Hyper tension

Cur r i c u l u m

R e v i e w

Donald G. Vidt, MD, Section Editor

Hypertensive Pregnancy Disorders: Current Concepts

Steven J. Wagner, MD;1 Snezana Barac, MD;2 Vesna D. Garovic, MD1

Hypertensive pregnancy disorders complicate 10% of all pregnancies and cover a spectrum of conditions, namely preeclampsia, eclampsia, and chronic and gestational hypertension. Preeclampsia is a pregnancy-specific disorder clinically characterized by hypertension and proteinuria that occurs after 20 weeks of gestation. It remains a leading cause of both fetal and maternal morbidity and mortality worldwide. Traditionally, hypertensive pregnancy disorders were considered not to have any long-term impact on mothers cardiovascular health; however, recent studies consistently have supported the role of hypertension in pregnancy as a risk factor for cardiovascular disease later in life. Therefore, improved screening, and preventive and treatment strategies may not only optimize management of hypertensive pregnancy disorders, but may have a long-term impact on womens cardiovascular events and outcomes years after the affected pregnancies. This article will provide a brief review of hypertensive pregnancy disorders and important recent discoveries regarding their pathogeneses, while focusing on current diagnostic and treatment strategies. (J Clin Hypertens. 2007;9:560566) 2007 Le Jacq

From the Mayo Clinic, Rochester, MN;1 and the University of Manitoba, Winnipeg, Manitoba, Canada2 Address for correspondence: Vesna Garovic, MD, Division of Internal Medicine, Department of Nephrology and Hypertension, Mayo Clinic, 200 1st Street, Rochester, MN 55905 E-mail: garovic.vesna@mayo.edu

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ypertensive pregnancy disorders complicate 10% of all pregnancies and cover a spectrum of conditions, namely preeclampsia, eclampsia, and chronic and gestational hypertension. Preeclampsia is a pregnancy-specific disorder clinically characterized by hypertension and proteinuria that occurs after 20 weeks of gestation. A recent report of pregnancy-related maternal deaths at 20 weeks of gestation in the United States recognized preeclampsia together with eclampsia (the convulsive form of the disorder) as one of the major causes, accounting for 790 of 4024 maternal deaths that occurred from 1979 to 1992. Traditionally, hypertensive pregnancy disorders (including preeclampsia) were not considered to have any long-term impact on mothers cardiovascular health. Recent studies have consistently supported the role of hypertension in pregnancy as a risk factor for cardiovascular disease later in life, however. One possible mechanism for this relationship is that hypertensive pregnancy disorders (preeclampsia, in particular) and cardiovascular disease share several common risk factors (obesity, diabetes mellitus, renal disease) or, alternatively, hypertension in pregnancy may induce long-term metabolic and vascular abnormalities that may increase the overall risk for cardiovascular disease later in life. Therefore, improved screening and preventive and treatment strategies may not only optimize management of hypertensive pregnancy disorders but may have a long-term impact on womens cardiovascular events and outcomes years after the affected pregnancies. This article will provide a brief review of hypertensive pregnancy disorders and important recent discoveries regarding their pathogeneses, while focusing on current diagnostic and treatment strategies.
VOL. 9 NO. 7 JULY 2007

The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Karen Hurwitch at KHurwitch@bos.blackwellpublishing.com or 781-388-8470.

Table I. Classification and Diagnostic Features of Hypertension in Pregnancy

HYPERTENSIVE DISORDERS IN PREGNANCY Preeclampsia/eclampsia DEFINITION AND CLINICAL CHARACTERISTICS Preeclampsia, a pregnancy-specific disorder that occurs in 3%5% of pregnancies, is a multisystem disease characterized by hypertension and protein level 300 mg in a 24-hour urine collection. Eclampsia, the convulsive form of preeclampsia, affects 0.1% of all pregnancies. Blood pressure 140/90 mm Hg before pregnancy or before the 20th week of gestation. Most patients in this category will have a benign course with normalization of blood pressure midpregnancy. Up to 30% of women with chronic hypertension develop preeclampsia, heralded by proteinuria that occurs for the first time in the third trimester, which is absent in uncomplicated chronic hypertension. Hypertension that occurs for the first time during the second half of pregnancy in the absence of proteinuria. It includes both women with preeclampsia who have not yet developed proteinuria and those with hypertension only; in a subset of patients with gestational hypertension, blood pressure remains elevated after delivery, leading to the diagnosis of chronic hypertension. Transient hypertension is characterized by blood pressure normalization by 12 weeks postpartum.

