4 u1.0-b978-1-4160-4224-2..50038-7..docpdf

Classifi cation of Hypertensive DisordersInterpreting epidemiologic studies of the hypertensive disorders of pregnancy is diffi cult because the terminology is inconsistent.1 Several systems of nomenclature are in use around the world. The system prepared by the National Institutes of Health (NIH) Working Group on Hypertension in Pregnancy,2 although imperfect, has the advantage of clarity and is available in published form for investigators through-out the world. The NIH system has four main classes: chronic hyper-tension, preeclampsia and eclampsia, preeclampsia superimposed on chronic hypertension, and gestational hypertension.

Chronic HypertensionChronic hypertension is defi ned as hypertension that is observable before pregnancy or that is diagnosed before the 20th week of gesta-tion. Hypertension is defi ned as a persistent blood pressure greater than 140/90 mm Hg. Hypertension for which a diagnosis is confi rmed for the fi rst time during pregnancy and that persists beyond the 84th day after delivery is also classifi ed as chronic hypertension.

Preeclampsia and EclampsiaThe diagnosis of preeclampsia is determined by increased blood pres-sure accompanied by proteinuria. The diagnosis requires a systolic pressure of 140 mm Hg or higher or a diastolic pressure of 90 mm Hg or higher. Diastolic blood pressure is defi ned as the Korotkoff phase V value (i.e., disappearance of sounds). Gestational blood pressure eleva-tion should be determined by at least two measurements, with the repeat blood pressure performed in a manner that reduces the likeli-hood of artifact and patient anxiety.3 Absent from the diagnostic cri-teria is the former inclusion of an increment of 30 mm Hg in systolic or 15 mm Hg in diastolic blood pressure, even when absolute values are below 140/90 mm Hg. This defi nition was excluded because avail-able evidence shows that women in this group are not likely to suffer increased adverse outcomes.4,5 Nonetheless, women who have an increase of 30 mm Hg in systolic or 15 mm Hg in diastolic blood pres-sure warrant close observation, especially if proteinuria and hyperuri-cemia (i.e., uric acid ≥ 5.5 mg/dL)6 are also present.3

Proteinuria is defi ned as the urinary excretion of at least 300 mg of protein in a 24-hour specimen. This usually correlates with 30 mg/dL of protein (i.e., 1+ dipstick reading) or more in a random urine deter-

mination. Because of the discrepancy between random protein deter-minations and 24-hour urine protein values in women with preeclampsia (which can be higher or lower),7-9 the diagnosis should be based on a 24-hour urine specimen or on a timed collection corrected for creatinine excretion if a 24-hour collection is not feasible.3

Preeclampsia occurs as a spectrum but is arbitrarily divided into mild and severe forms. This terminology is useful for descriptive pur-poses but does not indicate specifi c diseases, nor should it indicate arbitrary cutoff points for therapy. The diagnosis of severe preeclamp-sia is confi rmed when any of the following criteria are met10:

� Blood pressure of 160 mm Hg systolic or higher or 110 mm Hg diastolic or higher on two occasions at least 6 hours apart while the patient is on bed rest

� Proteinuria of 5 g or higher in a 24-hour urine specimen or 3+ or greater on two random urine samples collected at least 4 hours apart

� Oliguria of less than 500 mL in 24 hours� Cerebral or visual disturbances� Pulmonary edema or cyanosis� Epigastric or right upper quadrant pain� Impaired liver function� Thrombocytopenia� Fetal growth restriction

Eclampsia is the occurrence of seizures that cannot be attributed to other causes in a woman with preeclampsia.

Edema occurs in too many normal pregnant women to be discrimi-nant and has been abandoned as a marker in preeclampsia by the National High Blood Pressure Education Program and by other clas-sifi cation schemes.11,12 Edema of the hands and face occurs in 10% to 15% of women whose blood pressure remains normal throughout pregnancy.13 Edema can be massive in women with severe preeclamp-sia, rendering the patient virtually unrecognizable (Fig. 35-1).

Preeclampsia Superimposed on Chronic HypertensionThere is ample evidence that preeclampsia can occur in women who are already hypertensive and that the prognosis for mother and fetus is much worse with both conditions than with either alone. Distin-guishing superimposed preeclampsia from worsening chronic hyper-tension tests the skills of the clinician. For clinical management, the principles of high sensitivity and unavoidable overdiagnosis are appro-

Chapter 35

Pregnancy-Related HypertensionJames M. Roberts, MD, and Edmund F. Funai, MD

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652 CHAPTER 35 Pregnancy-Related Hypertension

priate, especially with advancing gestational age. The suspicion of superimposed preeclampsia mandates close observation, with delivery indicated by the overall assessment of maternal and fetal well-being rather than by any fi xed end point. The diagnosis of superimposed preeclampsia is highly likely with the following fi ndings:

1. In women with documented hypertension and no proteinuria before 20 weeks’ gestation� New-onset proteinuria, defi ned as the urinary excretion of 0.3 g

of protein or more in a 24-hour specimen2. In women with hypertension and proteinuria before 20 weeks’

gestation� A sudden increase in proteinuria� A sudden increase in blood pressure in a woman whose blood

pressure has previously been well controlled� Objective evidence of involvement of multiple organ systems,

such as thrombocytopenia (platelet count < 100,000/mm3), an increase in liver transaminases to abnormal levels,3 or sudden worsening of renal function

Gestational HypertensionA woman who has no proteinuria and a blood pressure elevation detected for the fi rst time during pregnancy is classifi ed as having ges-tational hypertension. This is a provisional diagnosis that includes women with preeclampsia who have not yet manifested proteinuria and women who do not have preeclampsia. The hypertension may be accompanied by other concerning signs or symptoms that can infl u-ence management. A fi nal determination that the woman does not have preeclampsia can be made only after delivery. If preeclampsia has not developed and blood pressure has returned to normal by 12 weeks after delivery, the diagnosis of transient hypertension of pregnancy can

be assigned. If blood pressure elevation persists, the diagnosis is chronic hypertension. The diagnosis of gestational hypertension is used during pregnancy only until a more specifi c diagnosis can be assigned after delivery.3

Problems with Classifi cationThe degree of blood pressure elevation that constitutes gestational hypertension is controversial. Because average blood pressure in women younger than 30 years is 120/60 mm Hg, the standard defi ni-tion of hypertension (i.e., blood pressure >140/90 mm Hg) is judged by some to be too high,14 resulting in the suggestion that women with blood pressure increases greater than 30 mm Hg systolic or 15 mm Hg diastolic should be observed closely even if absolute blood pressure has not exceeded 140/90 mm Hg.3

Blood pressures measured in early pregnancy to diagnose chronic hypertension are problematic. Blood pressure usually decreases early in pregnancy, reaching its nadir at about the time women often present for obstetric care (Fig. 35-2). The decrease averages 7 mm Hg for dia-stolic and systolic readings. In some women, blood pressure may decline by more than 7 mm Hg; in others, the early decline and sub-sequent return of blood pressure to pre-pregnant levels in late gesta-tion may satisfy criteria for a diagnosis of preeclampsia. Women with hypertension before pregnancy have a greater decrease in blood pres-sure in early pregnancy than do normotensive women,15 and they are more likely to be misdiagnosed as preeclamptic according to blood pressure criteria.

The diagnosis of chronic hypertension based on the failure of blood pressure to return to normal by 84 days after delivery can be in error. In a long-range, prospective study by Chesley,16 many women who remained hypertensive 6 weeks after delivery were normotensive at long-term follow-up. Neither proteinuria nor hypertension is specifi c

A B

FIGURE 35-1 Facial edema in severe preeclampsia. Markedly edematous facies of this severely preeclamptic woman (A) is especially evident when compared with her appearance 6 weeks after delivery (B).

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653CHAPTER 35 Pregnancy-Related Hypertension

to preeclampsia, and their presence in pregnancy can have other explanations.

Renal biopsy specimens from women with preeclampsia demon-strate these diagnostic diffi culties (Table 35-1).17 Of 62 women with a diagnosis of preeclampsia in their fi rst pregnancies, 70% had a glo-merular lesion believed to be characteristic of the disorder, but 24% had evidence of chronic renal disease that was not previously sus-pected. Renal biopsy specimens of multiparous women with a clinical diagnosis of superimposed preeclampsia also demonstrate the uncer-tainty of diagnosis. Of 152 subjects, only 3% had the characteristic glomerular lesion, but 43% had evidence of preexisting renal or vas-cular disease.

Preeclampsia has a clinical spectrum ranging from mild to severe forms. The illness in affected women does not begin with eclampsia or the severe manifestations of preeclampsia. Rather, the disease pro-

gresses at various rates. In most cases, progression is slow, and the disorder may remain mild. In others, the disease can progress rapidly, changing from mild to severe over days to weeks or, in fulminant cases, progressing in days or hours.

In a series of eclamptic women analyzed by Chesley,18 25% had evidence of only mild preeclampsia in the days preceding convulsions. For purposes of clinical management, overdiagnosis must be accepted because prevention of the serious complications of preeclampsia and eclampsia requires increased sensitivity and early treatment, primarily through the timing of delivery. For this reason, studies of preeclampsia are necessarily confounded by inclusion of women diagnosed as pre-eclamptic who have another cardiovascular or renal disorder.

