prevention of preeclampsia. End points were rates of gestational hypertension, rates of preeclampsia, and perinatal outcomes among women with hypertensive disorders. RESULTS: Women with twin gestations had higher rates of gestational hypertension (relative risk, 2.04; 95% confidence interval, 1.60-2.59) and preeclampsia (relative risk, 2. 62; 95% confidence interval, 2.03-3.38). In addition, women with gestational hypertension during twin gestations had higher rates of preterm delivery at both <37 weeks' gestation (51.1% vs 5.9%; P <. 0001) and <35 weeks' gestation (18.2% vs 1.6%; P <.0001) and also had higher rates of small-for-gestational-age infants (14.8% vs 7. 0%; P =.04). Moreover, when outcomes associated with preeclampsia were compared, women with twin gestations had significantly higher rates of preterm delivery at <37 weeks' gestation (66.7% vs 19.6%; P <.0001), preterm delivery at <35 weeks' gestation (34.5% vs 6.3%; P <.0001), and abruptio placentae (4.7% vs 0.7%; P =.07). In contrast, among women with twin pregnancies, those who remained normotensive had more adverse neonatal outcomes than did those in whom hypertensive complications developed. CONCLUSIONS: Rates for both gestational hypertension and preeclampsia are significantly higher among women with twin gestations than among those with singleton gestations. Moreover, women with twin pregnancies and hypertensive complications have higher rates of adverse neonatal outcomes than do those with singleton pregnancies.

Risks of preeclampsia and adverse neonatal outcomes among women with pregestational diabetes mellitus. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.

OBJECTIVES: This study was undertaken to determine the frequencies of preeclampsia and adverse neonatal outcomes among women with pregestational diabetes. STUDY DESIGN: This was a prospective observation of pregnancy outcomes among 462 women with pregestational diabetes mellitus (White classes B-F) and singleton pregnancies who were enrolled in a multicenter trial to compare low-dose aspirin with placebo for preeclampsia prevention. The main outcome measures were preeclampsia and neonatal outcomes. RESULTS: Among 462 women with pregestational diabetes, 92 (20%) had preeclampsia. Preeclampsia frequency rose significantly with increasing severity of diabetes according to White classification (class B, 11%; class C, 22%; class D, 21%; class R plus class F, 36%; P <.0001). Preeclampsia was also more common among women who had proteinuria at baseline (28% vs 18%; odds ratio, 1.75; 95% confidence interval, 1.02-3.01). Frequency of preterm delivery at <35 weeks' gestation rose greatly with increasing severity of diabetes (P =.0002). Women with proteinuria at baseline were significantly more likely to be delivered at <35 weeks' gestation (29% vs 13%; odds ratio, 2.6; 95% confidence interval, 1.5-4.6) and to have small-for-gestational-age infants (14% vs 3%; odds ratio, 5. 4; 95% confidence interval, 2.7-17.7), and they were less likely to have large-for-gestational-age infants (14% vs 40%; odds ratio, 0.2; 95% confidence interval, 0.1-0.5). CONCLUSION: Among women with pregestational diabetes mellitus, the frequency of preeclampsia rose with increasing severity of diabetes. Proteinuria early in pregnancy was associated with marked increases in adverse neonatal outcomes independent of preeclampsia development.

Safety of labor epidural anesthesia for women with severe hypertensive disease. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.

OBJECTIVE: The aim of this study was to determine whether epidural anesthesia during labor increased the frequencies of cesarean delivery, pulmonary edema, and renal failure among women with severe hypertensive disease. STUDY DESIGN: We performed a secondary retrospective analysis of a subgroup population within a multicenter double-blind trial of low-dose aspirin therapy for women at high risk for development of preeclampsia. Subjects in whom severe hypertensive disease developed were selected. The primary outcomes were the overall frequencies of cesarean delivery among women with severe hypertensive disease who had labor with and without epidural anesthesia. Other maternal and neonatal outcomes were also compared between women who did and did not receive epidural anesthesia. RESULTS: Among the women with severe hypertensive disease (n = 444) 327 had labor. Among the women with severe disease who had labor there was no difference in either the overall cesarean delivery rate (32.1% vs 28.0%; P =.44) or the rate of cesarean delivery for fetal distress or failure to progress (27.8% vs 22.0%; P =.26) between women who did and did not receive epidural analgesia. Women with chronic hypertension were more likely to have a cesarean delivery overall if they received epidural anesthesia, but there was otherwise no difference in the frequencies of cesarean delivery for these indications between women with and without epidural anesthesia within each of the high-risk groups. Pulmonary edema was rare and acute renal failure did not develop in any women. CONCLUSION: Epidural anesthesia use did not increase the frequencies of cesarean delivery, pulmonary edema, and renal failure among women with severe hypertensive disease.