Chronic hypertension

Preeclampsia superimposed on chronic hypertension

Gestational hypertension

DIAGNOSIS AND CLASSIFICATION OF HYPERTENSIVE PREGNANCY DISORDERS Table I outlines the classification and diagnostic features of the hypertensive disorders of pregnancy. In 2000, The Working Group of the National High Blood Pressure Education Program (NHBPEP) defined hypertension as systolic blood pressure 140 mm Hg or diastolic blood pressure 90 mm Hg on 2 readings at least 4 hours apart. Proteinuria is defined as a protein level 300 mg in a 24-hour specimen. When a 24-hour specimen cannot be obtained or a diagnosis is urgently needed, a random sample with 1+ protein by dipstick analysis may substitute for the gold-standard 24-hour urine collection. Preeclampsia: Pure vs Superimposed Preeclampsia seems to arise from complex interactions among placenta-derived products, maternal constitutional factors (eg, obesity, diabetes mellitus, hypertension), and exaggerated adaptive mechanisms that normally occur during pregnancy (inflammatory response, hypercoagulable state). It is estimated that about 5% of otherwise normal pregnancies will be affected with preeclampsia and that as many as 25% of women with preexisting risk factors, such as chronic hypertension, will develop superimposed preeclampsia. The diagnosis of preeclampsia is rather straightforward in women who are healthy at baseline. It becomes more complicated in patients for whom prepregnancy values are not available or patients who are hypertensive or proteinuric before pregnancy. In women with chronic hypertension, preeclampsia is heralded by proteinuria that occurs for the first time in the third trimester, which is typically

Table II. Risk Factors for Preeclampsia

History of preeclampsia with previous pregnancies Extremely old or young maternal age Multiparity Multiple gestations Family history of preeclampsia Chronic hypertension (either essential or secondary) Thrombophilias Trophoblastic disease Diabetes mellitus Autoimmune and connective tissue diseases Renal disease

absent in uncomplicated chronic hypertension. For women with preexisting proteinuria, the diagnosis of preeclampsia is certain if more severe forms develop, such as either hemolysis, elevated liver enzyme levels, and thrombocytopenia (HELLP) syndrome or eclampsia. In addition, the following criteria for superimposed preeclampsia have been suggested: an elevated serum alanine aminotransferase level (>70 U/L) or worsening hypertension (2 diastolic blood pressure readings of at least 110 mm Hg 4 hours apart, no more than 1 week before delivery; or 1 diastolic blood pressure measurement of at least 110 mm Hg, no more than 1 week before delivery, if the woman has been treated for hypertension) plus one of the following: worsening proteinuria, severe headaches, or epigastric pain. Management of Preeclampsia High-Risk Patients. While a first pregnancy is traditionally considered to impose an increased risk of preeclampsia, several other risk factors may help in identifying patients at high risk (Table II). For high-risk patients, the following laboratory values

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The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Karen Hurwitch at KHurwitch@bos.blackwellpublishing.com or 781-388-8470.

