National High Pressure Education Program

WORKING GROUP ArchiveREPORT ON HIGH for historical Reference Only IN

NATIONAL INSTITUTES OF HEALTH NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

Archive for historical Reference Only National High Blood Pressure Education Program

WORKING GROUP ArchiveREPORT ON HIGH BLOOD PRESSURE for historical Reference Only IN PREGNANCY

National Institutes of Health National Heart, Lung, and Blood Institute National High Blood Pressure Education Program

NIH Publication No. 00-3029 Originally Printed 1990 Revised July 2000

Archive for historical Reference Only

TABLE OF CONTENTSArchive for historical Reference Only The National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy ...... v

Acknowledgements ...... vi

The National High Blood Pressure Education Program Coordinating Committee Member Organizations ...... vii

Foreword ...... viii

Introduction ...... 1

Evidence Base ...... 2

Classification of the Hypertensive Disorders of Pregnancy ...... 3 Classification ...... 3 Clinical Implications of Classification ...... 5

Pathophysiology ...... 6 Pathogenic Mechanisms ...... 6 Pathophysiology of the Maternal Manifestations of Preeclampsia ...... 6

Differential Diagnosois ...... 9 Laboratory Tests ...... 9

Chronic in Pregnancy ...... 11 Prepregnancy Counseling ...... 11 Treatment of Chronic Hypertension ...... 11 Selection ...... 12 Pregnancy, Hypertension, and Renal Disease ...... 13 Treating Hypertension That Persists Postpartum ...... 14 Treating Hypertension During Lactation ...... 14 Fetal Assessment in Chronic Hypertension ...... 15

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Preeclampsia ...... 16 Prevention of Preeclampsia ...... 16 Management of Preeclampsia ...... 17 NonpharmacologicalArchive Management ...... 17 Postpartumfor historical Counseling and Followup Reference ...... Only...... 23 Counseling for Future ...... 23 Remote Cardiovascular Prognosis ...... 23

Recommendations for Future Research ...... 25 A Research Diagnosis of Preeclampsia ...... 25 Other Research Needs ...... 25

References ...... 27

Tables Table 1. Laboratory Evaluation and Its Rationale for Women Who Develop Hypertension After Midpregnancy ...... 10 Table 2. Fetal Monitoring in Gestational Hypertension and Preeclampsia ...... 18 Table 3. Indications for Delivery in Preeclampsia ...... 19 Table 4. Treatment of Acute Severe Hypertension in Preeclampsia ...... 22

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THE NATIONAL HIGH BLOOD PRESSURE EDUCATION PROGRAM WORKING GROUP ON HIGH BArchiveLOOD PRESSURE IN PREGNANCY for historical Reference Only Ray W. Gifford, Jr., M.D., Chair James M. Roberts, M.D. Emeritus Professor and Vice Chair (Research) Department of Nephrology and Hypertension Department of and Gynecology and Cleveland Clinic Foundation Reproductive Sciences Cleveland, Ohio University of Pittsburgh Fountain Hills, Arizona Elsie Hilliard Hillman Chair in Women’s and Infants’ Health Research Phyllis A. August, M.D. Director, Magee-Women’s Research Institute Professor of Medicine, Obstetrics and Gynecology Vice President for Research, Magee-Women’s Chief, Hypertension Division Hospital Weill Medical College of Cornell University Pittsburgh, Pennsylvania New York Presbyterian Hospital New York, New York Edward J. Roccella, Ph.D., M.P.H. Coordinator Gary Cunningham, M.D. National High Blood Pressure Education Program Professor and Chair Office of Prevention, Education, and Control Department of Obstetrics and Gynecology National Heart, Lung, and Blood Institute University of Texas Southwestern Medical Center National Institutes of Health Dallas, Texas Bethesda, Maryland Lee A. Green, M.D., M.P.H. Baha M. Sibai, M.D., F.A.C.O.G. Associate Professor and Assistant Chair Professor and Chair Department of Family Medicine Department of Obstetrics and Gynecology University of Michigan University of Cincinnati Ann Arbor, Michigan Cincinnati, Ohio Marshall D. Lindheimer, M.D. Sandra J. Taler, M.D. Professor of Medicine, Obstetrics and Gynecology, Assistant Professor of Medicine and Clinical Pharmacology Consultant, Division of Hypertension and Internal University of Chicago Medicine Chicago, Illinois Mayo Clinic Donald McNellis, M.D. Rochester, Minnesota Special Assistant for Obstetrics Pregnancy and Perinatology Branch Center for Research for Mothers and Children National Institute of Child Health and Human Development National Institutes of Health Bethesda, Maryland

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ACKNOWLEDGEMENTSArchive for historical Reference Only e appreciate the advice and contributions Mark A. Brown, M.D. W provided by: Professor of Medicine St. George Hospital The American College of Obstetricians and Kogarah NSW Gynecologists Australia Committee on Obstetric Practice Michael F. Greene, M.D., Chairman Claudia Flatau, M.P.H. Director of Maternal-Fetal Medicine R.O.W. Sciences, Inc. Vincent Memorial Obstetrics Division Rockville, Maryland Massachusetts General Hospital Joanne Karimbakas, M.S., R.D. Harvard Medical School Prospect Associates, Inc. Boston, Massachusetts Silver Spring, Maryland Darrell E. Anderson, M.S. NHBPEP Partnership Leader Prospect Associates, Inc. Silver Spring, Maryland David J. Birnbach, M.D. Associate Professor of Anesthesiology, Obstetrics and Gynecology College of Physicians and Surgeons of Columbia University Director of Obstetric Anesthesiology Immediate Past President of the Society for Obstetric Anesthesia and Perinatology St. Lukes Roosevelt Hospital Center New York, New York

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THE NATIONAL HIGH BLOOD PRESSURE EDUCATION PROGRAM COORDINATING COMMITTEEArchiveMEMBER ORGANIZATIONS for historical Reference Only he NHBPEP Coordinating Committee includes American Public Health Association representatives from the following member T American Red Cross organizations: American Society of Health-System Pharmacists American Academy of Family Physicians American Society of Hypertension American Academy of Insurance Medicine Association of Black Cardiologists American Academy of Neurology Citizens for Public Action on High Blood Pressure American Academy of Ophthalmology and Cholesterol, Inc. American Academy of Physician Assistants International Society on Hypertension in Blacks American Association of Occupational Health National Black Nurses Association, Inc. Nurses National Hypertension Association, Inc. American College of Cardiology National Kidney Foundation, Inc. American College of Chest Physicians National Medical Association American College of Occupational and Environmental Medicine National Optometric Association American College of Physicians—American National Stroke Association Society of Internal Medicine NHLBI Ad Hoc Committee on Minority American College of Preventive Medicine Populations American Dental Association Society of Geriatric Cardiology American Association Society for Nutrition Education

American Dietetic Association Federal Agencies: American Heart Association Agency for Health Care Policy and Research American Hospital Association Department of Veterans Affairs American Medical Association Health Care Financing Administration American Nurses Association Health Resources and Services Administration American Optometric Association National Center for Health Statistics, Centers for Disease Control and Prevention American Osteopathic Association National Heart, Lung, and Blood Institute American Pharmaceutical Association National Institute of Diabetes and Digestive and American Podiatric Medical Association Kidney Diseases

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FOREWORDArchive for historical Reference Only his report updates the 1990 National High management considerations in women with comor- T Blood Pressure Education Program Working bid conditions. A discussion of the pharmacologic Group Report on High Blood Pressure in treatment of hypertension in pregnancy includes Pregnancy and focuses on classification, patho- recommendations for specific agents. The use of physiology, and management of the hypertensive low-dose aspirin, calcium, or other dietary supple- disorders of pregnancy. Using evidence-based ments in the prevention of preeclampsia is medicine and consensus, this report updates con- described, and expanded sections on counseling temporary approaches to hypertension control dur- women for future pregnancies and recommenda- ing pregnancy by expanding on recommendations tions for future research are included. Once again made in the Sixth Report of the Joint National we thank Dr. Ray Gifford, Jr., and his committee Committee on Prevention, Detection, Evaluation, for volunteering their time to produce this impor- and Treatment of High Blood Pressure (JNC VI). tant report. We hope it helps the busy clinician The recommendations to use K5 for determining prevent and manage a very important problem. diastolic pressure and to eliminate as a cri- terion for diagnosing preeclampsia are discussed. In addition, the use of blood pressure increases of 30 mm Hg systolic or 15 mm Hg diastolic as a diagnostic criterion has not been recommended, as Claude Lenfant, M.D. available evidence shows that women in this group Director are not likely to suffer increased adverse outcomes. National Heart, Lung, and Blood Institute Management considerations are made between and chronic hypertension that is present before preg- Chair nancy and those occurring as part of the pregnan- National High Blood Pressure Education Program cy-specific condition preeclampsia, as well as Coordinating Committee

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INTRODUCTION Archive for historical Reference Only ypertensive disorders during pregnancy are the guidance to practicing clinicians on managing (1) H second leading cause, after , of patients with hypertension who become pregnant maternal mortality in the United States, accounting and (2) patients who develop hypertensive disor- for almost 15 percent of such deaths.1 ders during gestation. The members of the work- Hypertensive disorders occur in 6 to 8 percent of ing group recognize that the responsible clinician’s pregnancies and contribute significantly to still- judgment of the individual patient’s needs remains births and neonatal morbidity and mortality.1 paramount. Therefore, this national guideline Expectant mothers with hypertension are predis- should serve as a tool to be adapted and imple- posed to the development of potentially lethal mented in individual situations. Using evidence- complications, notably abruptio placentae, dissem- based medicine and consensus, the report updates inated intravascular coagulation, cerebral hemor- contemporary approaches to hypertension control rhage, hepatic failure, and acute renal failure. The during pregnancy. This report expands and etiology of most cases of hypertension during updates recommendations made in The Sixth pregnancy, particularly preeclampsia, remains Report of the Joint National Committee on unknown. Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI).2 The purpose of the National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy is to provide

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EVIDENCEArchiveBASE for historical Reference Only he studies that provided evidence supporting F Prospective followup; also known as cohort T the recommendations for treatment sections of studies, including historical cohort studies this report were classified and reviewed by the and long-term followup members of the working group and staff. The fol- X Cross-sectional population studies; also lowing classification of references used in JNC VI known as prevalence studies and originally adapted from Last and Abramson3 will be used in this report: Pr Previous review or position statements M Meta-analysis; an analysis of a compendium C Clinical interventions (nonrandomized) of experimental studies These explanatory symbols are appended to some Ra Randomized controlled trials; also known as of the references in the reference section of the experimental studies document and to some of the citations in the text. Re Retrospective analyses; also known as case- control studies