HELLP SyndromeThe pathophysiologic changes of preeclampsia can occur in the absence of hypertension and proteinuria. This is not surprising, because the traditional diagnostic criteria have more historical than pathophysio-logic relevance.18 This situation presents a challenge to clinicians and demands that they remain alert to the possibility of preeclampsia in pregnant women with signs and symptoms that may be explained by reduced organ perfusion. One clear setting in which this occurs is the HELLP syndrome (hemolysis, elevated liver enzymes, and low plate-lets), a combination of fi ndings that defi nes a reasonably consistent syndrome.19

For management purposes, it is appropriate to consider HELLP as a variant of preeclampsia, but they may be different entities. Women with HELLP are more often older, white, and multiparous than preeclamptic women. Not all women with HELLP have hypertension.20 From a pathophysiologic perspective, changes in the renin-angiotensin system characteristic of preeclampsia are not present in HELLP.21 Nonetheless, progression of the disease and its termination with deliv-ery argue for an observation and management strategy similar to that for preeclampsia.

Preeclampsia and EclampsiaEpidemiology of Preeclampsia and EclampsiaDespite the diffi culties in clinical diagnosis, there exists a disorder unique to pregnancy characterized by poor perfusion of many vital organs (including the fetoplacental unit) that is completely rever-sible with the termination of pregnancy. Pathologic, pathophysiologic, and prognostic fi ndings indicate that preeclampsia is not merely an unmasking of preexisting, underlying hypertension. Although the unique nature of preeclampsia has been well documented for many years, controversies in therapy persist because of management strate-gies based on principles used to treat hypertension in nonpregnant individuals. The successful management of preeclampsia requires an understanding of the pathophysiologic changes in this condition and recognition that the signs of preeclampsia (i.e., increased blood pres-sure and proteinuria) are only signs and do not cause the other features of preeclampsia.

Women at RiskPreeclampsia occurs in about 4% of pregnancies that continue past the fi rst trimester. Nulliparity is the most common feature of women who develop preeclampsia. At least two thirds of cases occur in the fi rst pregnancy that progresses beyond the fi rst trimester. Other risk

mm Hg

Systolic

PARA 0

PARA 1+

Diastolic

PARA 0

PARA 1+

Gestational age (weeks)

16 20 24 28 32 36 4060

65

70

75

110

115

120

125

FIGURE 35-2 Blood pressure correlated with gestational age. The mean blood pressure was plotted against gestational age for 6000 white women between the ages of 25 and 34 years who delivered singleton term infants. (From Christianson R, Page EW: Studies on blood pressure during pregnancy: Infl uence of parity and age. Am J Obstet Gynecol 125:509, 1976. Courtesy of the American College of Obstetricians and Gynecologists.)

TABLE 35-1 RENAL BIOPSY FINDINGS IN PATIENTS WITH A CLINICAL DIAGNOSIS OF PREECLAMPSIA

Biopsy Findings

Primigravidas

(n = 62)

Multigravidas

(n = 152)

Glomeruloendotheliosis with or without nephrosclerosis

70% 14%

Normal histology 5% 53%Chronic renal disease, chronic

glomerulonephritis, or chronic pyelonephritis

25% 21%

Arteriolar nephrosclerosis 0% 12%

Modifi ed from McCartney CP: Pathological anatomy of acute

hypertension of pregnancy. Circulation 30(Suppl II):37, 1964; by

permission of the American Heart Association, Inc.

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factors for preeclampsia are similar in nulliparous and parous women.22

Although preeclampsia was thought to be more common among women of lower socioeconomic status, this impression may be a con-sequence of the associations of preeclampsia with age, race, and parity. Studies of pregnant women in Scotland23 from Aberdeen,24 Finland,25 and Israel26 found that preeclampsia was not related to socioeconomic status. Eclampsia, in contrast, is clearly more common in women of lower socioeconomic status,23,25,26 related to the lack of availability of quality obstetric care for indigent women. Remarkably, preeclampsia and eclampsia were once thought to occur more frequently in women of higher socioeconomic status.18

There is a relationship between the extremes of childbearing age and the incidence of eclampsia and preeclampsia. Because most fi rst pregnancies occur in young women, most cases of preeclampsia and eclampsia occur in this age group, but the association with young maternal age is lost when parity is considered. In the studies cited,23,25,26 a higher incidence of preeclampsia was found in older women inde-pendent of parity.

The relationship of preeclampsia and eclampsia to race is compli-cated by the higher prevalence of chronic hypertension in African Americans and the diffi culty in differentiating preeclampsia from unrecognized preexisting chronic hypertension. Some studies indicate a relationship.26,27 In a small case-control study of carefully defi ned preeclampsia, black race was a signifi cant risk factor only in nullipa-rous women (odds ratio [OR] = 12.3; 95% confi dence interval [CI], 1.6 to 100.8).28 Other studies support a more modest increased risk in African-American women.29,30 Studies that include the more severe forms of preeclampsia more often suggest an increased incidence among African-American women.28

In contrast, the incidence of rigorously defi ned preeclampsia did not differ by race after other risk factors were controlled in two large, prospective trials of medical prophylaxis that enrolled 294731 and 431432 nulliparous women. Maternal nonwhite race appears to be related more to the severity than the incidence of disease.

A diverse array of medical disorders that often coexist with preg-nancy, including diabetes, chronic hypertension, chronic renal disor-ders, and rheumatologic conditions, have been associated with preeclampsia. The existence and severity of diabetes have been associated with an increased risk for preeclampsia, and diabetic microvascular disease further increases this risk. This relationship has been found in Sweden33 and in the United States.34 Both studies33,34 demonstrated that the risk of preeclampsia was approxi-mately 20% and 21% in 491 and 462 pregnancies, respectively. This estimate is far more modest than the 50% incidence reported in his-torical cohorts.18 The preeclampsia risk increased according to the severity of disease, with an 11% to 12% risk among women with class B diabetes and 21% to 23% with class C and D diabetes. Microvascular disease increased this risk to 36% to 54% in diabetics with class F or R disease.33,34

Chronic renal insuffi ciency and hypertension are well-recognized risk factors. Of women with hypertension antedating pregnancy, 25% develop preeclampsia.35,36 Renal insuffi ciency with33,37 and without dia-betes38-40 also is an important risk factor.38,40

Connective tissue disorders such as systemic lupus erythe-matosus41,42 and antiphospholipid antibody syndrome43-45 have been reported as risk factors for preeclampsia. With lupus, the risk is par-ticularly elevated with hypertension or nephropathy.46,47 However, data concerning an association between isolated antiphospholipid antibodies and preeclampsia have been confl icting, with some studies demonstrating no relationship48,49 and others confi rming the association.44,50

Obesity is a risk factor for preeclampsia.28,51 In the National Insti-tute of Child Health and Human Development (NICHD) study of aspirin to prevent preeclampsia in low-risk pregnancies,31 the inci-dence of preeclampsia increased with maternal body mass index. Even in women of normal weight, there is a linear relationship between pre-pregnancy body mass index and the frequency of preeclampsia.52 The mechanism may be related to increased insulin resistance, because preeclampsia is more common in another setting of increased insulin resistance: gestational diabetes.53 With a threefold increased risk for obese women and with 35% to 50% of women of reproductive age in the United States being obese, obesity has become a major attributable risk factor for preeclampsia, which is associated with more than one third of cases of preeclampsia.

Certain conditions of pregnancy increase the risk of preeclampsia. The incidence is increased among parous and nulliparous women with multiple gestations, although to a larger degree in the latter.36,54 In a study of 34,374 pregnancies with singleton, twin, triplet, or quadruplet pregnancies, the incidence of preeclampsia increased with each addi-tional fetus. The incidences were 6.7%, 12.7%, 20.0%, and 19.6%, respectively.55 The disease process may be initiated earlier and may be more severe in these cases.54

Preeclampsia affects 70% of women with large, rapidly growing hydatidiform moles and occurs earlier than usual during gestation.56 In cases of preeclampsia occurring before 24 weeks’ gestation, hyda-tidiform mole should be suspected and sought.

An interesting variant of preeclampsia is the mirror syndrome, in which the mother’s peripheral edema mirrors the fetal hydrops. It occurs with fetal hydrops, although not with erythroblastosis uncom-plicated by hydrops. The incidence approaches 50% of pregnancies complicated by hydrops. The mirror syndrome is not confi ned to hydrops resulting from isoimmunization. In one series, mirror syn-drome occurred in 9 of 11 pregnancies with hydropic infants of non-immune origin.57 This condition can manifest early in pregnancy with severe signs and symptoms of preeclampsia, and it has resolved with treatment of the underlying process.58-60 Proteinuria is massive, and blood pressure elevation and edema are marked. Eclampsia occurs rarely (see Chapter 26).