Table III. Elements of Severe Preeclampsia

CRITERIA Severe hypertension Severe proteinuria Oliguria Microangiopathic hemolytic anemia Renal impairment Neurologic signs and symptoms of impending eclampsia Cardiac decompensation Impaired liver function Thrombocytopenia Fetal complications REMARKS Blood pressure 160 mm Hg systolic or 110 mm Hg diastolic 5 g protein in 24 hours or 3+ protein by dipstick analysis Urine output <500 mL in 24 hours Schistocytes on blood smear Serum creatinine level >1.2 mg/dL Altered mental status, headache, or visual changes or loss Pulmonary edema Right upper quadrant pain (may herald impending hepatic rupture) Elevated liver function test results Platelet count <100 109/L Fetal growth restriction Intrauterine fetal distress

should be obtained early in pregnancy: hemoglobin, hematocrit, platelet count, serum uric acid, and creatinine level. In addition, patients should have a urinalysis, which, if confirming the presence of 1+ protein, should be followed by a 24-hour urine protein measurement. Patients who develop hypertension in the second half of pregnancy should be tested biweekly, with additional testing to include serum transaminase levels, lactate dehydrogenase levels, and peripheral blood smear and serum albumin levels to monitor for hepatic dysfunction, hemolysis, and capillary leak, respectively. The role of early testing and serial measurements is to facilitate an early diagnosis of preeclampsia and to assess disease severity and progression. Delivery vs Watchful Waiting. Preeclampsia generally resolves with elimination of the placenta; thus, delivery remains the definitive treatment. The decision to induce labor should be based on the severity of disease and gestational age. Because the severity of preeclampsia at presentation does not reliably predict the likelihood of progressing to more severe forms, women should be hospitalized initially for close monitoring. For those women who demonstrate mild, nonprogressive forms of preeclampsia (treatment-responsive hypertension, proteinuria <1 g/24 hours, without signs of liver or coagulation abnormalities) before 32 weeks of gestation, watchful waiting is a viable option. Postponing delivery, while closely monitoring for signs of fetal distress and maternal signs and symptoms of progression to more severe forms, may allow further fetal maturation. Urgent delivery is indicated for severe forms of preeclampsia in women at or near term, for eclampsia, HELLP syndrome, and severe hypertension not responding to treatment after 24 to 48 hours and in women who develop symptoms and signs of disease progression
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(Table III). Corticosteroids should be given to aid fetal pulmonary development in patients with severe forms of preeclampsia necessitating delivery at less than 34 weeks gestation. Medical Treatment of Hypertension in Preeclamptic Patients. Treatment of blood pressure 160/110 mm Hg has been shown to lessen the incidence of cardiac and cerebral insults in women. It is generally accepted that therapy should be initiated as diastolic blood pressure approaches 100 mm Hg. The medications most commonly used for urgent control of hypertension include hydralazine, which is considered first-line intravenous treatment by the NHBPEP, and labetalol. Other medications that may be useful but are rarely used because of potential serious adverse effects include oral nifedipine and nitroprusside. If delivery is not expected within 48 hours, an oral agent is preferred. Medications currently being used and their beneficial and potential adverse effects are presented in Table IV and discussed below. Nonpharmacologic treatment consists of bed rest, which has been shown to lower blood pressure, promote diuresis, and reduce premature labor. Seizure Prophylaxis. Control of blood pressure does not prevent progression to eclampsia (ie, seizures). Therefore, all preeclamptic patients should receive intravenous magnesium sulfate, which has been shown to be more efficacious than either phenytoin or diazepam for seizure prophylaxis. Treatment should be administered during labor and delivery and for at least 24 hours after delivery. Our typical protocol consists of a 4-g loading dose, followed by infusion at 2 g/h, aiming for a plasma magnesium level of 6 mg/dL. In women with renal insufficiency, continuous magnesium sulfate infusion can lead to toxic magnesium levels. For these
VOL. 9 NO. 7 JULY 2007

The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Karen Hurwitch at KHurwitch@bos.blackwellpublishing.com or 781-388-8470.