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CLASSIFICATION OFArchive THE HYPERTENSIVE DISORDERS OF PREGNANCY for historical Reference Only he most important consideration in the classifi- pressure—K4, muffling6,7 or K5, disappearance.4,8 T cation of diseases in which blood pressure rises We chose K5 because substantial data now support abnormally is differentiating hypertensive disor- its use.9–13 ders that antedate pregnancy from a potentially In chronic hypertension, elevated blood pressure is more ominous disease peculiar to pregnancy: the cardinal pathophysiologic feature, whereas in preeclampsia. Preeclampsia is a pregnancy-specif- preeclampsia, increased blood pressure is impor- ic syndrome of reduced organ perfusion secondary tant primarily as a sign of the underlying disorder to vasospasm and activation of the coagulation cas- and is a potential cause of maternal morbidity. As cade. Although our understanding of this syn- might be expected, the impact of the two condi- drome has increased, the criteria used to identify tions on mother and is different, as is their the disorder remain a subject of confusion and management. Attempts to differentiate the two controversy. This doubtless reflects the fact that conditions have led to confusion in terminology preeclampsia is a syndrome and that attempts at worldwide. We have modified the ACOG classifi- definition use arbitrarily selected markers rather cation slightly by adding the term “gestational than changes of pathophysiologic importance. The hypertension” for the woman who has hyperten- editors of the 1990 version of this document4 elect- sion without during pregnancy, reserv- ed to modify minimally the criteria presented by ing “transient hypertension” for a definitive the American College of Obstetricians and diagnosis made postpartum. According to this ter- Gynecologists (ACOG) Committee on minology, women with increased blood pressure Terminology in 1972.5 This decision was prompt- are divided into the groups discussed below: ed by the opinion that this classification was sim- ple and used widely and that much of what was understood about the prevalence of these disorders CLASSIFICATION and their outcomes was based on data generated with this classification. Our current opinion is • Chronic hypertension largely the same. • Preeclampsia-

1 Several groups, including the ACOG, the • Preeclampsia superimposed upon chronic Australasian Society for the Study of Hypertension hypertension in Pregnancy,6 and the Canadian Hypertension Society,7 have published classification schemes and • Gestational hypertension: (1) transient hyper- diagnostic criteria that differ from one document to tension of pregnancy if preeclampsia is not the other and contrast with those below. They present at the time of delivery and blood pres- include recommendations to eliminate edema from sure returns to normal by 12 weeks postpartum diagnostic criteria, to abandon the use of changes (a retrospective diagnosis) or (2) chronic hyper- in blood pressure as diagnostic,1,7 to use only dias- tension if the elevation persists. tolic pressures,7 and to add systemic changes to proteinuria as diagnostic markers.8 Of these, we Chronic Hypertension determined that only the elimination of edema and Chronic hypertension is defined as hypertension changes in blood pressure as diagnostic criteria that is present and observable before pregnancy or can be justified on the basis of available data. that is diagnosed before the 20th week of gesta- There were also differences in designating the tion. Hypertension is defined as a blood pressure Korotkoff sound that determines diastolic blood equal to or greater than 140 mm Hg systolic or

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Classification of the Hypertensive Disorders of Pregnancy

90 mm Hg diastolic. Hypertension that is diag- This will usually correlate with 30 mg/dL nosed for the first time during pregnancy and that (“1+ dipstick”) or greater in a random urine deter- does not resolve postpartum is also classified as mination with no evidence of urinary tract infec- chronic hypertension. tion. However, because of the discrepancy Archivebetween random protein determinations and Preeclampsia-Eclampsia 24-hour urine protein in preeclampsia (which may The pregnancy-specific syndrome usually occurs be either higher or lower),16–18 it is recommended afterfor 20 weeks historical of gestation (or earlier Reference with tro- that the Only diagnosis be based on a 24-hour urine if at phoblastic diseases such as hydatidiform mole or all possible or a timed collection corrected for cre- hydrops). It is determined by increased blood atinine excretion if this is not feasible. pressure (gestational blood pressure elevation) Preeclampsia always presents potential danger to accompanied by proteinuria. Gestational blood mother and baby. Other conditions may increase pressure elevation is defined as a blood pressure blood pressure and even result in proteinuria; thus, greater than 140 mm Hg systolic or 90 mm Hg as the certainty of the diagnosis increases, the diastolic in a woman normotensive before 20 requirements for careful assessment and considera- weeks. In the absence of proteinuria the disease is tion for delivery also increase. The following find- highly suspect when increased blood pressure ings increase the certainty of the diagnosis of the appears accompanied by the symptoms of preeclampsia syndrome and indicate such fol- headache, blurred vision, and abdominal pain, or lowup: with abnormal laboratory tests, specifically, low platelet counts and abnormal liver enzymes. • Blood pressure of 160 mm Hg or more systolic, or 110 mm Hg or more diastolic. In the past it has been recommended that an incre- ment of 30 mm Hg systolic or 15 mm Hg diastolic • Proteinuria of 2.0 g or more in 24 hours (2+ or blood pressure be used as a diagnostic criterion, 3+ on qualitative examination). The proteinuria even when absolute values are below 140/90 mm should occur for the first time in pregnancy and Hg. This definition has not been included in our regress after delivery. criteria because the only available evidence shows • Increased serum creatinine (>1.2 mg/dL unless that women in this group are not likely to suffer known to be previously elevated). increased adverse outcomes.14,15 Nonetheless, it is the collective clinical opinion of this panel that • Platelet count less than 100,000 cells/mm3 women who have a rise of 30 mm Hg systolic or and/or evidence of microangiopathic hemolytic 15 mm Hg diastolic blood pressure warrant close anemia (with increased lactic acid dehydroge- observation, especially if proteinuria and hyper- nase). uricemia (uric acid [UA] greater than or equal to 6 mg/dL) are also present. • Elevated hepatic enzymes (alanine aminotrans- ferase [ALT] or aspartate aminotransferase Diastolic blood pressure is determined as the dis- [AST]). appearance of sound (Korotkoff 5). Measuring the blood pressure successively may result in very dif- • Persistent headache or other cerebral or visual ferent readings. It is recommended that gestational disturbances. blood pressure elevation be defined on the basis of • Persistent epigastric pain. at least two determinations. The repeat blood pressure should be performed in a manner that will Eclampsia is the occurrence, in a woman with reduce the likelihood of artifact and/or patient anx- preeclampsia, of seizures that cannot be attributed iety.2 For database studies, the measurements of to other causes. increased blood pressure should be no more than Edema occurs in too many normal pregnant 1 week apart. women to be discriminant and has been abandoned Proteinuria is defined as the urinary excretion of as a marker in this and other classification 0.3 g protein or greater in a 24-hour specimen. schemes.1,7,8

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Preeclampsia Superimposed Upon Chronic Gestational Hypertension Hypertension The woman who has blood pressure elevation There is ample evidence that preeclampsia may detected for the first time after midpregnancy, occur in women already hypertensive (i.e., who without proteinuria, is classified as having gesta- have chronic hypertension)Archive and that the prognosis tional hypertension. This nonspecific term for mother and fetus is much worse than with includes women with the preeclampsia syndrome either condition alone. Distinguishing superim- who have not yet manifested proteinuria as well as posed preeclampsiafor from historical worsening chronic Referencewomen who do not Only have the syndrome. The hypertension tests the skills of the clinician. For hypertension may be accompanied by other signs clinical management, the principle of high sensi- of the syndrome, which will influence manage- tivity and unavoidable overdiagnosis is appropri- ment. The final differentiation that the woman ate. The suspicion of superimposed preeclampsia does not have the preeclampsia syndrome is made mandates close observation, with delivery indicat- only postpartum. If preeclampsia has not devel- ed by the overall assessment of maternal-fetal oped and blood pressure has returned to normal by well-being rather than any fixed end point. The 12 weeks postpartum, the diagnosis of transient diagnosis of superimposed preeclampsia is highly hypertension of pregnancy can be assigned. likely with the following findings: If blood pressure elevation persists, the woman is diagnosed as having chronic hypertension. Note • In women with hypertension and no proteinuria that the diagnosis of gestational hypertension is early in pregnancy (<20 weeks), new-onset pro- used during pregnancy only until a more specific teinuria, defined as the urinary excretion of diagnosis can be assigned postpartum. 0.3 g protein or greater in a 24-hour specimen.

• In women with hypertension and proteinuria CLINICAL IMPLICATIONS OF CLASSIFICATION before 20 weeks’ gestation. The clinical spectrum of preeclampsia ranges from • Sudden increase in proteinuria. mild-to-severe forms. In most women, progression • A sudden increase in blood pressure in a through this spectrum is slow, and the disorder woman whose hypertension has previously been may never proceed beyond mild preeclampsia. In well controlled. others, the disease progresses more rapidly, chang- ing from mild to severe in days or weeks. In the • (platelet count <100,000 most serious cases, progression may be fulminant, 3 cells/mm ). with mild preeclampsia evolving to severe • An increase in ALT or AST to abnormal levels. preeclampsia or eclampsia within days or even hours. Thus, for clinical management, preeclamp- sia should be overdiagnosed, because a major goal in managing preeclampsia is the prevention of maternal and perinatal morbidity and mortality, primarily through timing of delivery.

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PATHOPHYSIOLOGYArchive for historical Reference Only reeclampsia is a syndrome with both maternal placental perfusion in preeclampsia, which may P and fetal manifestations. The maternal disease ultimately lead to early placental hypoxia. is characterized by vasospasm, activation of the Research on how alterations in the immune coagulation system, and perturbations in many response at the maternal interface might lead to humoral and autacoid systems related to volume preeclampsia addresses the link between placental and blood pressure control. Oxidative stress and and maternal disease. A nonclassical human inflammatory-like responses may also be impor- leukocyte antigen (HLA), HLA G, is expressed in tant in the pathophysiology of preeclampsia. The normal placental tissue and may play a role in pathologic changes in this disorder are primarily modulating the maternal immune response to the ischemic in nature and affect the placenta, kidney, immunologically foreign placenta.24,25 Placental liver, and brain. Of importance, and distinguishing tissue from preeclamptic pregnancies may express preeclampsia from chronic or gestational hyperten- less or different HLA G proteins,26 resulting in sion, is that preeclampsia is more than hyperten- breakdown of maternal tolerance to the placenta. sion; it is a systemic syndrome, and several of its Additional evidence for alterations in immunity in “nonhypertensive” complications can be life- pathogenesis includes the disease’s prominence in threatening when blood pressure elevations are nulliparous gestations with subsequent normal quite mild. pregnancies, a decreased prevalence after heterolo- gous blood transfusions, long cohabitation before PATHOGENIC MECHANISMS successful conception, and observed pathologic changes in the placental vasculature in preeclamp- The cause of preeclampsia is not known. Many sia that resemble allograft rejection.27 Finally, consider the placenta the pathogenic focus for all there are increased levels of inflammatory manifestations of preeclampsia because delivery is cytokines in the placenta and maternal circulation, the only definitive cure of this disease. Thus as well as evidence of increased “natural killer” research has focused on the changes in the mater- cells and neutrophil activation in preeclampsia.27 nal blood vessels that supply blood to the placenta.

