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.

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.

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.

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.

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.

Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.

BACKGROUND: Whether low-dose aspirin prevents preeclampsia is unclear. It is not recommended as prophylaxis in women at low risk for preeclampsia but may reduce the incidence of the disease in women at high risk. METHODS: We conducted a double-blind, randomized, placebo-controlled trial in four groups of pregnant women at high risk for preeclampsia, including 471 women with pregestational insulin-treated diabetes mellitus, 774 women with chronic hypertension, 688 women with multifetal gestations, and 606 women who had had preeclampsia during a previous pregnancy. The women were enrolled between gestational weeks 13 and 26 and received either 60 mg of aspirin or placebo daily. RESULTS: Outcome data were obtained on all but 36 of the 2539 women who entered the study. The incidence of preeclampsia was similar in the 1254 women in the aspirin group and the 1249 women in the placebo group (aspirin, 18 percent; placebo, 20 percent; P=0.23). The incidences in the aspirin and placebo groups for each of the four high-risk categories were also similar: for women with pregestational diabetes mellitus, the incidence was 18 percent in the aspirin group and 22 percent in the placebo group (P=0.38); for women with chronic hypertension, 26 percent and 25 percent (P= 0.66); for those with multifetal gestations, 12 percent and 16 percent (P=0.10); and for those with preeclampsia during a previous pregnancy, 17 percent and 19 percent (P=0.47). In addition, the incidences of perinatal death, preterm birth, and infants small for gestational age were similar in the aspirin and placebo groups. CONCLUSIONS: In our study, low-dose aspirin did not reduce the incidence of preeclampsia significantly or improve perinatal outcomes in pregnant women at high risk for preeclampsia.

Preeclampsia selectively impairs endothelium-dependent relaxation and leads to oscillatory activity in small omental arteries.

The vascular pathophysiology of preeclampsia, a hypertensive disorder unique to human pregnancy, has been postulated to be due to endothelial dysfunction, primarily manifest as deficient nitric oxide (NO) synthesis. We evaluated contraction (KCl and arginine vasopressin [AVP]) and dilation (acetylcholine and bradykinin) in small resistance-size omental arteries obtained during surgery from women with preeclampsia, postulating that these vessels would exhibit augmented contraction and diminished endothelium-dependent relaxation, most likely due to decreased NO synthesis. For comparison, vessels were also obtained from normotensive gravidas, pregnant women with chronic hypertension, or with chronic hypertension and superimposed preeclampsia, as well as from premenopausal nonpregnant controls. Vessels of approximately 200 micron in internal diameter were studied in vitro using a Mulvany-Halpern myograph. Maximal contraction due to either KCl or AVP was significantly augmented in vessels from women with preeclampsia; these vessels all exhibited endothelium- and cyclooxygenase-dependent phasic oscillations while vessels from all other groups exhibited only tonic contractions. Acetylcholine and bradykinin both led to dose- and endothelium-dependent relaxation which was unaffected by inhibitors of NO synthesis. Responses to bradykinin were similar in vessels from normal pregnant and preeclamptic women while those to acetylcholine were absent in vessels from women with preeclampsia. These data suggest specific defects in resistance-artery endothelium from women with preeclampsia.

Serial assessment of the cardiovascular system in normal pregnancy. Role of arterial compliance and pulsatile arterial load.

BACKGROUND: Temporal changes in systemic arterial compliance and wave propagation properties (pulsatile arterial load) and their role in ventricular-systemic arterial coupling during gestation have not been explored. Noninvasive methods combined with recently developed mathematical modeling techniques were used to characterize vascular and left ventricular (LV) mechanical adaptations during normal gestation. METHODS AND RESULTS: Fourteen healthy women were studied at each trimester of pregnancy and again postpartum. Experimental measurements included instantaneous aortic pressure (subclavian pulse tracings) and flow (aortic Doppler velocities) and echocardiographic imaging of the LV. A small increase in LV muscle mass and end-diastolic chamber dimension occurred by late gestation, with no significant alterations in myocardial contractility. Cardiac output increased and the steady component of arterial load (total vascular resistance) decreased during pregnancy. Several changes in pulsatile arterial load were noted: Global arterial compliance increased (approximately 30%) during the first trimester and remained elevated thereafter. The magnitude of peripheral wave reflections at the aorta was reduced. The mathematical model-based analysis revealed that peripheral wave reflections at the aorta were delayed and that both conduit and peripheral vessels contributed to the increased arterial compliance. Finally, coordinated changes in the pulsatile arterial load and LV properties were responsible for maintaining the efficiency of LV-to-arterial system energy transfer. CONCLUSIONS: The rapid time course of compliance changes and the involvement of both conduit and peripheral vessels are consistent with reduced vascular tone as being the main underlying mechanism. The pulsatile arterial load alterations during normal pregnancy are adaptive in that they help to accommodate the increased intravascular volume while maintaining the efficiency of ventricular-arterial coupling and diastolic perfusion pressure.

Diagnosis and management of diabetes insipidus during pregnancy.