Table IV. Medical Treatment of Hypertension in Pregnancy BP MEDICATION BENEFITS 2-Adrenergic agonists Safe and efficacious
Methyldopa Vasodilators Hydralazine Nitroprusside Calcium channel blockers Nifedipine -Blockers Labetalol Proven to be safe, decreased second-trimester fetal losses Urgent control of severe HTN Efficacious Effective in severe HTN Effective for refractory HTN Potent tocolytics in preterm labor Lowers BP without effects on blood flow in the umbilical artery Effective BP control

Lowers BP without altering cerebral autoregulation Lower risk of arrhythmia than with vasodilatory agents Atenolol N/Anot recommended for pregnant patients Intrauterine growth retardation with second-trimester use Diuretics Efficacious in chronic HTN Electrolyte abnormalities Renal failure Hypotension in volume-depleted preeclamptic women Congestive heart failure Abbreviations: BP, blood pressure; HTN, hypertension.

ADVERSE EFFECTS Maternal fatigue, depression, orthostatic hypotension, xerostomia Maternal fatigue, depression, orthostatic hypotension, xerostomia Maternal hypotension and oliguria, fetal distress Maternal pyridoxine-responsive polyneuropathy and druginduced lupus, neonatal thrombocytopenia and lupus Cyanide and thiocyanate toxicity Interaction with magnesium sulfate: profound hypotension Limited data regarding fetal safety Interaction with magnesium-sulfate: profound hypotension Limited data regarding fetal safety Fetal bradycardia, neonatal hypoglycemia, impaired fetal response to hypoxia, decreased uteroplacental flow Fetal bradycardia, neonatal hypoglycemia, impaired fetal response to hypoxia, decreased uteroplacental flow

patients, the maintenance dose should be either reduced or discontinued with early signs and symptoms of magnesium toxicity (nausea, weakness, slurred speech, double vision), which are typically associated with plasma levels of 9 to 12 mg/dL and heralded by the loss of patellar reflexes. In these patients, magnesium levels should be checked more frequently (every 12 hours) compared with women who have normal renal function (every 46 hours). Effective therapy for magnesium toxicity is calcium gluconate that should be available at the bedside. In more severe cases, with rising plasma magnesium levels (>15 mg/dL), muscular paralysis, respiratory arrest, and finally, cardiac arrest may ensue. These patients require intubation and assisted ventilation until magnesium levels normalize and normal breathing resumes. Prevention of Preeclampsia Several different approaches have been tried for prevention of preeclampsia, including use of lowdose aspirin, calcium and magnesium supplements, a low-salt diet, diuretics, and antioxidants. Data thus far have identified few subsets of patients who may benefit from these agents. For example, calcium supplementation may offer protection for calcium-deficient women, but there is no benefit in patients with adequate daily calcium intake.

Similarly, low-dose aspirin may be beneficial for women at high risk, such as those with a history of chronic hypertension and preeclampsia in a previous pregnancy. Initial promising data related to a potential benefit of antioxidants (vitamins C and E) were not confirmed in a large, placebo-controlled, prospective trial. Screening Test for Preeclampsia: Have We Learned Enough to Develop One? A critical role of endothelial dysfunction in the pathogenesis of preeclampsia is supported by the presence of generalized vasoconstriction, coupled with up-regulation of several potent mediators of endothelial dysfunction. Recent work demonstrated that women with preeclampsia have elevated levels of a soluble fms-like tyrosine kinase-1, likely produced in response to placental hypoxia, which binds to vascular endothelial growth factor (VEGF) and closely related placental growth factor (PlGF). The resulting decreases in available VEGF and PlGF may be responsible for endothelial damage resulting in the clinical syndrome of hypertension and proteinuria. A recent systematic review, however, has concluded that current evidence, short of prospective studies employing strict laboratory and study design criteria, is insufficient to recommend these markers for preeclampsia screening.

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The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Karen Hurwitch at KHurwitch@bos.blackwellpublishing.com or 781-388-8470.