Early in gestation the spiral arteries (the terminal PATHOPHYSIOLOGY OF THE MATERNAL branches of the uterine artery) are transformed MANIFESTATIONS OF PREECLAMPSIA from thick-walled, muscular vessels to sac-like flaccid vessels, which eventually accommodate a tenfold increase in uterine blood flow. This trans- Blood Pressure in Preeclampsia formation involves invasion of the spiral arteries Women with preeclampsia do not usually develop by endovascular trophoblast cells of the placen- frank hypertension until the second half of gesta- ta.19–22 There is evidence in women destined to tion, but vasoconstrictor influences may be present develop preeclampsia that trophoblastic invasion of earlier. For instance, alterations in vascular reac- the uterine spiral arteries is incomplete, the vessels tivity may be detected by gestational week 20, and remaining thick-walled and muscular.20,22,23 The numerous surveys suggest that women destined to cause of this may be a failure of cytotrophoblast develop preeclampsia have slightly higher “nor- cells to express the adhesion molecules necessary mal” blood pressure (e.g., diastolic levels >70 mm for normal remodeling of the maternal spiral arter- Hg) as early as the second trimester,28 confirmed ies.21,22 Failure of the spiral arteries to remodel is by ambulatory blood pressure monitoring tech- postulated as the morphologic basis for decreased niques.29,30

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High blood pressure in preeclampsia is due mainly The Kidney to a reversal of the vasodilation characteristic of The renal lesion that is characteristic of preeclamp- normal pregnancy, replaced by marked increases in sia is termed “glomerular endotheliosis.”62–65 The 31,32 peripheral vascular resistance. Normally, the glomeruli are enlarged and swollen but not hyper- vasculature of normotensiveArchive gravidas manifests a cellular, due primarily to hypertrophy of the intra- decreased pressor responsiveness to several capillary cells (mainly endothelial but mesangial as vasoactive peptides and amines, especially to well), which encroach on the capillary lumina, giv- angiotensin II (AII).for The historical vessels of women with Referenceing the appearance Onlyof a bloodless glomerulus. preeclampsia, however, become hyperresponsive to these hormones, and in the case of AII, such Both glomerular filtration rate (GFR) and renal changes may occur months before the appearance blood flow decrease in preeclampsia, the former of overt disease,33 although this has not been more so than the latter, leading to a decrease in fil- observed by all investigators.30 Hypertension in tration fraction.31 The decrement is usually modest preeclampsia can be labile and may be accompa- (25 percent) even when morphological changes are nied by a blunting and even reversal of normal cir- pronounced. Since renal function normally rises 35 cadian blood pressure rhythms.34 Blood pressure to 50 percent during pregnancy, creatinine levels in normalizes postpartum, usually within the first few women with preeclampsia may still be below the days of the puerperium, but may take as long as 2 upper limits of normal for pregnancy (0.8 mg/dL). to 4 weeks, especially in severe cases.35 Renal insufficiency is rarely severe, but acute tubu- lar or cortical necrosis has been linked to The mechanisms underlying vasoconstriction and preeclampsia.66 Fractional urate clearance decreas- altered vascular reactivity in preeclampsia remain es, producing hyperuricemia, which is an important obscure. Research has focused on changes in the marker of preeclampsia.31 Proteinuria may appear ratio of vasodilating and vasoconstricting late in the clinical course and tends to be nonselec- prostanoids, since there is evidence suggesting tive.31 Preeclampsia is associated with hypocalci- decrements and increments in the production of uria, in contrast with the increased urinary calcium 36–38 prostacyclin and thromboxane, respectively. excretion observed during normal pregnancy.67 More recently, investigators have postulated that Alterations in calcium regulatory hormones, includ- the vasoconstricting potential of pressor substances 53 ing reduced plasma levels of 1,25(OH)2D3, and (e.g., AII and endothelin) is magnified in increased parathyroid hormone54 are also present. preeclampsia as a consequence of a decreased activity of nitric oxide (NO) synthase and Sodium excretion may be impaired in preeclampsia, decreased production of NO-dependent or -inde- although this is variable.68 Some of the severest pendent endothelium relaxing factor (EDRF).39–43 forms of the disease occur in the absence of edema. Also under investigation is the role of endothelial Even when edema is marked, plasma volume is cells (the site of prostanoid, endothelin, and EDRF lower than that of normal gestation, and there is evi- production), which in preeclampsia may be dys- dence of hemoconcentration, believed to be due in functional, due perhaps to inflammatory cytokines part to extravasation of albumin into the intersti- (e.g., TNF alpha) and increased oxidative stress.44–51 tium. In addition, central venous pressure (CVP) Other factors postulated to play a role in and pulmonary capillary wedge pressure (PCWP) preeclamptic hypertension are the sympathetic are often low or low normal. The reductions in ,52 calciotropic hormones,53,54 intravascular volume and the lack of evidence for insulin,55–58 and magnesium metabolism.59 elevations in central pressures, along with decre- ments in placental perfusion, are major reasons to The Heart avoid diuretic therapy in women with preeclamp- 62 The heart is usually unaffected in preeclampsia, sia. the decrements in cardiac performance represent- The cause of the impaired renal sodium excretion is ing a normally contracting ventricle against a unclear; the changes in GFR and several volume- 31,60 markedly increased afterload. Cardiac decom- sensitive hormones fail to explain this observation. pensation may complicate this disorder; however, Filtered sodium, though decreased compared with this is most often due to the presence of preexist- that in normal pregnancy, is still above that ing heart disease.61

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Pathophysiology

measured in nonpregnant women. Suppression of The Central Nervous System the renin angiotensin system is a well-documented Eclampsia, the convulsive phase of preeclampsia, 69 feature of preeclampsia and may be a consequence remains a significant cause of maternal mortality. rather than a cause of impaired sodium excretion. Other central nervous system manifestations Atrial natriureticArchive hormone is reported to be include headache and visual disturbances including 70,71 increased. blurred vision, scotomata, and, rarely, cortical blindness. Occasionally, focal neurologic signs The Coagulation System for historical Referencemay develop,Only which should prompt radiologic Thrombocytopenia, rarely severe, is the most com- investigation. monly found hematologic abnormality in pre- eclampsia. Circulating fibrin degradation products The pathogenesis of eclampsia remains disputed occasionally may be elevated, and unless the dis- and has been attributed both to coagulopathy and ease is accompanied by , plas- fibrin deposition, as well as hypertensive encephal- ma fibrinogen levels are unaffected.72 However, opathy. The latter explanation is difficult to recon- antithrombin III levels are lower and cellular cile with the clinical observations that many fibronectin levels higher in women with women develop convulsions with only mild or preeclampsia compared with normal pregnant moderate hypertension. However, vasoconstriction women—observations consistent with vascular in eclampsia may be selective, and the results of endothelial injury.73,74 studies using ultrasonographic Doppler techniques suggest that severe cerebral vasospasm may occur Platelet counts below 100,000 cells/mm3 signal even when peripheral vasoconstriction is less serious disease, and if delivery is delayed, levels evident.80,81 may continue to fall precipitously. Although platelet counts have not been correlated with The best descriptions of gross and microscopic maternal hemorrhagic complications, very low pathology in eclampsia remain those of Sheehan 77 platelet counts would be expected to increase the and Lynch, in which most autopsies were per- risk of bleeding. formed within 1 to 2 hours of death, eliminating most of the postmortem changes that usually con- The cause of the thrombocytopenia is also unclear. found interpretation of brain pathology. There are It has been ascribed to platelet deposition at sites varying degrees of hemorrhages and petechiae, of endothelial damage72 and to an immunologic vasculopathy with vessel wall damage and fibri- process.75 There is no firm evidence that the fetus- noid necrosis (possibly related to chronic hyper- es born to women with severe preeclampsia- tension), ischemic brain damage, and eclampsia will develop thrombocytopenia, despite microinfarcts.77,82 severe maternal thrombocytopenia.76 Women with eclampsia have been evaluated with The Liver computerized axial tomography (CAT) and mag- 83,84 The pathologic changes in the liver in preeclamp- netic resonance imaging (MRI) techniques. sia have been well described in the autopsy studies Some studies have been relatively normal, and oth- of Sheehan and Lynch.77 They include periportal ers describe a variety of abnormalities, most of hemorrhages, ischemic lesions, and fibrin deposi- which are usually transient. Lesions consistent tion. Liver damage accompanying preeclampsia with cerebral edema and hemorrhage, as well as may range from mild hepatocellular necrosis with hypodense areas believed to represent localized serum enzyme abnormalities (aminotransferase edema induced perhaps by hypoxia, have been 85 and lactate dehydrogenase) to the ominous hemol- described in the CAT scans. Hemorrhage and ysis, elevated liver enzymes, and low platelet count edema have also been documented by MRI, and of (HELLP) syndrome, with markedly elevated interest are reports of changes in the posterior enzyme levels and even subcapsular bleeding or hemispheres or in the vascular watershed areas, hepatic rupture. The latter syndrome represents findings consistent with global ischemia induced 86 serious disease and is associated with significant by vasospasm. Predominance of posterior lesions maternal morbidity.78,79 may explain the increased incidence in preeclamp- sia-eclampsia of visual disturbances.

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DIFFERENTIAL DIAGNOSISArchive for historical Reference Only ecisions regarding hospitalization and delivery Efforts to identify an ideal screening or predictive D that have significant impact on maternal and test for preeclampsia have not been successful to fetal health are often based on whether the patient date.7 Several parameters, such as midpregnancy is believed to have preeclampsia or a more benign blood pressure, ambulatory blood pressure moni- form of high blood pressure, such as chronic or toring, serum ß-hCG, AII sensitivity, urinary calci- gestational hypertension. The correct diagnosis is um excretion, urinary kallikrein, uterine artery important when counseling patients regarding Doppler, plasma fibronectin, and platelet activa- future pregnancies. (See the Prepregnancy tion, have been shown to be statistically valid early Counseling section.) markers of disease; however, they have not been demonstrated to have sufficient predictive value or The period in gestation when hypertension is first practical utility for application to individual documented is helpful in determining the correct patients.87 diagnosis. Documentation of hypertension before conception, or before gestational week 20, favors a High-Risk Patients Presenting With Normal diagnosis of chronic hypertension (either essential Blood Pressure or secondary). High blood pressure presenting at Pregnant women whose gestations are considered midpregnancy (weeks 20 to 28) may be due either “high risk” for preeclampsia (e.g., history of to early preeclampsia (rare before 24 weeks), tran- increased blood pressure before conception or in a sient hypertension, or unrecognized chronic hyper- previous gestation, especially before week 34, or tension. Concerning the latter, blood pressure when the subject is multiparous; women with dia- normally falls in the initial trimesters, and this betes, collagen vascular disease, or underlying “physiologic” decrement may even be exaggerated renal vascular or renal parenchymal disease; and in patients with essential hypertension, masking those with a multifetal pregnancy) will benefit the diagnosis in pregnancy. Hypertension may be from a database of laboratory tests performed in noted later in pregnancy, however, as part of the early gestation.88,89 Tests that by later comparison normal third trimester rise in blood pressure or will help establish an early diagnosis of pre- when superimposed preeclampsia occurs. eclampsia (pure or superimposed) include hemat- ocrit, hemoglobin, and platelet count as well as LABORATORY TESTS serum creatinine and uric acid levels. Observation of 1 plus protein by routine urine analysis, docu- Laboratory tests recommended to diagnose or mented by a clean-catch specimen, should be fol- manage hypertension in pregnancy serve primarily lowed by a 24-hour collection for measurement of to distinguish preeclampsia from either chronic or protein as well as creatinine content (to determine transient hypertension. They are also useful in accuracy of collection and to permit calculation of assessing the severity of disease, particularly in the the creatinine clearance). High-risk patients case of preeclampsia, which is usually associated require accurate dating and assessment of fetal with laboratory abnormalities that deviate signifi- growth. If conditions are not optimal for clinical cantly from those of normal pregnant women. dating, sonographic dates should be established as These same measurements are usually normal in early in pregnancy as possible. A baseline sono- women with uncomplicated chronic or transient gram for evaluating fetal growth should be consid- hypertension. ered at 25 to 28 weeks in these circumstances.