Short-Term Prognosis for PreeclampsiaPERINATAL MORTALITYThe perinatal mortality rate is increased in infants of preeclamptic

women.61-63 In a study that examined 10,614,679 singleton pregnancies in the United States from 1995 to 1997 after 24 weeks’ gestation, the relative risk for fetal death was 1.4 for infants born to women with any of the gestational hypertensive disorders and 2.7 for those born to women with chronic hypertensive disorders compared with low-risk controls. Causes of perinatal death are placental insuffi ciency and abruptio placentae,64 which cause intrauterine death before or during labor, and prematurity. Predictably, the mortality rate is higher for infants of women with more severe forms of the disorder. At any level of disease severity, the perinatal mortality rate is greatest for women with preeclampsia superimposed on preexisting vascular disease.

The stillbirth rate attributable to preeclampsia has declined dra-matically in the past 35 years. However, infants born of preeclamptic pregnancies continue to have an approximately twofold increased risk for neonatal death.65 Although neonatal survival rates have improved dramatically, delivery before 34 weeks’ gestation continues to be associ-ated with an increased risk of long-range neurologic disability (see Chapter 58).

Growth restriction is more common in infants born to preeclamp-tic women (see Chapter 34) and more pronounced with increasing

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severity and earlier diagnosis.66 As with perinatal mortality, intrauter-ine growth restriction (IUGR) is more common in infants of chroni-cally hypertensive women with superimposed preeclampsia.67

The dramatic decrease in perinatal mortality rate among infants of preeclamptic women is the result in part of improved medical and obstetric management, including improved assessment of fetal well-being in the antepartum and intrapartum periods. The primary effect on the perinatal mortality rate, however, has come from improvements in neonatal care.

MATERNAL MORTALITYMaternal death associated with preeclampsia predominantly re-

sults from complications of abruptio placentae, hepatic rupture, and eclampsia. Historically, the mortality rate of eclamptic women was most effectively reduced by avoiding iatrogenic complications related to overmedication and overzealous attempts at vaginal delivery. In series from the late 19th century, when immediate delivery was the practice, the mortality rate of eclamptic women was 20% to 30%. Expectant management with profound maternal sedation with narcot-ics and hypnotics in the early 20th century was associated with a 10% to 15% mortality rate. The change to magnesium as the exclusive agent in the 1920s and 1930s resulted in a maternal mortality rate of 5%. Although magnesium was undoubtedly helpful, the primary factor responsible for improved mortality was decreased maternal sedation.18 The currently used combination of magnesium sulfate (MgSO4) and antihypertensive drugs as sole pharmacologic agents, followed by timely delivery, has produced a maternal mortality rate of almost zero68,69 because of an appreciation of the profound pathophysiologic abnormalities of preeclampsia, careful cardiopulmonary monitoring, and limitation of unproven interventions.

RECURRENCE IN SUBSEQUENT PREGNANCIESData from classic series indicate that the likelihood of recurrent

preeclampsia is infl uenced by the certainty of the clinical diagnosis in the fi rst pregnancy. Of 225 women with hypertension during preg-nancy chosen for study without regard to parity, 70% had a recurrence of preeclampsia in their next pregnancy.70 In a study of primiparas with severe preeclampsia, the recurrence rate was 45% .71 Because the diag-nosis in these studies was based solely on clinical fi ndings, these groups probably included patients with unrecognized preexisting blood pres-sure elevation or underlying renal or cardiovascular disease.

Recurrence rates were reported in 2006 for 896 parous women in Iceland according to standardized diagnostic criteria in both pregnan-cies (i.e., National High Blood Pressure Criteria3). The rates of recur-rence differed substantially by the diagnosis in the fi rst pregnancy, as seen in Table 35-2.72

To determine the subsequent pregnancy outcomes of women who clearly had preeclampsia, Chesley and colleagues74 followed 270 women with eclampsia for more than 40 years; only two were lost to follow-up. Among 187 women who had eclampsia in the fi rst pregnancy, 33% had a hypertensive disorder in any subsequent pregnancy. In most, the condition was not severe, but 5% had recurrent eclampsia. Twenty women with eclampsia as multiparas had recurrent hypertension in 50% of subsequent pregnancies.

Women with a clinical diagnosis of preeclampsia have increased risk for hypertensive disorders in subsequent pregnancies. The chances of recurrence decrease as the likelihood of true preeclampsia increases. If the condition does recur, it will usually not be worse, and if pre-eclampsia truly arose de novo, it probably will be less severe in subse-quent pregnancies. Some women, however, are normotensive between pregnancies but have recurrent preeclampsia. The risk of such recur-rence is increased when preeclampsia occurs in the late second or early third trimester.73 The recurrence of severe preeclampsia or eclampsia in one pregnancy predicts its likely recurrence in subsequent pregnancies.

Preeclampsia and Cardiovascular Disease

in Later LifeEvidence that preeclampsia is associated with long-term maternal health consequences is based on the work of Chesley and coworkers,74 who followed a cohort of white women with eclampsia in their fi rst pregnancy and reported no increased risk of subsequent chronic hypertension. However, mortality was twofold to fi vefold higher over the next 35 years among women with eclampsia in any pregnancy after the fi rst (Fig. 35-3). The fi ndings of Chesley and colleagues74 led to speculation that multiparous women with preeclampsia or eclampsia were more likely to have had unrecognized underlying chronic hyper-tension and that this, not preeclampsia, caused the subsequent increase in mortality. Sibai and associates71 also found that women with recur-rent preeclampsia were more likely to develop chronic hypertension. These studies are the basis for a statement by The National High Blood Pressure Education Program’s Working Group on High Blood Pressure during Pregnancy that recurrent hypertension in pregnancy, pre-eclampsia in a multipara, and early-onset disease in any pregnancy may all herald increased future health risks.2

Women with idiopathic preeclampsia (i.e., preeclampsia occurring in nulliparous women without underlying renal or cardiovascular disease, including chronic hypertension) were not thought to have increased risk of later vascular disease until a report from Norway75 found modest (1.65-fold) increased cardiovascular mortality for nul-liparous women with preeclampsia at term and an eightfold increased risk when preeclampsia was severe enough to lead to preterm delivery.

TABLE 35-2 TYPE OF RECURRENT HYPERTENSION DURING THE SECOND PREGNANCY BY TYPE OF HYPERTENSION IN THE FIRST PREGNANCY

First Pregnancy

Second Pregnancy*

NormalGestational

Hypertension PreeclampsiaChronic

HypertensionSuperimposed Preeclampsia

All Recurrences

Gestational hypertension (n = 511) 153 (29.9%) 239 (46.8%) 25 (4.9%) 82 (16%) 12 (2.3%) 358 (70.1%)Preeclampsia/eclampsia (n = 151) 63 (41.7%) 52 (34.4%) 17 (11.3%) 16 (10.6%) 3 (2%) 88 (58.3%)Chronic hypertension (n = 200) 24 (12%) 69 (34.5%) 6 (3%) 91 (45.5%) 10 (5%) 176 (88%)Superimposed preeclampsia (n = 34) 2 (5.9%) 10 (29.4%) 4 (11.8%) 14 (41.2%) 4 (11.8%) 32 (94%)Total (N = 896) 242 (27%) 370 (41.3%) 52 (5.8%) 203 (22.7%) 29 (3.2%) 654 (73%)

*No women had eclampsia in the second pregnancy.

From Hjartardottir S, Leifsson BG, Geirsson RT, Steinthorsdottir V: Recurrence of hypertensive disorder in second pregnancy. Am J Obstet Gynecol

194:916-920, 2006.

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Scottish investigators reported a fourfold increased risk of subsequent hypertension in nulliparous women with preeclampsia2,76,77 (OR = 3.98; CI, 2.82 to 5.61). Funai and colleagues78 described excess long-term mortality in women with prior preeclampsia that was largely attributed to a threefold increase in deaths due to cardiovascular disease. Other reports support a link between preeclampsia and mater-nal ischemic heart disease,79,80 which is sometimes evident 20 years after the preeclamptic pregnancy and coincident with the onset of menopause.78,80 A family history of cardiovascular disease increases the association between preeclampsia and cardiovascular outcomes.81 Obesity is a known risk factor for preeclampsia and cardiovascular disease. Although controlling for obesity attenuates the increased risk of death for postmenopausal women, this risk is not fully explained by obesity alone.82

The relationships among obesity, insulin resistance, and preeclamp-sia are part of an interesting relationship of preeclampsia to the meta-bolic or insulin resistance syndrome.83 This syndrome predisposes to cardiovascular disease in later life and consists of obesity, hypertension, dyslipidemia (i.e., increased low-density lipoprotein [LDL] cholesterol, decreased high-density lipoprotein [HDL] cholesterol, and increased triglycerides), and increased uric acid, all of which are found in women with preeclampsia.83 Other conditions predisposing to later-life cardio-vascular disease—including elevated levels of homocysteine,84 evidence of androgen excess (including polycystic ovarian syndrome),85 elevated testosterone levels,86 male fat distribution (i.e., increased waist-to-hip ratio),87 and lipoprotein lipase mutations88—are also linked to an increased risk for preeclampsia.