We have recently provided evidence that proteinuria in preeclampsia is not merely a function of endothelial dysfunction but likely a consequence of glomerular epithelial cell (podocyte) damage as well. We have shown that renal sections from women who died of complications of preeclampsia demonstrated decreased expressions of nephrin and synaptopodin, the slit diaphragm proteins that play a critical role in the normal function of the glomerular filtration barrier. In addition, we have documented that preeclampsia is associated with glomerular epithelial cell (podocyte) urinary loss (ie, podocyturia). Urinary shedding of podocytes may indicate podocyte loss from the glomeruli that may disrupt the glomerular filtration barrier and lead to proteinuria. Whether podocyturia predates proteinuria and the clinical syndrome of preeclampsia remains to be determined. Despite recent evidence that has improved our understanding of the mechanisms underlying preeclampsia, there are no clinically useful early markers of this condition yet. Eclampsia Eclampsia affects 0.1% of all pregnancies and is heralded by the onset of convulsions in a preeclamptic patient. The seizures and other mental status changes of eclampsia are likely secondary to hypertensive encephalopathy. The mainstay of treatment is magnesium sulfate, for prevention of recurrent seizures, and immediate delivery. HELLP Syndrome HELLP syndrome is a severe form of preeclampsia. It may develop in patients with only mild to moderate blood pressure elevations and occasionally in the absence of proteinuria. The hallmark of HELLP syndrome is liver involvement that may lead to liver failure and, in most severe cases, liver rupture, which is associated with high maternal and fetal mortality rates. Therefore, the diagnosis of HELLP syndrome typically leads to urgent delivery. Gestational Hypertension Hypertension that occurs for the first time during the second half of pregnancy in the absence of proteinuria is termed gestational hypertension. It includes both women with preeclampsia who have not yet developed proteinuria and those with hypertension only. In a subset of patients with gestational hypertension, blood pressure remains elevated after delivery, leading to the diagnosis of chronic hypertension. Transient hypertension is characterized by blood pressure normalization by 12 weeks

postpartum. These women have a tendency not only for hypertension in subsequent pregnancies but for chronic hypertension later in life. Chronic Hypertension The diagnostic feature of chronic hypertension is blood pressure 140/90 mm Hg before pregnancy or before the 20th week of gestation. Most patients in this category will have a benign course with normalization of blood pressure midpregnancy, when frequently antihypertensive medications may be discontinued. Antihypertensive therapy for chronic hypertension in pregnancy is usually initiated or restarted for systolic blood pressure 150 mm Hg and/or diastolic blood pressure 100 mm Hg, unless there is evidence of end-organ damage (eg, renal disease, proteinuria, left ventricular hypertrophy, retinopathy). Under these circumstances, it is reasonable to initiate antihypertensive therapy for diastolic blood pressure 90 mm Hg. It is important to mention that it remains unclear whether early and successful treatment of chronic hypertension prevents preeclampsia. These studies are urgently needed because women with preeclampsia superimposed on chronic hypertension are at a particularly high risk for cerebral hemorrhage and placental abruption. Ideally, these women should have a prepregnancy evaluation for end-organ damage that will help define their blood pressure goals during pregnancy. Young patients with resistant hypertension and clinical features suggestive of secondary hypertension should undergo a workup for secondary causes (pheochromocytoma, primary hyperaldosteronism, renovascular hypertension). Secondary hypertension should also be considered in patients who present with accelerated hypertension or severe preeclampsia, particularly if it occurs early in pregnancy or if there is a history of 2 or more affected pregnancies. We have recently shown that revascularization for renovascular hypertension due to renal artery stenosis after an unsuccessful pregnancy may result in improved maternal and fetal outcomes in subsequent pregnancies. Medical Treatment of Hypertension Treatment of hypertensive pregnancy disorders crosses specialties and commonly involves, but is not limited to, obstetricians, nephrologists, cardiologists, family practitioners, and internists. While consensus has been reached for initiation of treatment in chronic hypertension (150/100 mm Hg) and severe hypertension in preeclampsia (160/100 mm Hg), few clinical issues provoke

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The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Karen Hurwitch at KHurwitch@bos.blackwellpublishing.com or 781-388-8470.