9

Differential Diagnosis

Patients Presenting With Hypertension Before higher risk for the development of intrauterine Gestation Week 20 growth restriction, early baseline sonography for Most women presenting with hypertension before dating and fetal size is also indicated for these gestation week 20 have, or will develop, essential patients. hypertension; theirArchive management is discussed in the Patients Presenting With Hypertension After next section. Some may be already under the care Midpregnancy of primary physicians and screened for .for historical Young women with preexisting Reference or Table 1Only summarizes the laboratory tests that are early gestational hypertension are among the popu- recommended in the evaluation of women with lation in which secondary hypertension is more apt hypertension after midpregnancy and the rationale to be found (e.g., renal disease, renovascular for testing them biweekly or more often if clinical hypertension, primary aldosteronism, Cushing syn- circumstances lead to hospitalization of the patient. drome, and pheochromocytoma). Thus, further Not only do such tests help to distinguish pre- evaluation with noninvasive testing may be war- eclampsia from chronic and transient hypertension, ranted, especially when there is suspicion of those but they are useful in assessing disease progression forms of secondary hypertension that are associat- and severity. It is important to recognize that in ed with more maternal and fetal complications. women with preeclampsia, one or more abnormali- ties may be present even when blood pressure ele- The same database described above (high-risk vation is minimal. If there is a life-threatening women presenting with normal blood pressure) is abnormality such as coagulopathy or abnormal helpful in determining whether further increments hepatic or renal function, it may be necessary to in pressure in the third trimester represent the terminate the pregnancy despite only mild hyper- “physiologic” increments or the onset of superim- tension. (See the section on Management of posed preeclampsia. Since these are at Preeclampsia.)

TABLE 1. LABORATORY EVALUATION AND ITS RATIONALE FOR WOMEN WHO DEVELOP HYPERTENSION AFTER MIDPREGNANCY Test Rationale Hemoglobin and hematocrit Hemoconcentration supports diagnosis of preeclampsia and is an indicator of severity. Values may be decreased, however, if hemolysis accompanies the disease. Platelet count Thrombocytopenia suggests severe preeclampsia. Quantification of protein excretion Pregnancy hypertension with proteinuria should be considered preeclampsia (pure or superimposed) until it is proved otherwise. Serum creatinine level Abnormal or rising serum creatinine levels, especially in association with oliguria, suggest severe preeclampsia. Serum uric acid level Increased serum uric acid levels suggest the diagnosis of preeclampsia. Serum transaminase levels Rising serum transaminase values suggest severe preeclampsia with hepatic involvement. Serum albumin, lactic acid For women with severe disease, these values indicate the extent dehydrogenase, blood smear, of endothelial leak (hypoalbuminemia), presence of hemolysis and coagulation profile (latic acid dehydrogenase level increase, schizocytosis, spherocytosis), and possible coagulopathy, including thrombocytopenia.

10

CHRONIC HYPERTENSIONArchive IN PREGNANCY for historical Reference Only PREPREGNANCY COUNSELING vigorous exercise. Although regular exercise is beneficial for hypertensive individuals who are not omen with hypertension should be evaluated pregnant and may be safe for normotensive preg- W before pregnancy to define the severity of nant women,94F,95F there are no data on safety in the their hypertension and to facilitate planning for setting of chronic hypertension and pregnancy. In potential lifestyle changes that a pregnancy may view of the theoretical concerns with maintaining require. As recommended in JNC VI,2Pr the diag- adequate placental blood flow in hypertensive nosis should be confirmed by multiple measure- women who are at increased risk for preeclampsia, ments and may incorporate home or other our recommendation is to discourage aerobic exer- out-of-office blood pressure readings. If hyperten- cise in hypertensive pregnant women until more sion is confirmed and particularly if it is severe data are available. Weight reduction during preg- (stage 3: systolic pressure ≥ 180 mm Hg or dias- nancy, even in obese women, is not recommended. tolic pressure ≥ 110 mm Hg), a woman should be Although obesity may be a risk factor for superim- evaluated for potentially reversible causes. posed preeclampsia, there is no evidence that lim- Angiotensin-converting enzyme inhibitors and AII iting weight gain reduces its occurrence. Although receptor antagonists should be discontinued. (For the evidence is sparse in pregnant women, many a discussion of drug therapy, see the next section.) experts recommend restriction of sodium intake to the same 2.4 g sodium intake recommended for Women with a history of hypertension for several essential hypertension. Women who already fol- years should be evaluated for target organ damage low a more restricted sodium intake may continue including left ventricular hypertrophy, retinopathy, to follow that dietary approach. and renal disease. If damage is present, the woman should be advised that pregnancy may The use of alcohol and tobacco during pregnancy exacerbate the condition. Women with chronic should be strongly discouraged. Both have a hypertension are at higher risk for adverse neonatal deleterious effect on the fetus and the mother. outcomes independent of the development of Excessive consumption of alcohol can cause or preeclampsia, if proteinuria is present early in aggravate maternal hypertension. Tobacco is asso- pregnancy.88F The risks of fetal loss and accelerat- ciated with a substantive risk for placental abrup- ed deterioration of maternal renal disease are tion and fetal growth restriction. increased if serum creatinine is above 1.4 mg/dL at conception, although it may be difficult to separate TREATMENT OF CHRONIC HYPERTENSION the effects of the pregnancy from progression of the underlying renal disease.90F,91F In patients with The majority of women with chronic hypertension impaired renal function, relative risk of fetal loss in pregnancy have Stage 1 to 2 hypertension has been reported to be increased tenfold when (defined as systolic blood pressure of 140 to hypertension is present and not controlled at con- 179 mm Hg or diastolic blood pressure of 90 to ception, compared with pregnancy without hyper- 109 mm Hg) and are at low risk for cardiovascular tension or with well-controlled hypertension.92F,93Re complications within the short timeframe of preg- nancy. Among women with Stage 1 to 2 preexist- Chronic hypertension before pregnancy requires ing essential hypertension and normal renal planning for lifestyle changes. For example, preg- function, most pregnancies will have good mater- nant women with hypertension may need to restrict nal and neonatal outcomes. These women are can- their activities at work and home and refrain from didates for nondrug therapy because, to date, there

11

Chronic Hypertension in Pregnancy

is no evidence that pharmacologic treatment results women with chronic hypertension and complicates in improved neonatal outcomes.96Ra,97Ra Since blood almost 25 percent of such pregnancies. The inci- pressure usually falls during the first half of preg- dence is even higher if the high blood pressure is nancy, hypertension may be easier to control with associated with renal insufficiency, the presence of less or no medication.Archivehypertension for at least 4 years, and a history of hypertension in a previous pregnancy.88F,90F,91F The The value of continued administration of antihy- incidence of placental abruption is markedly pertensive drugs to pregnant women with chronic increased in the presence of superimposed hypertensionfor historical continues to be an area Referenceof debate. Only preeclampsia.102Pr Although it may be beneficial for the mother with hypertension to reduce her blood pressure, lower On the basis of available data, some centers cur- pressure may impair uteroplacental perfusion and rently manage women with chronic hypertension thereby jeopardize fetal development.98,99M by stopping antihypertensive medications under Although it is not generally agreed whether antihy- close observation.101F,103Pr In patients with hyperten- pertensive therapy is beneficial or detrimental to sion for several years, with evidence of target pregnancy outcome, several studies offer some organ damage, or on multiple antihypertensive clinical guidance. Over the past 30 years, at least agents, medications may be tapered on the basis of seven studies have compared antihypertensive ther- blood pressure readings but should be continued if apy with either no medication or a placebo in preg- needed to control blood pressure. End points for nant women with mild chronic hypertension.100Pr reinstituting treatment include exceeding threshold Higher fetal losses during the second trimester blood pressure levels of 150 to 160 mm Hg sys- were noted among untreated women in several tolic or 100 to 110 mm Hg diastolic or the pres- early trials, but this finding was not confirmed. ence of target organ damage such as left Indeed, overall prevalence rates of these adverse ventricular hypertrophy or renal insufficiency. outcomes were very low. Rey and Couturier retro- is preferred by most practitioners. spectively evaluated the course of 298 pregnant Alternatively, women who are well controlled on women with chronic hypertension whose antihy- antihypertensive therapy before pregnancy may be pertensive medications had been discontinued or kept on the same agents (with the exception of whose doses were reduced early in pregnancy.101F angiotensin-converting enzyme inhibitors, AII Treatment did not decrease the frequency of super- receptor antagonists) during pregnancy. imposed preeclampsia, preterm delivery, abruptio placentae, or perinatal death when compared with ANTIHYPERTENSIVE DRUG SELECTION untreated groups. Much uncertainty about the ben- efits of lowering blood pressure in pregnant While the goal of treating chronic hypertension is women with mild chronic hypertension stems from to reduce maternal risk, the agents selected must published trials that are too small to detect modest be efficacious and safe for the fetus, especially in reductions in obstetrical complications. regard to acute and long-range neurologic effects. Evidence from several studies indicates the effec- Methyldopa is preferred by many physicians as tiveness of antihypertensive drugs in preventing first-line therapy, on the basis of reports of stable exacerbation of chronic hypertension to severe uteroplacental blood flow and fetal hemodynam- 104F hypertension during pregnancy.96Ra,100Pr These trials ics, and one followup study after 7.5 years, in a have included heterogeneous populations of limited number of infants, showed no long-term women with preexisting hypertension and gesta- adverse effects on development of children 105F tional hypertension, different thresholds for treat- exposed to methyldopa in utero. Methyldopa ment by gestational age, and the presence or causes somnolence in many individuals. If this absence of proteinuria, and they often included agent cannot be tolerated, alternatives such as multiple treatment agents. are selected based on more limited clini- cal experience. If methyldopa is ineffective, alter- Most of the increased risk associated with chronic natives can be substituted (see below) based on hypertension occurs in the setting of superimposed rational considerations of mechanisms of action. preeclampsia.88F Preeclampsia is more common in In the latter respect, salt retention may cause