Women who appear normal years after a preeclamptic pregnancy may nevertheless demonstrate subtle metabolic and cardiovascular abnormalities. Compared with women with uncomplicated pregnan-cies, formerly preeclamptic women have evidence of endothelial dys-function,89,90 higher blood pressures,89 increased insulin resistance,91

dyslipidemia,92 altered angiogenic factors,93 and increased antibodies to the angiotensin-2 receptor.94 These data may explain the common risk factors for preeclampsia and cardiovascular disease, but alternative explanations, such as that preeclampsia causes vascular injury that increases cardiovascular risk or that normal pregnancies have a protec-tive effect, cannot be excluded.

Clinical PresentationPreeclampsia can manifest with a wide spectrum of disease, ranging from life-threatening neurologic, renal, hepatic, and coagulation abnormalities to mild fi ndings of preeclampsia with minimal end-organ involvement. The fetus may be severely compromised by the maternal condition and by extreme preterm delivery or only minimally affected. These variations have puzzled clinicians and researchers for many years. An understanding of the pathophysiology of the disorder provides insight into the diverse clinical presentations.

SymptomsMost women with early preeclampsia are asymptomatic. The absence of symptoms is the rationale for frequent obstetric visits in late preg-nancy. In most cases, signs such as increased blood pressure and pro-teinuria antedate overt symptoms.

The various symptoms associated with preeclampsia, especially preeclampsia of increasing severity, are listed in Table 35-3. Because preeclampsia is a disease of generalized poor perfusion, the diversity of symptoms related to many organ systems is not surprising. Symp-toms suggesting hepatic, neurologic, and visual involvement are par-ticularly worrisome. They include epigastric pain, “stomach upset,” and pain penetrating to the back. Headache and mental confusion indicate poor cerebral perfusion and may be precursors of convulsions. Visual symptoms ranging from scotomata to blindness indicate retinal arte-rial spasm and edema. Symptoms suggesting congestive heart failure or abruptio placentae also represent signifi cant complications of pre-eclampsia. Other symptoms, such as tightness of hands and feet and paresthesias resulting from medial or ulnar nerve compression, may alarm the patient but have little prognostic signifi cance.

SignsSigns of preeclampsia usually antedate symptoms. The most common sequence is increased blood pressure followed by proteinuria.18

BLOOD PRESSURE CHANGEAn increase in blood pressure is required for the diagnosis of

preeclampsia. Blood pressure variation in normal pregnancy can

100

90

80

70

60

50

40

30

10 20 30 40 45

Per

cent

ages

sur

vivi

ng

Years

FIGURE 35-3 Eclampsia survivorship. Survival times are plotted for women with eclampsia in the fi rst pregnancy (solid line) and those with eclampsia in a later pregnancy (dashed line). Survival of women with fi rst-pregnancy eclampsia was not different from survival of a control group. (From Chesley LC, Annitto JE, Cosgrove RA: The remote prognosis of eclamptic women: Sixth periodic report. Am J Obstet Gynecol 124:446, 1976, Courtesy of the American College of Obstetricians and Gynecologists.)

TABLE 35-3 SIGNS AND SYMPTOMS OF PREECLAMPSIA OR ECLAMPSIA

Cerebral Blurred vision Headache Amaurosis Dizziness Gastrointestinal Tinnitus Nausea Drowsiness Vomiting Change in respiratory rate Epigastric pain Tachycardia Hematemesis Fever RenalVisual Oliguria Diplopia Anuria Scotomata Hematuria

Hemoglobinuria

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lead to misdiagnosis. In clinical practice, the serious effects of pre-eclampsia on the mother and fetus warrant such overdiagnosis. The primary pathophysiologic alteration, poor tissue perfusion resulting from vasospasm, is revealed more by blood pressure changes than by absolute blood pressure levels. Although a diagnosis of preeclampsia is not made without absolute blood pressure increases to 140 mm Hg systolic or 90 mm Hg diastolic, women who reach this level from a low early pregnancy value typically manifest more vasospasm than those for whom 140/90 mm Hg represents a smaller increase.

Although maternal and fetal risks rise with increasing blood pres-sure,95 serious complications can occur in women who experience only modest blood pressure elevation. In two series, 20% of women with eclampsia never had a systolic blood pressure above 140 mm Hg.18,96 In a large, prospective study from the United Kingdom, there were 383 confi rmed cases of eclampsia, of which 77% were hospitalized before seizures occurred. Of these, 38% of the cases were not preceded by documented proteinuria or hypertension.97 Others have noticed similar fi ndings.98,99

PROTEINURIAAmong the diagnostic signs of preeclampsia, proteinuria in the

presence of hypertension is the most reliable indicator of fetal jeopardy. In two studies of preeclampsia, the perinatal mortality rate tripled for women with proteinuria,100 and the amount of proteinuria correlated with increased perinatal mortality rate and the number of growth-restricted infants.101 A later study demonstrated that the risk for delivering a small-for-gestational-age fetus was higher in women with hypertension and proteinuria (52%) compared with women with new-onset gestational hypertension (15%) or chronic hypertension (12%). The perinatal mortality rate was fourfold higher with proteinuria and hypertension than in pregnancies complicated by hypertension alone.102

RETINAL CHANGESRetinal vascular changes on funduscopic examination occur in

retinal arterioles in at least 50% of women with preeclampsia, and they are important because they correlate best with renal biopsy-proven changes of preeclampsia.103 Localized retinal vascular narrowing is visualized as segmental spasm, and the generalized narrowing is indi-cated by a decrease in the ratio of arteriolar-venous diameter from the usual 3 : 5 to 1 : 2 or even 1 : 3. It can occur in all vessels or, in early stages, in single vessels.104 Preeclampsia does not cause chronic arterio-lar changes; the presence of arteriolar sclerosis detected by increased light refl ex, copper wiring, or arteriovenous nicking indicates preexist-ing vascular disease.

HYPERREFLEXIAAlthough hyperrefl exia is given much clinical attention and deep

tendon refl exes are increased in many women before seizures, convul-sions can occur in the absence of hyperrefl exia,68 and many pregnant women are consistently hyperrefl exic without being preeclamptic. Changes, or lack thereof, in deep tendon refl exes are not part of the diagnosis of preeclampsia.

OTHER SIGNSOther signs that occur less commonly in preeclampsia are indica-

tors of involvement of specifi c organs in the preeclamptic process. Women with marked edema may have ascites and hydrothorax, and those with congestive heart failure display increased neck vein disten-tion, gallop rhythm, and pulmonary rales. Hepatic capsular distention, manifested by hepatic enlargement and tenderness, is a particular concern, as is disseminated intravascular coagulation (DIC) suffi cient to cause petechiae or generalized bruising and bleeding.

Laboratory FindingsMajor changes revealed by laboratory studies occur in severe pre-eclampsia and eclampsia. In the patient with mild preeclampsia, changes in most of these indicators may be minimal or absent.

RENAL FUNCTION STUDIESSerum Uric Acid Concentration and Urate Clearance. Uric

acid is the most sensitive laboratory indicator of preeclampsia available to clinicians. A decrease in uric acid clearance precedes a measurable decrease in the glomerular fi ltration rate (GFR). Hypertension with hyperuricemia but without proteinuria was associated with growth restriction as commonly as hypertension and proteinuria without ele-vated uric acid in one series.105 Although increased serum uric acid concentration is often attributed to altered renal function, an alterna-tive view favors increased production caused by oxidative stress.106 An elevated uric acid level may itself have pathogenic effects.107 Table 35-4 shows normal uric acid levels during gestation and levels associated with preeclampsia.

Serum Creatinine Concentration and Creatinine Clearance. Creatinine clearance is decreased in most patients with severe pre-eclampsia, but it can be normal in women with mild disease. Serial serum creatinine determinations may indicate decreased clearance, but single values are not helpful unless markedly elevated because of the wide range of normal values. The serum creatinine concentration varies as a geometric function of creatinine clearance so that small changes in glomerular fi ltration are best determined by measurements of creatinine clearance.

TABLE 35-4 PLASMA URATE CONCENTRATIONS IN NORMOTENSIVE AND HYPERTENSIVE PREGNANT WOMEN

Weeks of Gestation

Normotensive Patients Hypertensive Patients

mmol/L SD* mg/dL mmol/L SD* mg/dL

24-28 0.18 (20%) 3.02 0.24 (20%) 4.0329-32 0.18 (35%) 3.02 0.28 (25%) 4.733-36 0.20 (30%) 3.36 0.30 (20%) 5.0437-40 0.26 (20%) 4.4 0.31 (23%) 5.2841-42 0.25 (24%) 4.2 0.32 (12%) 5.38

*Each number in parentheses is the standard deviation given as a percentage of the mean values shown. Values for hypertensive and normotensive

women are statistically different at all gestational ages (P < .05).

Modifi ed from Shuster E, Weppelman B: Plasma urate measurements and fetal outcome in preeclampsia. Gynecol Obstet Invest 12:162, 1981.

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LIVER FUNCTION TESTSAlthough most tests of liver function are not highly predictive of

severity of preeclampsia,18 the association between microangiopathic anemia and elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) carries an especially disturbing prognosis for the mother and infant.19,108 These fi ndings usually correlate with the severity of disease and, when associated with hepatic enlargement, may be a sign of impending hepatic rupture.