more debate than the question of how, if at all, to treat mild to moderate hypertension. Central to this controversy is the lack of studies to support the benefit of treatment for mild diastolic hypertension (9099 mm Hg) in pregnant patients, which is further confounded by the concerns with respect to fetal safety. Aggressive blood pressure lowering may decrease placental perfusion and jeopardize fetal well-being while providing no extra benefit to the mother. Supportive evidence came from a meta-analysis that confirmed a relationship between treatment-induced falls in blood pressure and impaired fetal growth. This finding was independent of antihypertensive class, underlying cause of hypertension, or duration of therapy. Consequently, treatment goals are higher for pregnant than for nonpregnant patients, with the exception of those with end-organ damage, in whom the goal for blood pressure control is similar to that of the general hypertensive population (ie, diastolic blood pressure <90 mm Hg). In practice, treatment of hypertension in pregnancy is a fine balancing act between the maternal benefit from improved blood pressure control and fetal risks. According to the Working Group report of the NHBPEP, methyldopa is the preferred agent and first-line oral medication because of its effectiveness and documented lack of both short- and long-term fetal adverse effects. For most of the other antihypertensive medications, data regarding fetal safety are lacking. Their current uses in pregnancy (Table IV) are based on different treatment guidelines formed by experts opinions, meta-analyses, extrapolation from studies in nonpregnant patients, small observational studies, and case reports, but few randomized prospective trials. Commonly, these medications are considered when adequate blood pressure control cannot be achieved with first-line agents (ie, methyldopa, hydralazine) or when their use results in intolerable adverse effects. It should be noted that ACE inhibitors and related angiotensin receptor blockers should never be used in pregnancy. While their ability to reduce proteinuria might seem attractive, extensive literature confirms an unacceptable risk of birth defects. Until recently, these medications were considered relatively safe in the first trimester of pregnancy, while they were contraindicated during the second and third trimesters because of increased risk of craniofacial deformities and renal dysplasia, leading to oligohydramnios, anuria, and renal failure. In 2006, Cooper and colleagues reported an increased risk of major congenital malformations,

mostly cardiovascular and neurologic, with only first-trimester exposure to ACE inhibitors. This new evidence calls for counseling women of the risks associated with pregnancy while on this medication. In addition, if pregnancy is discovered in women taking them, they should be switched to another antihypertensive medication immediately and offered fetal ultrasonography and echocardiography at 18 weeks gestation. Hypertensive Pregnancy Disorders in Patients With Autoimmune Connective Tissue Diseases Women with autoimmune connective tissue diseases are at increased risk for hypertensive pregnancy disorders, particularly preeclampsia, especially in the presence of active disease at conception, proteinuria with renal impairment, and antiphospholipid syndrome. Women with a history of antiphospholipid syndrome and arterial thrombotic events should be advised against pregnancy due to high risk not only of pregnancy losses but of stroke and related maternal morbidity and mortality. Systemic sclerosis (scleroderma) is up to 5 times more prevalent in women than in men, with a mean age at onset of 40 years, and thus is not commonly seen in women of childbearing age. Up to 10% of all scleroderma patients develop scleroderma renal crisis, a condition that presents with an abrupt onset of renin-mediated hypertension and renal failure in patients with diffuse sclerotic skin changes. It remains unclear whether the risk of scleroderma renal crisis is increased in pregnancy. Adequate treatment of this condition involves angiotensin-converting enzyme (ACE) inhibitors and thus poses a major challenge because these medications, along with angiotensin type 2 receptor blockers, are contraindicated during pregnancy. Unlike scleroderma, systemic lupus erythematosus commonly affects women of reproductive age. Up to 25% of pregnancies in women with systemic lupus erythematosus are complicated by hypertension. Distinguishing between lupus nephritis and preeclampsia may be difficult because they share common features, such as hypertension, proteinuria, impaired renal function, and thrombocytopenia. Differentiation between these 2 conditions is important because treatments substantially differ. Active lupus nephritis is characterized by increased titers of anti-double stranded DNA, fall in complement (C3 and C4) levels, presence of red blood cells or their casts in the urine, and coexisting extrarenal manifestations. In preeclampsia, proteinuria typically occurs without active urine sediment, and uric acid levels are elevated. The