12

refractoriness to vasodilator therapy, in which case concluded that gestation does not preclude use of a diuretic added to the regimen restores blood diuretic drugs to reduce or control blood pressure pressure control and permits prolongation of the in women whose hypertension predated conception pregnancy. Archiveor manifested before midpregnancy. Most of the published experience with other agents Angiotensin-converting enzyme inhibitors are con- comes from trials using adrenergic-blocking drugs traindicated during pregnancy because of associa- including beta-blockers and the alpha-beta-blocker tions with fetal growth restriction, oligohydram- labetalol.106M Therefor is a historicalsuggestion that beta-block- Referencenios, neonatal renal Only failure, and neonatal ers prescribed early in pregnancy, specifically death.115Pr,116,117Re,118 Although no data are available atenolol, may be associated with growth restric- on human use of angiotensin II receptor antago- tion.106M,107Re,108F,109Ra On the other hand, none of nists, adverse effects are likely to be similar to these agents has been associated with any consis- those reported with angiotensin converting enzyme tent ill effects; however, long-term followup stud- inhibitors, and these agents should be avoided. ies are lacking. There are no placebo-controlled trials examining Experience with calcium antagonists is limited, the treatment of severe hypertension in pregnancy, with most reported uses being late in pregnancy. and none are likely to be performed, because of A multicenter prospective cohort study of first ethical considerations. Early reports of experience trimester drug exposures reported no increase in with severe chronic hypertension in the first major teratogenicity from these agents.110F A trimester described fetal loss of 50 percent and sig- recent multicenter study randomizing patients to nificant maternal mortality.119F Most of the poor slow-release nifedipine or no treatment beginning outcomes were in pregnancies complicated by in the second trimester reported neither benefits superimposed preeclampsia.119F Antihypertensive nor evidence of harm from nifedipine treatment.97Ra therapy is indicated for maternal benefit but may also permit prolongation of the pregnancy and The use of diuretic agents in pregnancy is contro- thereby improve fetal maturity. versial. The primary concern is theoretical. It is known that preeclampsia is associated with a reduction of plasma volume111F and that fetal out- PREGNANCY,HYPERTENSION, AND come is worse in women with chronic hyperten- RENAL DISEASE sion who fail to expand plasma volume.112Ra Whether this is a cause-and-effect relationship is Among pregnant women with mild renal disease not clearly established. Nonetheless, women using (serum creatinine less than 1.4 mg/dL), fetal sur- diuretics from early pregnancy do not increase vival is moderately reduced, and the underlying their blood volume to the degree usually occurring disease does not generally worsen.120Pr Women in normal pregnancy.113Ra Because of the theoreti- with renal diseases that tend to progress should be cal concerns, diuretics are usually not used as first- encouraged to complete their childbearing while line drugs. A meta-analysis of nine randomized their renal function is well preserved. The pres- trials involving more than 7,000 subjects receiving ence of hypertension before conception or early in diuretics revealed a decrease in the tendency of the pregnancy increases the incidence of maternal and women to develop edema and/or hypertension114M fetal complications, with a tenfold higher relative and confirmed no increased incidence of adverse risk of fetal loss.92F,121Re fetal effects. However, if their use is indicated, Moderate or severe renal insufficiency may accel- they are safe and efficacious agents, can markedly erate during pregnancy and jeopardize fetal sur- potentiate the response to other antihypertensive vival.90F,91F,120Pr,121Re Hypertension occurs in more agents, and are not contraindicated in pregnancy than half of these pregnancies.122Pr A decrease in except in settings where uteroplacental perfusion is birthweight correlates directly with rising maternal already reduced (preeclampsia and intrauterine serum creatinine concentration.91F As renal failure growth restriction). Although data concerning the progresses, the hypertension has a component of use of diuretics in pregnant women with essential volume overload and may require sodium restric- hypertension are sparse, this working group tion, use of loop diuretics, or dialysis.

13

Chronic Hypertension in Pregnancy

Recognition of superimposed preeclampsia may be chronic renal disease, superimposed preeclampsia difficult because proteinuria commonly increases in the second trimester, placental abruption com- in women with glomerular disease during pregnan- plicated by disseminated intravascular coagulation, cy. Chronic dialysis during pregnancy is associat- and requirement for multiple antihypertensive ed with significantArchive maternal morbidity, and agents.127C,128F Acute hypertensive changes induced conception should be discouraged. Infant survival by pregnancy usually dissipate rapidly, within the rates are higher in pregnancies where dialysis is first several days after delivery. Resolution of startedfor after historical conception (74 to 80 percent) Reference than in hypertension Only is more rapid in patients with gesta- those women who conceived while on mainte- tional hypertension and may lag in those with nance dialysis (40 to 50 percent),123X,124Re presum- preeclampsia, especially those with longer duration ably because the former are women with greater of preeclampsia and greater extent of renal impair- residual renal function. Infant survival may ment.35F This delay in resolution may reflect the improve with greater duration of dialysis each time needed for endothelial recovery. week. Although low birthweight and preterm Oral antihypertensive agents may be required after delivery are the rule, prognosis appears to be delivery to help control maternal blood pressure, in improving. particular, for women who were hypertensive Clinical Note: Magnesium sulfate is hazardous in before pregnancy. If prepregnancy blood pressures women with severe renal failure, and maintenance were normal or unknown, it is reasonable to stop doses must be reduced. The usual loading dose oral medication after 3 to 4 weeks and observe can be given as this distributes to total body water the blood pressure at 1- to 2-week intervals for and is not influenced by renal function. Then 1 month, then at 3- to 6-month intervals for 1 year. magnesium should be administered at a gram per If hypertension recurs, it should be treated. hour maintenance, with therapy guided by hourly to two hourly magnesium levels until steady state TREATING HYPERTENSION DURING is reached. Phenytoin may be considered as an ACTATION alternative. (See the Anticonvulsive Therapy L section.) Breastfeeding should be encouraged and can be Renal transplant recipients are advised to wait done safely with certain limits on antihypertensive 1.5 to 2 years after successful transplantation to drug choices. In mildly hypertensive mothers who undertake pregnancy and only if renal function is wish to breastfeed for a few months, the clinician stable with creatinine of 2.0 mg/dL or less.122Pr,125Pr may consider withholding medication, with close Although pregnancies may be complicated, 92 per- monitoring of blood pressure. After discontinua- cent of infants survive in those pregnancies that go tion of nursing, antihypertensive therapy can be beyond the first trimester. From the National reinstituted. For patients with more severe blood Transplantation Pregnancy Registry, in 115 renal pressure elevation and taking a single antihyper- transplant patients who received cyclosporine, high tensive agent, the clinician may consider reducing risks to the newborn were reported in settings of the dosage, then closely observing both the mother maternal hypertension and serum creatinine levels and the infant. greater than 1.5 mg/dL. Rates of prematurity Little information is available regarding excretion approach 55 percent; thus, all pregnancies in trans- of antihypertensive agents in human breast milk 126Re plant recipients are considered high risk. and effects on the newborn.129Pr Further, there are no data concerning long-term effects of these TREATING HYPERTENSION THAT PERSISTS drugs on infants exposed through breastfeeding. POSTPARTUM The reader is referred to the text by Briggs and colleagues130Pr and recommendations of the Women with chronic hypertension can develop Committee on Drugs of the American Academy of encephalopathy, heart failure and pulmonary Pediatrics.131Pr The available data suggest that all edema, and renal failure in the . studied agents are excreted into human breast Risk factors include underlying cardiac disease, milk, although differences in the milk/plasma ratio

14

are related to lipid solubility and extent of ioniza- fetal growth restriction. A plan of antepartum fetal tion of the drug at physiologic pH.132Pr No short- assessment is directed by these findings. Efforts term adverse effects have been reported from should, therefore, be directed at the early detection exposure to methyldopa or . Although of superimposed preeclampsia and fetal growth the Committee on Drugs considersArchive atenolol com- restriction. If these are excluded, then extensive patible with breastfeeding, this beta-blocker, as fetal antepartum testing is less essential. well as metoprolol and nadolol, appears to be con- An initial sonographic assessment of fetal size and centrated in breast milk. This property is not for historical Referencedating should be performedOnly at 18 to 20 weeks’ ges- shared by propranolol or labetalol; for that reason tation. Fetal growth should be carefully assessed these agents have been recommended if a beta- thereafter. If this is not possible with usual clinical blocker is indicated. No data on calcium-channel estimation of fundal height (e.g., maternal obesity blockers and lactation have been reported. or multiple examiners), sonographic assessment Diuretics may reduce milk volume and suppress should be performed at 28 to 32 weeks and month- lactation.133,134 Angiotensin-converting enzyme ly until term. If there is evidence of growth inhibitors and angiotensin receptor antagonists restriction, fetal well-being should be assessed by should be avoided on the basis of reports of nonstress tests or biophysical profiles as usual for adverse fetal and neonatal renal effects. Given the the growth-restricted fetus. Similarly, if pre- scarcity of data, breastfed infants of mothers tak- eclampsia cannot be excluded, then fetal assess- ing antihypertensive agents should be closely mon- ment as appropriate for the fetus of a woman with itored for potential adverse effects. preeclampsia is mandatory. If the infant is normal- ly grown and preeclampsia can be excluded, how- FETAL ASSESSMENT IN CHRONIC ever, there is no indication for these studies. HYPERTENSION

Much of the increased perinatal morbidity and mortality associated with chronic hypertension can be attributed to superimposed preeclampsia and/or

15

PREECLAMPSIAArchive for historical Reference Only PREVENTION OF PREECLAMPSIA Calcium Supplementation There are no data indicating that dietary supple- he ability to prevent preeclampsia is limited by mentation with calcium will prevent preeclampsia T lack of knowledge of its underlying cause. in low-risk women in the United States. Certainly, Prevention has focused on identifying women at a diet that provides 1,000 mg elemental calcium higher risk, followed by close clinical and labora- daily is recommended for general health.143Pr tory monitoring to recognize the disease process in Whether an enriched calcium diet beyond this its early stages. These women can then be select- amount may have benefit is unproven. ed for more intensive monitoring or delivery. Although these measures do not prevent pre- Results from a large NIH trial in 4,589 healthy eclampsia, they may be helpful for preventing nulliparous women randomized at 13 to 21 weeks some adverse maternal and fetal sequelae. to 2 g elemental calcium daily or placebo indicate that calcium supplementation neither reduced the Use of Low-Dose Aspirin To Prevent incidence or severity of preeclampsia nor delayed Preeclampsia its onset.144Ra There were no differences in the prevalence of nonproteinuric hypertension. Even Benefits of low-dose aspirin prophylaxis are within the subgroup of women with the lowest unproven for most women, including nulliparas. quintile of dietary calcium intake, similar to that The prevailing opinion is that women without risk reported for women in many developing countries, factors do not benefit from treatment, despite earli- no benefit of calcium supplementation was demon- er prospective studies that suggested that aspirin strated.145Ra,146Ra administration reduced the incidence of pre- eclampsia. The basis for this opinion is the results Still, randomized trials of calcium supplementation of eight large trials in different populations around in nulliparous women considered at high risk the world. Overall, the results of these trials, demonstrated significant reductions in incidence of which included more than 27,000 pregnant preeclampsia.147Ra,148Ra,149Ra,150Ra,151Ra women, demonstrate minimal to no reduction in the incidence of preeclampsia with low-dose Other Dietary Supplements aspirin.89Ra,135Ra,136Ra,137Ra,138Ra,139Ra,140Ra,141Ra,142Pr Prophylactic magnesium supplementation has not An important study on low-dose aspirin prophylax- been shown to be beneficial in preventing 152Ra,153Ra is in 2,539 women at higher risk for preeclampsia preeclampsia. was published recently by the National Institutes The results of three randomized trials of fish oil of Health (NIH).89Ra Included were four subgroups supplementation in women at high risk for pre- of women with pregestational insulin-treated dia- eclampsia revealed no reduction in incidence of betes mellitus, chronic hypertension, multifetal preeclampsia.154Ra,155Ra,156Ra A recent study showing gestation, or preeclampsia in a previous pregnancy. the benefits of vitamins C and E to prevent pre- The incidence of preeclampsia, perinatal death, eclampsia was encouraging but needs further preterm delivery, and fetal growth restriction was confirmation.157Ra,158 the same in the aspirin- and placebo-treated patients, with no significant differences in out- comes for any of the four subgroups at higher risk.