COAGULATION FACTORSAlthough overt DIC is rare, subtle evidence of activation of the

coagulation cascade occurs in many women with preeclampsia. The average platelet count in the patient with mild preeclampsia is similar to the platelet count in normal pregnant women.109 However, careful platelet counts performed sequentially may reveal decreased platelets in many patients.110 Highly sensitive indicators of activation of the clotting system, reduced serum concentrations of antithrombin III,111 a decrease in the ratio of factor VIII bioactivity to factor VIII antigen,112 and subtle indicators of platelet dysfunction, including alteration of turnover,6 activation,113 size,114 and content,115 exist in even mild pre-eclampsia and may antedate clinically evident disease.

METABOLIC CHANGESPreeclampsia is characterized by an increase in the insulin resis-

tance of normal pregnancy. Signs of the insulin resistance syndrome are exaggerated.110 Levels of circulating lipids already elevated in normal pregnancy116 are accentuated in women with preeclampsia.117 Triglycerides and fatty acid levels are elevated, changes that antedate clinically evident disease by weeks to months.118,119 Levels of the car-dioprotective HDL cholesterol are reduced in preeclamptic women,120 whereas levels of a variant of LDL cholesterol (i.e., small, dense cho-lesterol that is strongly associated with cardiovascular disease) are increased.121,122 These changes resolve after delivery.

Pathologic Changes in PreeclampsiaThe pathologic changes found in organs of women dying of eclampsia and in biopsy specimens from women with preeclampsia provide strong evidence that preeclampsia is not merely an unmasking of essential hypertension or a variant of malignant hypertension. These fi ndings also indicate that the elevation of blood pressure probably does not have primary pathogenetic importance.

BrainCerebral edema, once thought to be a common fi nding in women dying of eclampsia, was uncommon among postmortem examinations performed within 2 to 3 hours of death.123 However, studies using computed tomography again raised the possibility that cerebral edema is an important pathophysiologic event in some women with pre-eclampsia.124 Noninvasive studies of cerebral blood fl ow and resistance suggest that vascular barotrauma and loss of cerebral vascular auto-regulation contribute to the pathogenesis of cerebral vascular pathol-ogy in cases of preeclampsia or eclampsia.125

LiverGross lesions of the liver are visible in about 60% of women dying of eclampsia, and one third of the remaining livers are microscopically abnormal. Many early investigators thought that the hepatic changes were pathognomonic for eclampsia,126 but similar changes have been described in women dying of abruptio placentae.127

Two temporally and etiologically distinct hepatic lesions have been described.123 Initially, hemorrhage into the hepatic cellular columns

results from vasodilatation of arterioles, producing dislocation and deformation of the hepatocytes in their stromal sleeves (Fig. 35-4). Later, intense vasospasm causes hepatic infarction, ranging from small to large areas beginning near the sinusoids and extending into the area near the portal vessels (Fig. 35-5). Hemorrhagic changes are present in 66% and necrotic changes in 40% of eclamptic women and in about one half as many preeclamptic women. Hyalinization and thrombosis of hepatic vessels have been cited as evidence of DIC, but they may be the result of hemorrhage.

KidneyThe pathologic renal changes of preeclampsia and eclampsia are clearly different from those seen in other hypertensive or renal disorders.

FIGURE 35-4 Hemorrhagic hepatic lesions in eclampsia. Hemorrhage into the periportal area occurred with crescentic compression of liver cells. (From Sheehan HL, Lynch JB: Pathology of Toxemia in Pregnancy. London, Churchill Livingstone, 1973.)

FIGURE 35-5 Hepatic infarction in eclampsia. Hepatic infarction caused by intense vasospasm manifests as small to large areas beginning near the sinusoids and extending into the area near the portal vessels. (From Sheehan HL, Lynch JB: Pathology of Toxemia in Pregnancy. London, Churchill Livingstone, 1973.)

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Glomerular, tubular, and arteriolar changes have been described. The glomerular lesion is considered by some to be pathognomonic of pre-eclampsia and eclampsia, but identical changes have been seen in pla-cental abruption without evident preeclampsia.128 This change is not seen in any other form of hypertension.

GLOMERULAR CHANGESChanges seen by light microscopy in glomeruli that are character-

istic of preeclampsia include103 decreased glomerular size, with protru-sion of the glomerular tuft into the proximal tubule. The diameter of the glomerular capillary lumen is decreased and contains few blood cells. The endothelial-mesangial cells have increased cytoplasmic volume and can contain lipoid droplets (Fig. 35-6).

Electron microscopic examination of glomeruli provides more evi-dence that the primary pathologic change occurs in endothelial cells, which are greatly increased in size and can occlude the capillary lumen; their cytoplasm contains electron-dense material.129 The basement membrane bordering the epithelial cell may be slightly thickened, and it also contains electron-dense material. The epithelial cell podocytes are not altered (Fig. 35-7). These changes are collectively called glo-merular capillary endotheliosis.

Characteristic glomerular changes occur in 70% of primiparas but in only 14% of multiparas with a diagnosis of preeclampsia.17 The more likely the diagnosis of preeclampsia, the more common the glo-merular lesion. As the clinical condition worsens, the magnitude of the glomerular lesion increases. The glomerular lesions are reversible after delivery and are not present in subsequent biopsy specimens obtained 5 to 10 weeks later.103

The glomerular changes correlate more consistently with protein-uria than with hypertension, suggesting that proteins identifi ed immu-nohistochemically may be trapped in the glomerulus. These staining patterns are not found in other renal disorders with proteinuria. The glomerular changes of preeclampsia can be mimicked in animal studies by reducing the renal concentration of vascular endothelial growth factor (VEGF), which usually exists in high concentration in this tissue by increasing the synthesis of the VEGF antagonist soluble Fms-like tyrosine kinase 1 (sFlt1).130

NONGLOMERULAR CHANGESPathologic changes in renal tubules include dilatation of proximal

tubules with thinning of the epithelium,123 tubular necrosis,103 enlarge-ment of the juxtaglomerular apparatus,131 and hyaline deposition in renal tubules.123 Fat deposition in women with prolonged heavy pro-teinuria has been reported.123 Necrosis of the loop of Henle, a change that correlates with the degree of hyperuricemia, has also been described.131

Thickening of renal arterioles may be seen in preeclampsia, espe-cially in women with preexisting hypertension. Unlike the glomerular

FIGURE 35-6 Glomerular changes in preeclampsia are identifi ed by light microscopy. The enlarged glomerulus completely fi lls Bowman’s capsule. Diffuse edema of the glomerular wall is indicated by the vacuolated appearance. The visible capillary loops are extremely narrow, and there are virtually no red blood cells in the capillary tuft.

EN

BM

R

Ep Cy

BS R

En

En

Ep

P

A

B

FIGURE 35-7 Electron photomicrographs of renal glomeruli. A, Normal anatomy. B, Biopsy specimen from a preeclamptic woman. Endothelial cells (En) are markedly enlarged, obstruct the capillary lumen, and contain electron-dense inclusions. The basement membrane (BM) is slightly thickened with inclusions, but the epithelial foot processes (EP) are normal. BM, basement membrane; BS, Bowman’s space; Cy, cytoplasmic inclusions; EN, capillary endothelial cells that line the glomeruli; Ep, renal epithelial cells; L, capillary lumen containing red blood cells; P, podocytes; R, red blood cell. (From McCartney CP: Pathological anatomy of acute hypertension of pregnancy. Circulation 30[Suppl II]:37, 1964. By permission of the American Heart Association, Inc.)

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lesion, it does not regress after delivery,103 suggesting that the arteriolar change results from coincident disease, not preeclampsia.

Vascular Changes in the Placental SiteThe characteristic changes in the decidual vessels supplying the pla-cental site in normal pregnancy are depicted in Figure 35-8. In normal pregnancy, the spiral arteries (Fig. 35-9) increase greatly in diameter.132 Morphologically, the endothelium is replaced by trophoblast, and the internal elastic lamina and smooth muscle of the media are replaced by trophoblast and an amorphous matrix-containing fi brin (see Fig. 35-9).133 These changes occur originally in the decidual portion of the spiral arteries but extend into the myometrium as pregnancy advances and can even involve the distal portion of the uterine radial artery. The basal arteries are not affected. These morphologic changes are considered to be a vascular reaction to the trophoblast, occurring directly or humorally, that results in increased perfusion of the placen-tal site.

In placental-site vessels of women with preeclampsia, the normal physiologic changes do not occur, or they are limited to the decidual portion of the vessels. Myometrial segments of spiral arteries retain the nonpregnant component of intima and smooth muscle, and the diam-eter of these arteries is about 40% that of vessels in normal preg-nancy.134 Spiral arterioles in decidua and myometrium and basal and radial arterioles may become necrotic, with components of the normal vessel wall replaced by amorphous material and foam cells, a change called acute atherosis (Fig. 35-10).135 This lesion is best seen in the basal arteries because they do not undergo the normal changes of pregnancy. It is also present in decidual and myometrial spiral arteries and can progress to vessel obliteration. The obliterated vessels correspond to areas of placental infarction.