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The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Karen Hurwitch at KHurwitch@bos.blackwellpublishing.com or 781-388-8470.

differential diagnosis may be particularly important early in pregnancy because preeclampsia that occurs before 32 weeks of gestation tends to be particularly severe, commonly leading to early termination of pregnancy or delivery of a premature newborn; treatment of lupus nephritis with immunosuppression may allow continuation of pregnancy closer to term. In those cases, kidney biopsy may be considered to clarify the diagnosis and optimize therapy. CONCLUSIONS Hypertensive pregnancy disorders are the leading cause of maternal and fetal morbidity and mortality. Optimal treatment relies on identification and regular follow-up of individuals with hypertension, close monitoring for early signs of preeclampsia, prophylaxis for seizures in preeclamptic patients, judicious use of antihypertensive medications, and timing of delivery based on the severity of the disease. For severe preeclampsia, delivery is mandatory but may be postponed for mild forms, especially when remote from term, to avoid fetal complications related to prematurity. Hypertension in the absence of proteinuria typically has a benign course and can be managed on an outpatient basis. The ultimate goal of antihypertensive treatment is to prevent maternal cerebrovascular, cardiac, and renal complications without compromising fetal/neonatal well-being from intrauterine exposure to antihypertensive medications and overzealous blood pressure control.

SUGGESTED READINGS
Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol. 2000;183(1):S1S22. Maynard SE, Min JY, Merchan J, et al. Excess placental

soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111(5):649658. Widmer M, Villar J, Benigni A, et al. Mapping the theories of preeclampsia and the role of angiogenic factors: a systematic review. Obstet Gynecol. 2007;109(1):168180. Garovic VD, Wagner SJ, Petrovic LM, et al. Glomerular expression of nephrin and synaptopodin, but not podocin, is decreased in kidney sections from women with preeclampsia. Nephro Dial Transplant. 2007;22(4):11361143. Sibai BM, Lindheimer M, Hauth J, et al. Risk factors for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women with chronic hypertension. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med. 1998;339(10):667671. Altman D, Carroli G, Duley L, et al. Do women with preeclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet. 2002;359(9321):18771890. Caritis S, Sibai B, Hauth J, et al. 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. N Engl J Med. 1998;338(11):701705. Levine RJ, Hauth JC, Curet LB, et al. Trial of calcium to prevent preeclampsia. N Engl J Med. 1997;337(2):6976. Rumbold AR, Crowther CA, Haslam RR, et al, for the ACTS Study Group. Vitamins C and E and the risks of preeclampsia and perinatal complications. N Engl J Med. 2006;354(17):17961806. Thorsteinsdottir B, Kane GC, Hogan MJ, et al. Adverse outcomes of renovascular hypertension during pregnancy. Nat Clin Pract Nephrol. 2006;2(11):651656. Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006;354(23):24432451. Lin J, August P. Genetic thrombophilias and preeclampsia: a meta-analysis. Obstet Gynecol. 2005;105(1):182192. Petri M. Hopkins Lupus Pregnancy Center: 1987 to 1996. Rheum Dis Clin North Am. 1997;23(1):113. Kong NC. Pregnancy of a lupus patienta challenge to the nephrologist. Nephrol Dial Transplant. 2006;21(2):268272. von Dadelszen P, Ornstein MP, Bull SB, et al. Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis. Lancet. 2000;355(9198):8792. Garovic VD, Wagner SJ, Turner ST, et al. Urinary podocyte excretion as a marker for preeclampsia. Am J Obstet Gynecol. 2007;196:320.e1320.e7.

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The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq, a Blackwell Publishing imprint, located at Three Enterprise Drive, Suite 401, Shelton, CT 06484. Copyright 2007 by Le Jacq. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please contact Karen Hurwitch at KHurwitch@bos.blackwellpublishing.com or 781-388-8470.