16

MANAGEMENT OF PREECLAMPSIA affecting fetal well-being may be present before the clinical diagnosis. If there is a rationale for management other than delivery, it would be to Rationale for Treatment palliate the maternal condition to allow fetal The objectives of therapy forArchive preeclampsia are maturation and cervical ripening. based on a philosophy of management arising from the knowledge of the pathology, pathophysi- ology, and prognosis of the disorder for mother NONPHARMACOLOGICAL MANAGEMENT and baby. The forfollowing historical three important tenets Reference Only underlie management schemes: Fetal Evaluation Fetal surveillance is indicated for the woman with 1. Delivery is always appropriate therapy for the preeclampsia. (See the section on High-Risk mother but may not be so for the fetus. For Patients Presenting With Normal Blood Pressure.) maternal health, the goal of therapy is to pre- vent eclampsia as well as other severe compli- Nonstress testing (NST), ultrasound assessment of cations of preeclampsia. These disorders are fetal activity and volume (biophysi- completely reversible and usually begin to abate cal profile [BPP]), and fetal movement counts con- with delivery. Thus, if only maternal well- stitute the most common fetal surveillance being was considered, the delivery of all techniques. If determination of pulmonary maturi- women with preeclampsia, regardless of the ty would influence management, amniocentesis severity of preeclampsia or duration of gesta- should be done to determine this before the inter- tion, would be appropriate. Conversely, deliv- ruption of pregnancy. ery induction is not indicated for a preterm For all women with preeclampsia, daily fetal fetus with no evidence of fetal compromise in movement assessment is a useful screening assess- women with mild disease. There are two ment. More formal testing is indicated if move- important corollaries of this statement. First, ments are not normal. Formal testing (NST, BPP) any therapy for preeclampsia other than deliv- should be performed periodically with even normal ery must have as its successful end point the fetal activity. The frequency of formal testing will reduction of perinatal morbidity and mortality. be dictated by the clinical condition. Although Second, the cornerstone of obstetric manage- weekly to biweekly assessment will usually suf- ment of preeclampsia is based on whether the fice, for women with severe preeclampsia who are fetus is more likely to survive without signifi- being managed expectantly, daily testing is appro- cant neonatal complications in utero or in the priate. (See Table 2.) nursery. If possible fetal compromise is indicated by fetal 2. The pathophysiologic changes of severe surveillance, then decision-making for delivery preeclampsia indicate that poor perfusion is the requires judgment heavily weighted by fetal age. major factor leading to maternal physiologic derangement and increased perinatal morbidity Maternal Evaluation and mortality. Attempts to treat preeclampsia by natriuresis or by lowering blood pressure Antepartum monitoring has two goals. The first is may exacerbate the important pathophysiologic to recognize preeclampsia early; the second is to changes. observe progression of the condition, both to pre- vent maternal complications by delivery and to 3. The pathogenic changes of preeclampsia are determine whether fetal well-being can be safely present long before clinical diagnostic criteria monitored with the usual intermittent observations. are manifest. Several studies indicate that changes in vascular reactivity, plasma volume, At present, clinical management of preeclampsia is and renal tubular function antedate—in some directed by overt clinical . cases by weeks—the increases in blood pres- Although rapid weight increase and facial edema sure, protein excretion, and sodium retention. may indicate the fluid and sodium retention of These findings suggest that irreversible changes preeclampsia, they are neither universally present nor uniquely characteristic of preeclampsia.

17

Preeclampsia

TABLE 2. FETAL MONITORING IN GESTATIONAL HYPERTENSION AND PREECLAMPSIA Gestational Hypertension (hypertensionArchive only without proteinuria, with normal laboratory test results, and without symptoms) • Estimation of fetal growth and amniotic fluid status should be performed at diagnosis. If results are normal, repeat testing only if there is significant change in maternal condition. • Nonstress test (NST) should be performed at diagnosis. If NST is nonreactive, perform biophysical forprofile (BPP).historical If BPP value is eight Reference or if NST is reactive, repeat Only testing only if there is significant change in maternal condition.

Mild Preeclampsia (mild hypertension, normal platelet count, normal liver enzyme values, and no maternal symptoms) • Estimation of fetal growth and amniotic fluid status should be performed at diagnosis. If results are normal, repeat testing every 3 weeks. • NST, BPP, or both should be performed at diagnosis. If NST is reactive or if BPP value is eight, repeat weekly. Testing should be repeated immediately if there is abrupt change in maternal condition. • If estimated fetal weight by ultrasound is <10th percentile for gestational age or if there is ( ≤ 5 cm), then testing should be performed at least twice weekly.

These signs are, at most, a reason for closer moni- subsequent management may be continued in-hos- toring of blood pressure and urinary protein. Early pital, at a day-care unit, or at home on the basis of recognition of impending preeclampsia is based the initial assessment. Prolonged hospitalization primarily on blood pressure increases in the late for the duration of pregnancy allows rapid inter- second and early third trimesters. Once blood vention in case of fulminant progression to hyper- pressure starts to rise (this may be the first sign of tensive crisis, eclampsia, or abruptio placentae.159Pr developing preeclampsia), a repeat examination These complications are rare in compliant women within 1 to 3 days is recommended. In selected who have mild hypertension, minimal proteinuria, patients, blood pressure and urinary protein may no symptoms, and normal platelet counts and be checked at home. In either case, the woman serum liver enzyme levels. Recently, ambulatory should be evaluated for symptoms suggestive of management at home or at a day-care unit has preeclampsia—headaches, blurred vision, right been evaluated as an option for monitoring women upper quadrant or epigastric pain—and should with mild gestational hypertension or preeclampsia undergo laboratory testing for platelet count, renal remote from term. A number of observation- function, and liver enzymes. Quantification of a al160F,161F,162F,163F,164F and randomized studies165F,166Ra,167Ra 12- to 24-hour urine sample for proteinuria is rec- suggest a place for ambulatory management of ommended. (See Table 1.) These measures deter- selected women. If day care or home management mine how fast the condition is progressing to is selected, it should include frequent maternal and ensure that it is not following a fulminant course. fetal evaluation and access to health care The frequency of subsequent observations is deter- providers.159Pr If worsening of preeclampsia is mined by the initial observations and the ensuing diagnosed, as determined by laboratory findings, clinical progression. If the condition appears sta- symptoms, and clinical signs, hospitalization is ble, weekly observations may be appropriate. The indicated. initial appearance of proteinuria is an especially Hospitalization for the duration of pregnancy is important sign of progression and dictates frequent indicated for preterm onset of severe gestational observations. hypertension or preeclampsia. The decision to pro- Often, hospitalization is initially recommended for long the pregnancy in these women is determined women with new-onset preeclampsia. After mater- day by day. The women should receive intensive nal and fetal conditions are serially assessed, maternal and fetal surveillance, usually at a tertiary

18

care facility.168F,169Ra,170Ra Laboratory studies are per- mild disease and a favorable cervix for induction formed at frequent intervals and include serial deter- at 38 weeks’ gestation and should be considered in minations of platelet count, serum liver enzyme women who have severe preeclampsia beyond 32 levels, renal function, and urinary protein. to 34 weeks’ gestation. At gestational week 33 to Assiduous attention is givenArchive for worsening hyper- 34, the fetus may benefit from corticosteroid tension; evidence of central nervous system involve- administration. ment that includes severe headache, disorientation, Prolonged antepartum management in women with or visual symptoms; and hepatic involvement indi- for historical Referencesevere preeclampsia Only is possible in a select group of cated by epigastric pain and tenderness. women with fetal gestational age between 23 and Antepartum Management of Preeclampsia 32 weeks. In some women, preeclampsia improves after hospitalization and treatment with There is little to suggest that any therapy alters the magnesium sulfate and antihypertensive agents underlying pathophysiology of preeclampsia. given acutely.96Ra,169Ra,170Ra Such management may Therapeutic efforts that may be palliative, slow prolong pregnancy, with a decrease in perinatal progression of the disorder, and permit continua- morbidity and mortality. It should be attempted tion of pregnancy have not been shown to reverse only in centers equipped to provide close maternal the underlying disorder. Restricted activity is a and fetal surveillance.172Pr Delivery in these usual and reasonable recommendation for women preterm pregnancies is indicated by worsening with preeclampsia, although its efficacy is not maternal symptoms, laboratory evidence of end- clearly established. Strict sodium restriction and organ dysfunction, or fetal deterioration. diuretic therapy appear to have no role in manage- ment. Finally, results of several randomized trials Route of Delivery suggest that antihypertensive therapy for women Vaginal delivery is preferable to caesarean delivery with gestational hypertension or preeclampsia does for women with preeclampsia, thus avoiding the not improve perinatal outcomes.97Ra,100Pr,171Ra added stress of surgery to multiple physiologic Indications for Delivery aberrations. Acute palliation for several hours does not increase maternal risk if performed Delivery is the only definitive treatment for appropriately. should be carried preeclampsia, and some suggested indications are out aggressively once the decision for delivery is listed in Table 3. All women with this diagnosis made. In gestation remote from term in which should be considered for delivery at 40 weeks’ ges- delivery is indicated and with fetal and maternal tation. Delivery may be indicated for women with

TABLE 3. INDICATIONS FOR DELIVERY IN PREECLAMPSIA* Maternal Fetal Gestational age ≥ 38 weeks Severe fetal growth restriction Platelet count <100,000 cells/mm3 Nonreassuring fetal testing results Progressive deterioration in hepatic function Oligohydramnios Progressive deterioration in renal function Suspected abruptio placentae Persistent severe headaches or visual changes Persistent severe epigastric pain, nausea, or vomiting

* Delivery should be based on maternal and fetal conditions as well as gestational age.