Failed vascular remodeling and atherotic changes may be seen with fetal growth restriction in women without clinical evidence of preeclampsia. Atherotic changes occur in decidual vessels of some dia-betic women,136 and failed vascular remodeling is present in about one third of women who experience preterm labor.137 It appears that abnormal invasion may be necessary but is not suffi cient to cause preeclampsia.

Myo

met

rium

Spinal

Basal

Radial

Arcuate

End

omet

rium

FIGURE 35-8 Schematic representation of uterine arteries. The characteristic changes occur in the decidual vessels supplying the placental site in a normal pregnancy. (From Okkels H, Engle ET: Studies of the fi ner structure of the uterine vessels of the Macacus monkey. Acta Pathol Microbiol Scand 15:150, 1938.)

A

B

FIGURE 35-9 Spiral arterial changes in normal pregnancy. A, In the section of spiral arterioles at the junction of the endometrium and myometrium in a nonpregnant woman, notice the inner elastic lamina and smooth muscle. B, In a section of a spiral arteriole at the same scale and from the same location during pregnancy, notice the markedly increased diameter and absence of inner elastic lamina and smooth muscle. (From Sheppard BL, Bonnar J: Uteroplacental arteries and hypertensive pregnancy. In Bonnar J, MacGillivray I, Symonds G [eds]: Pregnancy Hypertension. Baltimore, University Park Press, 1980, p 205.)

F

FIGURE 35-10 Atherosis. Numerous lipid-laden cells (L) and fi brin deposition (F) are present in the media of this occluded decidual vessel. (From Sheppard BL, Bonnar J: Uteroplacental arteries and hypertensive pregnancy. In Bonnar J, MacGillivray I, Symonds G [eds]: Pregnancy Hypertension. Baltimore, University Park Press, 1980, p 205.)

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Changes characteristic of preeclampsia have been observed in the decidual vessels of one in seven primiparous women and in a lower percentage of multiparous women at the time of fi rst-trimester abor-tion.138,139 These fi ndings suggest that disordered placentation precedes the clinical presentation of preeclampsia. The cause of the decidual vascular lesions is unknown. The appearance of the atherotic vessels resembles vessels in transplanted kidneys that have undergone rejec-tion, suggesting an immunologic cause, which is consistent with fi nd-ings of a study that demonstrated components of complement (e.g., C3) in decidual vessels with the lesion.140

The vascular remodeling of spiral arteries supplying the intervillous space is intimately related to normal trophoblast invasion.141 The expression of adhesion molecules and their receptors that characterizes implantation is abnormal in preeclampsia.142 The trophoblast that lines the decidual vessels of normal pregnant women begins to express molecules usually present only on endothelium,143 a phenomenon that does not occur in preeclampsia.144 Potential mechanisms responsible for the normal and abnormal changes include decidually produced cytokines145-147 and local oxygen tension.148,149 There may be interac-tions of specifi c molecules on trophoblast and maternal decidual cells that drive invasion. Invasive cytotrophoblasts express a human leuko-cyte antigen (HLA) molecule (HLA-C) that is minimally hetero-geneous. Interaction of this molecule with a receptor on maternal decidual cells, killer immunoglobulin receptors (KIRs), causes various degrees of activation of the trophoblast cell, depending on the combi-nation of KIR and HLA-C subtypes. Mothers with the minimally acti-vating KIR subtype who have a fetus with a specifi c HLA-C subtype (HLA-C2) have an increased frequency of preeclampsia. This is not an immune interaction because the relationship persists regardless of maternal HLA-C subtype. Researchers propose that this combination does not favor trophoblast invasion and vascular remodeling. Popula-tion studies indicate that populations in which HLA-C2 is common have a reduced frequency of the specifi c inhibitory KIR subtype and vice versa.150

Placental Pathologic ChangesUltrastructural examination of placentas from women with pre-eclampsia reveals an abnormal syncytiotrophoblast containing areas of cell death and degeneration. Viable-appearing syncytiotrophoblast is also abnormal, with decreased density of microvilli, dilated endoplas-mic reticulum, and decreased pinocytotic and secretory activity. The cells of the villous cytotrophoblast cells are increased in number and have higher mitotic activity. The basement membrane of the tropho-blast is irregularly thickened, with fi ne fi brillary inclusions.151

The changes may be caused by local hypoxia. Similar syncytiotro-phoblastic changes are present in placental segments maintained under hypoxic conditions in vitro.152 The cytotrophoblastic alterations are also consistent with hypoxia. The cytotrophoblasts comprise the stem cells of the trophoblast and responds to damage by proliferation. The trophoblast of the preeclamptic placenta is characterized by increased apoptosis and necrosis,153,154 possibly caused by hypoxia or hypoxia reperfusion injury,155 and this may be the origin of the increased cir-culating syncytiotrophoblast microparticles in preeclampsia.156

Summary of Pathologic Changes

in PreeclampsiaStructural changes associated with preeclampsia and eclampsia lead to two important conclusions. First, preeclampsia is not an alternate form of malignant hypertension. The renal changes in preeclamptic and eclamptic women and the structural changes in other organs of women dying of eclampsia differ from the alterations caused by malignant

hypertension. Second, the pathologic fi ndings indicate that the primary pathology is poor tissue perfusion, not blood pressure elevation. The histologic data support the clinical impression that the poor perfusion results from profound vasospasm, which increases total peripheral resistance and blood pressure.

Pathophysiologic Changes in PreeclampsiaPreeclampsia can cause changes in virtually all organ systems. Several organ systems are consistently and characteristically involved, and these are discussed in the following sections.

Cardiovascular ChangesBlood pressure is the product of cardiac output and systemic vascular resistance. Cardiac output is increased by up to 50% in normal preg-nancy, but blood pressure does not usually increase, indicating that systemic vascular resistance decreases. Blood pressure is lower in the fi rst half of pregnancy than in the postpartum period, when cardiac output returns to nonpregnant levels (see Fig. 35-2). Some women destined to develop preeclampsia have a higher cardiac output before clinically evident disease. However, cardiac output is reduced to pre-pregnancy levels with the onset of clinical preeclampsia.157,158 Although some studies suggest increased cardiac output,159 most have found normal or slightly reduced cardiac output in women with untreated preeclampsia.160 Increased systemic vascular resistance is the mecha-nism for the increase in blood pressure in clinical preeclampsia.

There is substantial evidence that arteriolar narrowing occurs in preeclampsia. Changes in the caliber of retinal arterioles correlate with the clinical severity of the disorder and with renal biopsy-confi rmed diagnosis of preeclampsia.103 Similar fi ndings occur in vessels of the nail bed and conjunctiva. Measurements of forearm blood fl ow indi-cate higher resistance in preeclamptic than in normal pregnant women.161,162 It is unlikely that this effect is determined by the auto-nomic nervous system. Although normal pregnant women are exqui-sitely sensitive to the interruption of autonomic neurotransmission by ganglionic blockade and high spinal anesthesia, preeclamptic women are less sensitive.163 This fi nding suggests that the arteriolar constric-tion of preeclampsia is not maintained by the autonomic nervous system and that humoral factors are implicated. The increased sympa-thetic activity in preeclampsia, however, raises questions about these older fi ndings.164 Assays of concentrations of recognized endogenous vasoconstrictors are limited to determinations of catecholamines and angiotensin II. Results suggest minimal or no change in catechol-amines, whereas circulating angiotensin II concentrations are lower in preeclamptic women.165

Levels of endothelin-1, a vasoconstrictor produced by endothelial cells, are increased in the blood of preeclamptic women166 at concen-trations much lower than those necessary to stimulate vascular smooth muscle contraction in vitro. It is not clear whether these circulating concentrations refl ect endothelial production suffi cient to stimulate local vasoconstriction or low concentrations of endothelin potentiate contractile responses to other agonists.