A modified definition for peripartum cardiomyopathy and prognosis based on echocardiography.

The diagnosis of peripartum cardiomyopathy is one of exclusion, made after careful search for an underlying cause. Research in this area is compromised by the reliance of some on clinical criteria alone without strict echocardiographic criteria. This article argues for uniform criteria that define peripartum cardiomyopathy, similar to the criteria for idiopathic dilated cardiomyopathy set forth by a National Heart, Lung, and Blood Institute-sponsored workshop and proposes that the new definition include heart failure within the last month of pregnancy or 5 months postpartum; absence of preexisting heart disease; no determinable etiology, the traditional definition; and strict echocardiographic criteria of left ventricular dysfunction: ejection fraction less than 45%, or M-mode fractional shortening less than 30%, or both, and end-diastolic dimension more than 2.7 cm/m2. Mortality from peripartum cardiomyopathy remains high, 25-50%, and a recent review related long-term prognosis to echocardiographic measures of left ventricular chamber dimension and function at diagnosis and recovery. We describe a modified pharmacologic echocardiographic stress test that might be useful in determining left ventricular contractile reserve in women believed to be recovered by routine echocardiographic studies. The test reproduces hemodynamic stress akin to pregnancy, and the data might be useful when counseling women on future childbearing. Women who respond with reduced cardiac reserve might be advised to avoid pregnancy.

Maternal serum thromboxane B2 concentrations do not predict improved outcomes in high-risk pregnancies in a low-dose aspirin trial. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medical Units.

OBJECTIVE: The aim of the study was too determine whether, in a low-dose aspirin trial in high-risk pregnancies, a decrease in maternal serum thromboxane B2 level predicted improved pregnancy outcomes. STUDY DESIGN: This multicenter, randomized, double-blind trial included 2539 women, 1010 of whom had sufficient serum samples at enrollment and at 24 to 28 weeks' gestation, 34 to 38 weeks' gestation, or both to assess longitudinal changes in thromboxane B2 level and their effects on pregnancy outcomes. Women were randomly assigned between 13 and 26 weeks' gestation to receive daily aspirin (60 mg) or placebo. RESULTS: Overall and in all subgroups women assigned to receive aspirin had markedly lower maternal thromboxane B2 concentration values than did those assigned to receive a placebo (P =.0001). Changes in thromboxane levels were not, however, correlated with adverse pregnancy outcomes. Women with >/=50% reduction in maternal serum thromboxane B2 concentrations from baseline had occurrences of preeclampsia (P =.922), preterm birth (P =.375), small for gestational age neonates (P =.938), and grade III or IV intraventricular hemorrhage (P = 1.000) similar to those of women who had <50% reduction. Similar results were found for women with thromboxane B2 level decreases of <15 versus >15 ng/mL and women with thromboxane B2 level decreases to <10 versus >/=10, <5 versus >/=5, and <1 versus >/=1 ng/mL. Maternal thromboxane B2 concentrations at enrollment were also not predictive of adverse outcomes. CONCLUSION: Neither maternal serum thromboxane B2 concentrations at enrollment nor their subsequent reduction were predictive of adverse pregnancy outcomes in a low-dose aspirin trial.

Predictors of pre-eclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.

OBJECTIVE: We assessed several variables as predictors for pre-eclampsia risk in a group of women at high risk. STUDY DESIGN: We studied 2503 women with either diabetes mellitus, chronic hypertension, multifetal gestation, or pre-eclampsia in a previous pregnancy who participated in a multicenter study comparing aspirin and placebo in preventing pre-eclampsia. We evaluated multiple variables for predicting pre-eclampsia risk with use of univariate and multivariable analysis. RESULTS: Parity and mean arterial pressure at randomization were most predictive of pre-eclampsia risk. The risk was 8% with a mean arterial pressure at enrollment of <75 mm Hg versus 27% with a mean arterial pressure >85 mm Hg (relative risk and 95% confidence interval 3.3 [2.4 to 4.4]). The risk of pre-eclampsia was 26% in nulliparous patients versus 17% in parous subjects (relative risk and 95% confidence interval 1.5 [1.3-1.8]). CONCLUSIONS: The finding that second-trimester mean arterial pressure affects pre-eclampsia risk suggests that the pathophysiologic process of preeclampsia is initiated before that time.

Pregnancy in a nonimmunosuppressed transplant recipient.

A 30-year-old woman with a living related six-antigen-matched kidney allograft conceived 10 years posttransplantation. She had discontinued her immunosuppression medications 3 years previously. The allograft functioned well throughout gestation, which was complicated by preeclampsia, leading to induction at 35 weeks and delivery of a 2,175-g male.