19

Preeclampsia

conditions stable enough to permit pregnancy to be anesthesia poses considerably greater risk to par- prolonged 48 hours, glucocorticoids can be safely turients than regional anesthesia,175X the risk of a administered to accelerate fetal pulmonary maturi- failed intubation must be weighed against the risk ty. (See Table 3.) of transient hypotension when deciding between Archivegeneral and regional anesthesia for cesarean section The aggressive approach to induction includes in the severely preeclamptic/eclamptic patient. a clear end point for delivery, usually within Although neuraxial techniques have become the 24 hours of the decision to induce labor. Most preferred method to provide labor analgesia or expertsfor recommend historical a trial of induction Reference regardless Only anesthesia for cesarean section in women with of cervical condition. If vaginal delivery cannot be severe preeclampsia-eclampsia, they are relatively effected within a reasonable time, caesarean deliv- contraindicated in the presence of coagulopathy. ery is considered and is also performed for other Early consultation with an anesthesiologist is sug- usual obstetrical indications. gested for parturients with severe preeclampsia. Neuraxial (epidural, spinal, and combined spinal- epidural) techniques offer many advantages for Anticonvulsive Therapy labor analgesia and can be safely administered to Anticonvulsive therapy is usually indicated either to the preeclamptic parturient. Dilute epidural infu- prevent recurrent convulsions in women with sions of local anesthetic plus opioid produce ade- eclampsia or to prevent convulsions in women with quate sensory block without motor block or preeclampsia. There is universal agreement that clinically significant sympathectomy. When neu- women with eclampsia should receive anticonvulsive raxial techniques are used for cesarean delivery, therapy.176Ra Several randomized studies indicate that however, there is a possibility of extensive sympa- parenteral magnesium sulfate reduced the frequency tholysis with profound hypotension which may of eclampsia more effectively than phenytoin in a lead to decreased cardiac output and further dimin- mixed group of gestational hypertensive and ished uteroplacental perfusion. This may be more preeclamptic women.177Pr,178M Parenteral magnesium likely with single-shot spinal anesthesia, which sulfate is given during labor, delivery, and for vari- although considered acceptable by some experts, is able durations postpartum. There is not clear agree- still considered by others to be relatively con- ment concerning the use of prophylactic magnesium traindicated in women with severe preeclampsia. sulfate for women with preeclampsia.179Ra The A recent analysis, however, suggests that spinal results of two large randomized trials showed that anesthesia can be used safely in the severely parenteral magnesium sulfate reduces the frequency preeclamptic patient undergoing cesarean section, of eclampsia in women with either pregnancy- since the magnitude of maternal blood pressure induced hypertension or severe preeclampsia.179Ra,180Ra declines appear to be similar after spinal or epidur- Although parenteral magnesium sulfate should be al anesthesia.173Re Hypotension can usually be given peripartum to women with severe preeclamp- avoided by meticulous attention to anesthetic tech- sia, its benefits with mild gestational hypertension or nique and careful volume expansion. In one preeclampsia remain unclear. A multicenter ran- unblinded study of 80 women with severe domized trial to answer this question is urgently preeclampsia randomized to receive epidural, com- needed. Precautions regarding the use of magne- bined spinal-epidural, or general anesthesia, all sium sulfate during pregnancy in women with renal three regimens appeared equally safe.174Ra failure are discussed in the section on Pregnancy, Hypertension, and Renal Disease. With general anesthesia, significant hypertension may occur at the time of laryngoscopy and tracheal Invasive Hemodynamic Monitoring intubation and again during emergence and extuba- Some investigators recommend the use of invasive tion. These responses can usually be blocked by hemodynamic monitoring in managing women appropriate pretreatment with hydralazine, nitro- with severe preeclampsia-eclampsia. It has been glycerin, or labetalol. Airway edema may be seen used to monitor fluid therapy during plasma vol- in the preeclamptic patient and may increase the ume expansion;181Re in managing women with pul- risks of a “difficult airway” situation leading to monary edema, persistent oliguria unresponsive to failed intubation and ventilation. Because general fluid challenge, and intractable severe

20

hypertension; and in some patients receiving subsequent doses are dictated by the initial epidural anesthesia.182Pr There is no published evi- response. Once the desired effect is obtained, the dence that the use of invasive hemodynamic moni- drug is repeated as necessary (frequently in several toring is indicated for the purposes mentioned hours).185Re Parenteral labetalol has been shown to above. Archivebe effective for the treatment of acute severe hy- pertension in pregnancy.106M,184F The drug may be Treatment of Acute Hypertension used as intravenous bolus injections of 20 mg or Antihypertensivefor therapy historical is indicated when blood Reference40 mg, or as continuous Only intravenous infusion of pressure is dangerously high or rises suddenly in 1 mg/kg as needed. Labetalol is usually used as a women with preeclampsia, especially intrapartum. second-line drug. It should be avoided in women Antihypertensive agents can be withheld as long as with asthma and in those with congestive maternal pressure is only mildly elevated. Some heart failure. experts would treat persistent diastolic levels of The use of oral nifedipine has been described in a 105 mm Hg or higher. Others would withhold limited number of women with acute severe hyper- treatment until diastolic blood pressure levels tension during pregnancy.186F Details of these reach 110 mm Hg.103Pr In adolescents whose dias- reports are summarized elsewhere.100Pr Nifedipine tolic pressures were recently below 75 mm Hg, acts rapidly, causing significant reduction in arteri- treating persistent levels of 100 mm Hg or higher al blood pressure within 10 to 20 minutes of oral may be considered. When treatment is required, administration. Although it has favorable hemody- the ideal drug that reduces pressures to a safe level namic effects,186F physicians should be advised that should act quickly, reduce pressure in a controlled rapidly acting nifedipine (in capsules containing manner, not lower cardiac output, reverse uteropla- the liquid form) has never been approved by the cental vascular constriction, and result in no Food and Drug Administration for treating hyper- adverse maternal or fetal effects. The medications tension or hypertensive emergencies. The JNC used to treat hypertensive crises in pregnancy, and VI2Pr has recommended that it not be used for this their route of administration, are summarized in purpose because it has been associated with fatal Table 4. Details of their pharmacology and safety and nonfatal untoward cardiovascular events, espe- are discussed elsewhere.183Pr cially in older patients.187Pr Of the 16 case reports The most commonly used drug is hydralazine, reviewed by Grossman and colleagues,187Pr, 188 one administered as either intravenous (IV) or intra- was a 37-year-old pregnant woman whose blood muscular (IM), which, if given cautiously, is suc- pressure was reduced from 150/118 to 90/55, pre- cessful in most instances. It has been shown to be cipitating the need for caesarean section because effective against preeclamptic hypertension.184F,185Re of . Care should be exercised when Although this drug is sometimes given as an intra- using nifedipine or any calcium antagonist with venous infusion, the pharmacokinetics (maximal magnesium sulfate.189,190Pr,191 effect at 20 minutes, duration of action 6 to In the rare case, sodium nitroprusside may be indi- 8 hours) indicate intermittent bolus injections are cated after the failure of hydralazine, nifedipine, more sensible. A 5 mg bolus is given intravenous- and labetalol for acute hypertensive emergency. ly over 1 to 2 minutes. After 20 minutes,

21

Preeclampsia

TABLE 4. TREATMENT OF ACUTE SEVERE HYPERTENSION IN PREECLAMPSIA* BP ≥ 160 mm Hg systolic and/or ≥ 105 mm Hg diastolic if sustained • Hydralazine:Archive Start with 5 mg IV or 10 mg IM. If blood pressure is not controlled, repeat at 20-minute intervals (5 to 10 mg depending on response). Once BP control is achieved, repeat as needed (usually about 3 hours). If no success by 20 mg IV or 30 mg IM total, consider another drug. • Labetalol: Start with 20 mg IV as a bolus; if effect is suboptimal, then give 40 mg 10 minutes later and for80 mg everyhistorical 10 minutes for two additionalReference doses. Use a maximum Only of 220 mg. If desired blood pressure levels are not achieved, switch to another drug. Avoid giving labetalol to women with asthma or congestive heart failure. • Nifedipine: Start with 10 mg orally and repeat in 30 minutes if necessary. See precautions, in Treatment of Acute Hypertension section. (Short-acting nifedipine is not approved by FDA for managing hypertension.) • Sodium nitroprusside is rarely needed for hypertension not responding to the drugs listed above and/or if there are clinical findings of hypertensive encephalopathy. Start at a rate of 0.25 µg/kg/min to a maximum dose of 5 µg/kg/min. Fetal cyanide poisoning may occur if used for more than 4 hours.

* Side effects: See Physicians Desk Reference (53rd edition). Caution: Sudden and severe hypotension can result from the administration of any of these agents, especially short-acting oral nifedipine. The goal of blood pressure reduction in emergency situations should be a gradual reduction of blood pressure to the normal range. (See Treatment of Acute Hypertension section.) Clinical Note: In managing hypertensive emergencies, the IV route is safer than oral or IM administration because it is easier to combat inadvertent hypotension by stopping an IV injection or infusion than it is to stop intestinal or intramuscular absorption of an orally or IM-administered drug.

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POSTPARTUM COUNSELINGArchive AND FOLLOWUP for historical Reference Only omen who develop hypertension during preg- women who have not had a preeclamptic W nancy should be carefully reevaluated during pregnancy.196Re the immediate postpartum months and counseled Of interest are data indicating that women with with respect to future gestations and remote car- early-onset severe preeclampsia harbor metabolic diovascular risks as well. Any laboratory abnor- abnormalities or risk factors associated with vascu- mality or physical finding that has not returned to lar thrombosis. These include activated protein C normal before postdelivery discharge should be resistance (Factor V Leiden), antiphospholipid reassessed at postpartum followup. The expecta- antibodies, hyperhomocysteinemia, and protein S tion is that hypertension and other signs or symp- deficiency.197F,198F,199,200Re Therefore, patients with a toms of organ dysfunction associated with history of early-onset severe preeclampsia should preeclampsia will have remitted by the 6-week be evaluated for evidence of prior thromboembolic postpartum examination, but if abnormalities per- diseases and, if they have such a history, should sist, the patients should be reexamined 6 weeks be tested for the above-described abnormalities later, when persisting pathology will probably be (which when present jeopardize not only future chronic. pregnancies but the patients’ general health as well). COUNSELING FOR FUTURE PREGNANCIES

Women who have had preeclampsia are more REMOTE CARDIOVASCULAR PROGNOSIS prone to hypertensive complications in subsequent pregnancies. Risk is best established for nulliparas Preeclampsia-Eclampsia with a history of preeclampsia, the magnitude of The remote prognosis of women experiencing the recurrence rate increasing the earlier the dis- preeclampsia or eclampsia is best summarized as ease manifested during the index pregnancy. For follows: The more certain the diagnosis is instance, when preeclampsia presents clinically preeclampsia alone (e.g., nulliparity, especially if before gestational week 30, the recurrence rate complicated by eclampsia or confirmed by renal 192F,193F may be as high as 40 percent. Preeclampsia biopsy), the lower the prevalence of remote cardio- reappearance rates may also be population-specif- vascular disorders. Prevalence of remote hyperten- ic. For example, in white woman with well- sion, however, is increased in nulliparous women defined disease after gestational week 36, with preeclampsia or eclampsia manifesting hyper- 194Pr recurrence is barely 10 percent, but it may be tension in subsequent gestations, multiparas who 192F substantially greater in black patients. The develop the disorder, and women with severe recurrence rate for women with one episode of early-onset disease of any parity. The literature 195F HELLP is almost 5 percent. further suggests that preeclampsia-eclampsia, by Recurrence rates are higher for those experiencing itself, is not a cause of essential hypertension. In preeclampsia as multiparas compared with nulli- essence, it is the hypertension in subsequent gesta- parous women.196Re Risk is also increased in multi- tions, presence of preeclampsia in a multipara, or paras who conceive with a new father even when early-onset disease in any pregnancy that signals their first pregnancy was normotensive, the inci- that the disease has occurred in a patient with an dence being intermediate between that of primi- increased probability of essential hypertension parous women and monogamous multiparous later in life.89Ra,192F,193F,194Pr,201F