OBJECTIVE: To provide an overview of diagnostic and treatment strategies in pregnant patients with diabetes insipidus (DI). METHODS: We review the changes in osmoregulation during normal pregnancy, characterize the various types of DI that can occur during pregnancy, and discuss the recommended management. RESULTS: The incidence of DI is 2 to 4 cases per 100,000 gestations. Central DI can precede pregnancy or manifest initially during gestation. With preexistent central DI, pregnancy usually aggravates the disorder, and the requirements for antidiuretic hormone (ADH) usually increase. Such an effect is less likely to be noted in ADH-independent nephrogenic forms of DI. Currently, the major type of DI associated with pregnancy is a transient syndrome that is resistant to arginine vasopressin (AVP) but responsive to desmopressin (dDAVP); such cases of DI are often associated with liver abnormalities or preeclampsia. This syndrome is explained by excess vasopressinase, a placental enzyme which degrades AVP but not dDAVP. A transient recurrent type of DI can occur during gestation in patients with limited ADH-secreting capacity and is responsive to both AVP and dDAVP. Latent central DI manifesting after complicated delivery and transient nephrogenic DI, resistant to both AVP and dDAVP, have also been reported. CONCLUSION: The differential diagnosis of polyuric and polydipsic states during pregnancy is broad, and precise diagnosis may be difficult. The use of dDAVP to treat DI during gestation has proved effective and safe for both the mother and the fetus.

Pre-eclampsia-eclampsia 1996: preventable? Have disputes on its treatment been resolved?

The fetal and maternal morbidity and mortality associated with hypertension complicating pregnancy primarily results from pre-eclampsia. This review focuses on recent developments in the areas of prevention and management. It specifically analyses studies designed to determine whether low-dose aspirin or calcium supplements, taken throughout pregnancy, reduce the incidence of pre-eclampsia, a debate on whether we have been too aggressive in terminating pregnancies in patients with severe pre-eclampsia remote from term, and the efficacy of parenteral magnesium sulfate in the prevention or treatment, or both, of the eclamptic convulsion. We conclude that neither aspirin nor calcium appears to improve the gestational outcome, although large trials currently under way may alter this view. The debate on 'conservative' versus aggressive management of early-onset severe pre-eclampsia seems to be more apparent than real. After years of acrimonious debate there are data to support the superiority of magnesium over phenytoin to prevent pre-eclampsia and the efficacy of the drug in reducing recurrent convulsions in eclampsia. However, whether 'prophylactic' therapy is indeed necessary or whether blood pressure control alone will prevent eclampsia remains to be determined.

Effects of pregnancy on femoral microvascular responses in the rat.

OBJECTIVE: Our purpose was to test the hypothesis that augmented basal and vasodilator agonist-stimulated synthesis of endothelium-derived nitric oxide would blunt vasoconstrictor-induced contraction and enhance relaxation in isolated femoral resistance vessels from pregnant rats. STUDY DESIGN: Potassium chloride-, phenylephrine-, and angiotensin II-induced contraction and acetylcholine-induced relaxation were assessed in small (approximately 240 microns diameter) femoral resistance arteries from gravid and virgin animals studied under isometric conditions; the effects of potassium chloride, phenylephrine, and acetylcholine were also studied in the presence of nitroarginine. RESULTS: Maximal vasoconstriction was similar in vessels from virgin and pregnant rats, whereas phenylephrine potency was slightly enhanced in vessels from gravid animals. Nitroarginine augmented contraction in both groups but with greater effect on phenylephrine potency and on submaximal potassium chloride contractions in virgins. Acetylcholine-induced relaxation did not differ between groups and was similarly, but only partially, inhibited by nitroarginine. CONCLUSIONS: Pregnancy does not result in vasoconstrictor resistance, increased basal nitric oxide synthesis, or augmented agonist-stimulated endothelium-dependent relaxation in this particular isolated rat microvascular preparation. Further, endothelium-dependent relaxation of these vessels depends only partly on nitric oxide.

Altered glomerular permselectivity to neutral dextrans and heteroporous membrane modeling in human pregnancy.

Hyperfiltration precedes renal function loss in several nephropathies. Animal studies suggest this may be due to accompanying increases in transglomerular capillary hydrostatic pressure difference (delta P) and/or altered glomerular processing of macromolecules. Renal hemodynamics increase strikingly in human pregnancy. To test the hypothesis that these alterations are not potentially harmful, clearances of inulin, p-aminohippurate, and neutral dextrans were measured at 16- and 36-wk gestation, then 4 mo postpartum, in 11 normotensive women. Results were analyzed using two computer modeling programs. Glomerular filtration rate and renal plasma flow (RPF) were markedly elevated in early and late pregnancy (135 +/- 6 and 895 +/- 53 and 135 +/- 6 and 754 +/- 32 ml/min, respectively, vs. 87 +/- 7 and 520 +/- 17 ml/min postpartum). Gestational hyperfiltration was primarily due to RPF increments with a minor contribution from decrements in capillary oncotic pressure. Fractional dextran clearances (particularly the smaller dextrans, 30-39 A radii) were lower in early pregnancy, decreasing further in late pregnancy. There was no evidence of increased delta P and alterations in glomerular membrane porosity resolved postpartum. These data provide a database by which to study effects of pregnancy on chronic renal disease.