As indicated by the older term toxemia, early investigators sus-pected that preeclampsia was caused by circulating humors. Early reports suggesting etiologic agents such as pressor substances in blood, decidual extracts, placental extracts, and amniotic fl uid of preeclamp-tic patients have not been replicated. The explanation for the pressor effects was, in some studies, normal endogenous pressors; in others, the explanation was faulty methodology and failure to recognize the immunologic difference between the source of the extract and the

Ch035-X4224.indd 661 8/26/2008 4:05:42 PM


animals tested. In other experiments, no defect is obvious. The hypoth-esis that arteriolar constriction of preeclampsia is caused by new cir-culating pressors has largely been abandoned.18

A more compelling explanation for vasospasm in preeclampsia is increased response to normal concentrations of endogenous pressors. Women with preeclampsia have higher sensitivity to all the endoge-nous pressors that have been tested. They are exquisitely sensitive to vasopressin.167,168 Vasopressin can elicit marked blood pressure eleva-tion, seizures, and oliguria in some patients.168 Sensitivity to epineph-rine169 and norepinephrine170 is also increased (Fig. 35-11). The most striking difference is seen in the sensitivity of the preeclamptic woman to angiotensin II. Normal pregnant women are less sensitive to angio-tensin II than nonpregnant women, requiring approximately 2.5 times as much angiotensin to raise the blood pressure by a similar incre-ment.171 In contrast, preeclamptic women are much more sensitive to angiotensin II than are normal pregnant and nonpregnant women (Fig. 35-12).170

In a classic study, angiotensin II sensitivity was signifi cantly increased many weeks before the development of elevated blood pres-sure (Fig. 35-13).172 Although resistance to angiotensin II does not decrease to nonpregnant levels until 32 weeks’ gestation, signifi cant differences in sensitivity between women who later become hyperten-sive and those who remain normotensive have been observed as early as 14 weeks. However, a large British study did not confi rm this classic fi nding,173 perhaps refl ecting the heterogeneity of preeclampsia.174

The decreased sensitivity of normal pregnant women to angioten-sin II and the lower systemic vascular resistance in normal pregnancy suggest that arteriolar narrowing in preeclamptic women may result from decreased levels of circulating or local vasodilator substances, rather than from increased levels of circulating pressors. This attractive hypothesis, however, is not consistent with the unchanged sensitivi-ties to norepinephrine, epinephrine, and vasopressin in normal pregnancy.168-170

Coagulation ChangesThe syndrome of DIC occurs in preeclampsia and has been suggested as a primary pathogenetic factor175 (see Chapter 40). Activation of the

coagulation system manifests as the intravascular disappearance of procoagulants, intravascular appearance of degradation products of fi brin, and end-organ damage from the formation of microthrombi.176 In the most advanced form of DIC, procoagulants—especially fi brino-gen and platelets—decrease to a degree suffi cient to produce spontane-ous hemorrhage. In milder forms, only highly sensitive indicators of clotting system activation are present. Decreasing platelet concentra-tions is such a sign but may be evident only by serial observations.96 Sensitive indicators of intravascular coagulation, such as an elevated

PreeclampsiaNonpregnantNormal pregnancy

Dose, ng/kg

� M

BP,

mm

Hg

5 10 15 25 50 100 200

10

20

30

40

50

FIGURE 35-11 Mean dose-response graphs for norepinephrine. Women with preeclampsia have an increased sensitivity to all endogenous pressors. MBP, mean blood pressure. (From Talledo OE, Chesley LC, Zuspan FP: Renin-angiotensin system in normal and toxemic pregnancies. III. Differential sensitivity to angiotensin II and norepinephrine in toxemia of pregnancy. Am J Obstet Gynecol 100:218, 1968. Courtesy of the American College of Obstetricians and Gynecologists.)

50

40

30

20

10

5 10 15 25 50 100 200

PreeclampsiaNonpregnantNormal pregnancy

� M

BP,

mm

Hg

Dose, ng/kg

FIGURE 35-12 Mean dose-response graphs for angiotensin. Preeclamptic women are much more sensitive to angiotensin II than normal pregnant and nonpregnant women. MBP, mean blood pressure. (From Talledo OE, Chesley LC, Zuspan FP: Renin-angiotensin system in normal and toxemic pregnancies. III. Differential sensitivity to angiotensin II and norepinephrine in toxemia of pregnancy. Am J Obstet Gynecol 100:218, 1968. Courtesy of the American College of Obstetricians and Gynecologists.)

16

12

8

4 10 14 18 22 26 28 30 32 34 36 38 40

Weeks of gestation

ng/k

g/m

in

P<.05 P<.1

P<.01

P<.001

Nonpregnant mean

FIGURE 35-13 Angiotensin sensitivity throughout pregnancy. The dose of angiotensin II necessary to increase diastolic blood pressure 20 mm Hg in women who developed elevated blood pressure in late pregnancy (blue line, open circles) was compared with the dose for those who remained normotensive (red line, solid circles). The graph demonstrates that a signifi cantly lower dose was required in the former group as early as 10 to 14 weeks’ gestation. (From Gant NF, Daley GL, Chand S, et al: A study of angiotensin II pressor response throughout primigravid pregnancy. J Clin Invest 49:82, 1973. With permission of the American Society for Clinical Investigation.)

Ch035-X4224.indd 662 8/26/2008 4:05:42 PM


level of fi brin degradation products; increased platelet turnover,6 volume,114 and activation177; reduced platelet content178; increased platelet content in plasma179; reduced levels of antithrombin III111; and a reduced ratio of factor VIII activity to factor VIII antigen,180 are common when concentrations of procoagulants remain normal. Subtle signs of platelet dysfunction,6,114,177-179 reduced antithrombin III,111 and reduction in the ratio of factor VIII bioactivity to factor VIII antigen112 are present in women with mild preeclampsia and may precede its clinical signs.

Abnormalities of blood coagulation suffi cient to make a diagnosis of DIC are present in approximately 10% of women with severe pre-eclampsia or eclampsia.181 Results of highly sensitive assays of coagula-tion activation suggest, however, that abnormalities of the coagulation system are present in many patients with mild to moderate preeclamp-sia. Coagulation changes are thought to be secondary rather than primary pathogenetic factors182 because levels of procoagulants are usually normal, and another early sign of preeclampsia—increased serum uric acid—may precede changes in coagulation.110

The cause of the change in coagulation factors is uncertain. Vascu-lar damage resulting from vasospasm may initiate DIC182 and probably contributes to activation of the clotting system in severe preeclampsia. Signs of endothelial dysfunction also antedate clinical disease,183 and activation of platelets and other components of the coagulation cascade is a well-recognized consequence of endothelial dysfunction.184 Vascu-lar changes in the implantation site that appear to antedate blood pressure elevation may be pathogenetically important.

Whether coagulation changes measured in preeclamptic patients represent true DIC or a localized consumption of procoagulants in the intervillous space is not clear. Microthrombi and the presence of fi brin antigen have been inconsistently observed in liver, placenta, and kidney.185-187 Early coagulation changes such as factor VIII activity-antigen ratios and platelet count correlate better with the fetal outcome as measured by mortality and growth restriction rates than with the clinical severity of preeclampsia. Identical coagulation changes occur in normotensive women with growth-restricted fetuses,188 suggesting that localized coagulation in the intervillous space is important. Simi-larly, an increased concentration of fi brin antigen has been reported in the placentas of preeclamptic patients.185

Endothelial Cell DysfunctionThere is increasing support for endothelial dysfunction as a patho-physiologic component of preeclampsia.183,189,190 Alterations of glo-merular endothelial cells are a consistent feature of preeclampsia. Levels of cellular fi bronectin,191,192 growth factors,193 vascular cell adhe-sion molecule 1 (VCAM-1),194 factor VIII antigen, and peptides released from injured endothelial cells are increased in preeclamptic women before the appearance of clinical disease.112 Examination showed that the endothelial function of vessels of preeclamptic women was impaired in vitro.195,196

The endothelium is a complex tissue with many important func-tions. Prevention of coagulation and modulation of vascular tone have special relevance to preeclampsia. Intact vascular endothelium is resis-tant to thrombus formation.197 With vascular injury, endothelial cells can initiate coagulation by the intrinsic pathway (i.e., contact activa-tion)198 or by the extrinsic pathway (i.e., tissue factor).199 Platelet adhe-sion can also occur after injury with exposure of subendothelial components, such as collagen200 and microfi brils.

Endothelium profoundly infl uences the response of vascular smooth muscle to vasoactive agents. The response to some agents201 can change from dilation to constriction with the removal of endothe-lium. Prostacyclin, a highly potent vasodilator, is produced by endo-

thelium. Vessels from preeclamptic women and the umbilical vessels of their neonates generate less prostacyclin than similar vessels from normal pregnant women.202-204 If potent inhibitors preventing the syn-thesis of all prostaglandins (including prostacyclin) are administered to pregnant women, the usual resistance to the vasoconstrictor effect of angiotensin II is abolished.205 Conversely, if aspirin is used as an inhibitor of prostaglandin synthesis in a manner determined to specifi -cally reduce contractile prostanoids (e.g., thromboxane A2) much more than prostacyclin, the increased angiotensin II sensitivity of preeclamp-tic women is reduced.206

Nitric oxide (NO) is another bioactive material produced by normal endothelium.207 Its release is stimulated by several hormones and neu-rotransmitters and by hydrodynamic shear stress. NO is quite labile and acts synergistically with prostacyclin as a local vasodilator and inhibitor of platelet aggregation. Current thinking favors NO as an endogenous vasodilator of pregnancy. Administration of inhibitors of NO synthesis reduces blood fl ow much more strikingly in pregnant than in nonpregnant women.208 Production of NO is reduced with endothelial cell injury. Information about NO production in pre-eclampsia is confl icting,209-214 in part because of the use of blood con-centrations of NO metabolites to determine production in the setting of the reduced renal function of preeclampsia.215 Two studies have documented reduced urinary NO excretion in preeclampsia,212,216 and another found increased excretion.217 Perhaps the most compelling data are from estimates of the tissue concentrations of nitrotyrosine (i.e., product of the interaction of NO and superoxide). Nitrotyrosine residues are increased in the placenta218 and vessels219 of women with preeclampsia. It is posited that the placenta directly or indirectly pro-duces factors that alter endothelial function. Candidate molecules include the following:

� Cytokines220 (with increasing evidence that endothelial dysfunction is part of a generalized increased infl ammatory response221)

� Placental fragments (i.e., syncytiotrophoblast microvillous membranes)222

� Free radicals� Reactive oxygen species223

The latter hypothesis—that oxidative stress causes endothelial dysfunction—is especially interesting in view of the similarities of the lipid changes of preeclampsia to those of atherosclerosis,118 an endothelial disorder in which oxidative stress is thought to play a key role.224

The information available indicates that endothelial cell dysfunc-tion can alter vascular responses and intravascular coagulation in a manner consistent with the pathophysiologic abnormalities of pre-eclampsia. Evidence is accumulating that endothelial injury may play a central role in the pathogenesis of preeclampsia.