23

Postpartum Counseling and Followup

In summary, it is reasonable to counsel patients as gestational hypertension in any pregnancy are at follows: If preeclampsia occurred late in an initial increased cardiovascular risk—information of gestation, there is no evidence of remote cardio- importance for long-term health care strategies. vascular risk, but subsequent pregnancies will help The best news, however, is that women experienc- us define risk moreArchive accurately. Women with early- ing normotensive births have a reduced risk for onset disease, multiparous women with preeclamp- remote hypertension. sia foror only hypertension,historical and those manifestingReference Only

24

RECOMMENDATIONSArchive FOR FUTURE RESEARCH for historical Reference Only A RESEARCH DIAGNOSIS OF are absent from other hypertensive disorders are needed. Ideally, the clinical diagnosis of pre- PREECLAMPSIA eclampsia would be based on sensitive and specific diagnostic tests derived directly from the causative he clinical definitions used in this document mechanism of the disease. No such tests exist, and aim to protect both mother and fetus from T none is likely until we understand the pathogenesis adverse outcome. They were purposely chosen to of the syndrome more completely. Lacking such have a high sensitivity rather than specificity tests, clinical diagnosis should be based on the because overdiagnosis is a safe strategy that relationship of findings to outcomes or those find- ensures closer scrutiny of the patient and avoids ings’ ability to predict development of frank clini- morbidity. In the process, however, many women cal preeclampsia. Estimates of the prevalence of receiving the clinical diagnosis do not, in reality, preeclampsia at different threshhold values of have true preeclampsia. The use of patients blood pressure or change in pressure, and the mag- labeled preeclamptic by the clinical definition may nitude of overlap using the different criteria, must lead to erroneous findings in studies designed to be developed. Ideally, receiver-operating charac- determine outcome and epidemiologic associa- teristic curves should be defined for both absolute tions. Thus, more stringent criteria must be used blood pressure and change over baseline so that for selecting cases for research in preeclampsia. the most appropriate criterion values can be chosen Specifically, cases should be documented to be and the need for revising current definitions normotensive before pregnancy or 12 weeks after assessed. Use of current estimates of qualitative pregnancy. and quantitative protein excretion should be ana- Studies of nulliparous women are important in lyzed similarly, and these prospective studies order to distinguish unique pathologic features of should also be designed to determine the predictive preeclampsia from other preexisting or future value of other signs and symptoms to diagnose pathophysiology, which is often present in multi- preeclampsia when proteinuria is absent (e.g., paras who appear to develop the disorder. There platelets, liver function, abdominal and neurologic are situations in which studies of multiparas are symptoms, markers of endothelial activation58). useful, mainly those designed to understand factors Such data may help improve both the clinical and that predispose to preeclampsia (and that should research diagnoses of preeclampsia. eventually provide targets to prevent the disease or A substantial subset of the desired data, at least for improve management strategies). Included here blood pressures if not for other tests, may be are subsets of patients such as those with a variety obtained by reanalyzing the original data sets of of metabolic disorders and women with a history the large prospective trials of aspirin or calcium of early-onset preeclampsia.193 supplementation for prophylaxis. That may be the most cost-effective approach in the short term. OTHER RESEARCH NEEDS Clinical Trials Regarding Prevention and Studies To Establish Appropriate Diagnostic Management of the Hypertensive Complications Criteria for Preeclampsia There are few trials to guide choices of antihyper- Large prospective multicenter trials designed to tensive agents in pregnancy, and all appear to have detect markers that uniquely predict and/or specifi- one or more major flaws. Large multicenter ran- cally accompany the preeclamptic syndrome and domized trials, carefully designed to determine the

25

Recommendations for Future Research

teratogenicity of any prescribed medication and them separately for both outcome and pathophysi- other aspects of fetal jeopardy as well as maternal ology. This approach has increased our under- well-being, are needed. Such studies should standing of other complex syndromes (e.g., type 1 include substantial periods of neonatal followup. and type 2 diabetes). Criteria for determining sub- Given both theirArchive importance and costs, such trials sets could include gestational age at delivery, asso- can rarely rely on industry funding; they require ciation with intrauterine growth restriction, as well Government support. as research into the genetic predisposition of for historical Referencepreeclampsia Only including both population genetics Attempts To Identify Subsets of Women With the and biochemical markers for women at risk for Preeclampsia Syndrome preeclampsia. Such studies should identify women Efforts should be made to recognize different sub- at adverse risk for maternal and fetal outcome as a sets of women with preeclampsia and to examine result of preeclampsia.

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56. Long PA, Abell DA, Beischer NA. 65. Gaber LW, Lindheimer MD. Pathology of the Importance of abnormal glucose tolerance kidney, liver, and brain. In: Lindheimer MD, (hypoglycemia and hyperglycemia) in the Roberts JM, Cunningham FG, editors. etiology of pre-eclampsia. Lancet Hypertensive disorders in pregnancy. 1977;1:923-5. Stamford, CT: Appleton and Lange; 1999. p. 231-62. 57. Solomon CG, Graves SW, Greene MF, Seely EW. Glucose intolerance as a predictor of 66. Pertuiset N, Grünfeld JP. Acute renal failure hypertension in pregnancy. Hypertension in pregnancy. Baillieres Clin Obstet Gynaecol 1994;23:717-21. 1994;8:333-51.

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67. Taufield PA, Ales KL, Resnick LM, Druzin 76. Pritchard JA, Cunningham FG, Pritchard SA, ML, Gertner JM, Laragh JH. Hypocalciuria Mason RA. How often does maternal in preeclampsia. N Engl J Med 1987; preeclampsia-eclampsia incite 316:715-8. thrombocytopenia in the fetus? Obstet ArchiveGynecol 1987;69:292-5. 68. Brown MA, Gallery EDM, Ross MR, Esber RP. Sodium excretion in normal and 77. Sheehan HL, Lynch JB. Pathology of hypertensivefor pregnancy: historical a prospective study. Referencetoxaemia of pregnancy.Only London: Churchill, Am J Obstet Gynecol 1988;159:297-307. Livingstone; 1973.

69. August P, Sealey JE. The renin-angiotensin 78. Sibai BM, Kustermann L, Velasco J. Current system in normal and hypertensive pregnancy understanding of severe preeclampsia, and in ovarian function. In: Laragh JH, pregnancy-associated hemolytic uremic Brenner BM, editors. Hypertension: syndrome, thrombotic thrombocytopenic pathophysiology, diagnosis, and management. purpura, hemolysis, elevated liver enzymes, New York: Raven Press; 1990. p. 1761-78. and low platelet syndrome, and postpartum acute renal failure: different clinical 70. Castro LC, Hobel CJ, Gornbein J. Plasma syndromes or just different names? Curr levels of atrial natriuretic peptide in normal Opin Nephrol Hypertens 1994;3:436-45. and hypertensive pregnancies: a meta- analysis. Am J Obstet Gynecol 79. Weinstein L. Syndrome of hemolysis, 1994;171:1642-51. elevated liver enzymes, and low platelet count: a severe consequence of hypertension 71. Bond AL, August P, Druzin ML, Atlas SA, in pregnancy. Am J Obstet Gynecol Sealey JE, Laragh JH. Atrial natriuretic factor 1982;142:159-67. in normal and hypertensive pregnancy. Am J Obstet Gynecol 1989;160:1112-6. 80. Ohno Y, Kawai M, Wakahara Y, Kitagawa T, Kakihara M, Arii Y. Transcranial assessment 72. Barron WM, Heckerling P, Hibbard JU, of maternal cerebral blood flow velocity in Fisher S. Reducing unnecessary coagulation patients with pre-eclampsia. Acta Obstet testing in hypertensive disorders of Gynecol Scand 1997;76:928-32. pregnancy. Obstet Gynecol 1999;94:364-70. 81. Belfort MA, Saade GR, Grunewald C, Dildy 73. Lockwood CJ, Peters JH. Increased plasma GA, Abedejos P, Herd JA, Nisell H. levels of ED1+ cellular fibronectin precede Association of cerebral perfusion pressure the clinical signs of preeclampsia. Am J with headache in women with pre-eclampsia. Obstet Gynecol 1990;162:358-62. Br J Obstet Gynaecol 1999;106:814-21.

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84. Moodley J, Bobat SM, Hoffman M, Bill 92. Jungers P, Chauveau D, Choukroun G, PLA. Electroencephalogram and Moynot H, Skhiri H, Houillier P, Forget D, computerised cerebral tomography findings Grünfeld JP. Pregnancy in women with in eclampsia. Br J Obstet Gynaecol impaired renal function. Clin Nephrol 1993;100:984-8.Archive1997;47:281-8. F 85. Drislane FW, Wang AM. Multifocal cerebral 93. Packham DK, Fairley KF, Ihle BU, forhemorrhage historical in eclampsia and severe Reference pre- WhitworthOnly JA, Kincaid-Smith P. Comparison eclampsia. J Neurol 1997;244:194-8. of pregnancy outcome between normotensive and hypertensive women with primary 86. Morriss MC, Twickler DM, Hatab MR, glomerulonephritis. Clin Exp Hypertens Clarke GD, Peshock RM, Cunningham FG. 1988;B6:387-99. Re Cerebral blood flow and cranial magnetic resonance imaging in eclampsia and severe 94. Clapp III JF. Morphometric and preeclampsia. Obstet Gynecol 1997;89:561-8. neurodevelopmental outcome at age five years of the offspring of women who 87. Friedman SA, Lindheimer MD. Prediction continued to exercise regularly throughout and differential diagnosis. In: Lindheimer pregnancy. J Pediatr 1996;129:856-63. F MD, Roberts JM, Cunningham FG, editors. Chesley’s hypertensive disorders in 95. Clapp III JF, Simonian S, Lopez B, Appleby- pregnancy. Stamford, CT: Appleton and Wineberg S, Harcar-Sevcik R. The one-year Lange; 1999. p. 201-27. morphometric and neurodevelopmental outcome of the offspring of women who 88. Sibai BM, Lindheimer MD, Hauth J, Caritis continued to exercise regularly throughout S, VanDorsten P, Klebanoff M, MacPherson pregnancy. Am J Obstet Gynecol C, Landon M, Miodovnik M, Paul R, Meis P, 1998;178:594-9. F Dombrowski M. Risk factors for preeclampsia, abruptio placentae, and adverse 96. Sibai BM, Mabie WC, Shamsa F, Villar MA, neonatal outcomes among women with Anderson GD. A comparison of no chronic hypertension. N Engl J Med medication versus methyldopa or labetalol in 1998;339:667-71. F chronic hypertension during pregnancy. Am J Obstet Gynecol 1990[b];162:960-7. Ra 89. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E, VanDorsten P, Landon 97. Gruppo di Studio Ipertensione in Gravidanza. M, Paul R, Miodovnick M, Meis P, Thurnau Nifedipine versus expectant management in G. Low-dose aspirin to prevent preeclampsia mild to moderate hypertension in pregnancy. in women at high risk. National Institute of Br J Obstet Gynaecol 1998;105:718-22. Ra Child Health and Human Development Network of Maternal-Fetal Medicine Units. 98. De Swiet M. Maternal blood pressure and N Engl J Med 1998;338:701-5. Ra birthweight (editorial). Lancet 2000;355:81.

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