Renal Function ChangesRenal function changes characteristic of women with preeclampsia or eclampsia include decreased glomerular fi ltration and proteinuria. Changes in components of the renin-angiotensin system probably differ from those of normal pregnancy. Sodium excretion is decreased, resulting in fl uid retention and edema.

GLOMERULAR FUNCTIONAL CHANGESGlomerular Filtration Rate. Decreased glomerular fi ltration fre-

quently complicates preeclampsia, and it is explained only partially by decreased renal plasma fl ow (RPF). The fi ltration fraction (GFR/RPF)

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may be decreased18 because of intrarenal redistribution of blood fl ow.225 A more obvious explanation is glomeruloendotheliosis, in which the occlusion of glomerular capillaries by swollen endothelial cells probably renders many glomeruli nonfunctional.

Protein Leakage. The pathogenesis of proteinuria in preeclamp-sia is primarily explained by glomerular changes. The normal absence of protein in urine results from a relative impermeability of glomeruli to large protein molecules and from the tubular resorption of smaller proteins that cross the glomeruli. As glomerular damage occurs, per-meability to proteins increases. As damage increases, so does the size of the protein molecule that can cross the glomerular membrane. Increased permeability results in decreased selectivity. With minimal glomerular damage or tubular dysfunction, only small protein mole-cules are excreted, but with greater damage, large and small proteins are present in urine.

In women with preeclampsia, selectivity is low, indicating increased permeability and glomerular damage.226 The well-known clinical observation that the magnitude of proteinuria in preeclamptic women varies greatly over time was quantitated by Chesley,227 who noticed hourly variation in the urinary creatinine-to-protein ratio in women with preeclampsia that was not present in the urine of individuals with other proteinuric conditions.

Because structural glomerular changes are constant, proteinuria in preeclamptic women must in part depend on a varying functional cause (e.g., a variation in the intensity of the renal vascular spasm). That vascular spasm can cause proteinuria has been demonstrated by measuring urinary excretion of protein in individuals subjected to the cold pressor test. Immersing a patient’s hand in ice water for 60 seconds increases blood pressure by more than 16 mm Hg (systolic and dia-stolic), and an increase in protein excretion almost invariably occurs.228

RENAL TUBULAR FUNCTIONAL CHANGESUric Acid Clearance. Three separate processes are involved in the

renal excretion of urate. Urate is completely fi ltered at the glomerulus. It is not bound to plasma proteins under physiologic conditions,229 and glomerular urate concentration is equal to renal arterial plasma con-centration. Urate is secreted and reabsorbed by renal tubules. Most urate (98%) is reabsorbed, and about 80% of excreted urate is accounted for by urate secretion. Both processes occur predominantly in the proximal tubule. Reabsorption occurs to a greater extent than secre-tion, and urate clearance is about 10% of creatinine clearance.230

Abnormalities of uric acid clearance have long been recognized as a consistent phenomenon in preeclampsia231 and have been regarded as a function of decreased glomerular fi ltration.232 Several studies have demonstrated the discrepancy between uric acid clearance and both inulin clearance and creatinine clearance.233,234 Serial studies also reveal that decreased uric acid clearance precedes decreases in the GFR.235

Urate clearance is decreased by hypovolemia, presumably as a result of nonspecifi c stimulation of proximal tubular reabsorption.236 Plasma volume depletion is coincident with urate clearance changes,237 sug-gesting that volume change may account for the abnormality in urate clearance. However, the correlation between the degree of volume depletion and the decrease in urate clearance is poor.237

Angiotensin II infusion decreases urate clearance even in the pres-ence of normal blood volume.238 The increase in angiotensin II sensi-tivity seen in preeclampsia may account for the change in renal function. Local effects of angiotensin II may also be important because this substance can be produced locally,239 unassociated with increased circulating angiotensin II.

In summary, uric acid clearance changes earlier in preeclamptic pregnancy than does the GFR, suggesting a tubular rather than a glo-merular functional explanation. Although the exact mechanism for the urate clearance change is not established, the common feature in the suggested mechanisms is decreased renal perfusion; however, increased production by poorly perfused tissue cannot be excluded.106,240

Urinary Concentrating Capacity. Although the issue is not fully settled, the tubular concentrating capacity is probably unchanged in normal pregnancies.241 Assali and associates242 suggested that urinary concentrating ability is decreased in hypertensive women. The limita-tions of these studies include the failure to account for parallel changes in the concentrating capacity and GFR243 and the use of specifi c gravity—an unreliable estimate of osmolality—as the measure of concentration.18

Normal pregnant women were found to have decreased capacity to concentrate urine (measured as osmolar concentration and corrected for the GFR) in response to vasopressin administration, a decrease similar to that seen in pregnant women who were or later became hypertensive.244 Confl icting study results suggesting that tubular con-centrating capacity is unchanged in normal pregnancy are confounded by a failure to correct for the increased GFR of normal pregnancy, which concomitantly increases concentrating capacity.243

Excretion of Phenolsulfonphthalein. Because phenolsulfon-phthalein is secreted by proximal tubular cells, its excretion can be used as an indicator of proximal tubular function.235 However, phenolsul-fonphthalein excretion is altered independently of tubular secretory capacity with increased245 or decreased246 renal plasma fl ow or reduced GFR247 and with increased urinary dead space (a problem pertinent in pregnancy). When these factors are controlled, reduced phenolsulfon-phthalein excretion precedes changes in the GFR and clinically evident disease in women with preeclampsia.235

Renin-Angiotensin-Aldosterone System. The renin-angiotensin-aldosterone system (RAAS) is important in pressure and volume regu-lation in normal pregnancy (Fig. 35-14).248 Dramatic changes occur in the RAAS during pregnancy.249 The following components are increased:

� Angiotensinogen (i.e., renin substrate)� Plasma renin activity250

Juxtaglomerularapparatus

STIMULATION

Renin

Renin substrate Angiotensin I

Angiotensin II

Converting enzyme

INHIBITION

Sodium retentionVolume expansion

Intravascular volume decreasedSodium depletion

Pressoreffect

Stimulatesaldosterone secretion

FIGURE 35-14 Schematic representation of the renin-angiotensin system. The system regulates pressure and volume in normal pregnancies, and abnormalities contribute to preeclampsia.

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� Plasma renin concentration� Angiotensin II concentration250,251

� Aldosterone252

Abnormalities of the RAAS have been proposed as causal factors in preeclampsia253 because angiotensin II is a potent vasoconstrictor, it infl uences aldosterone secretion and consequent sodium retention, and at high concentrations, it can cause proteinuria. Myometrium and chorion can synthesize renin, which is stimulated in experimental animals by uterine ischemia.254

Most investigators agree that the angiotensinogen level remains elevated in preeclampsia.250,255 The plasma renin activity and plasma renin concentration are reduced in preeclampsia compared with normal pregnancy.256 In a prospective study of women with chronic hypertension, plasma renin activity was lower when superimposed preeclampsia developed (i.e., diagnostic blood pressure increase and proteinuria) than in chronic hypertensive women without superim-posed preeclampsia and in normal pregnant women. Concentrations were similar in early pregnancy in all groups and decreased only slightly before the increase in blood pressure.257

The reduced renin activity in preeclampsia suggests suppression of renin release. This is puzzling in view of the reduced plasma volume that is characteristic of preeclampsia. There is no apparent nonphysi-ologic suppression of renin activity, because usual physiologic pertur-bations result in appropriately increased and decreased concentrations of plasma renin activity (i.e., renin is increased with upright posture and head-up tilt258 and falls with volume expansion259). Despite the reduced content of the vascular compartment in preeclampsia, the intense vasoconstriction characteristic of preeclampsia results in a physiologic perception of overfi ll, suppressing renin release. The reduced renin activity in preeclampsia results in reduced angiotensin II165 and aldosterone concentrations260 compared with concentrations in normal pregnancy.

Attempts to test the role of the renin-angiotensin system (RAS) by using angiotensin II antagonists or by converting enzyme inhibitors have not clarifi ed this point. Administration of the angiotensin antago-nist (1-Sar-8-Ile-angiotensin II) to pregnant hypertensive women increases blood pressure,261 and because this antagonist is a partial agonist, the increase in blood pressure may refl ect the increased angio-tensin sensitivity of hypertensive pregnant women. The administration of the angiotensin antagonist saralasin262 or the angiotensin-converting enzyme inhibitor SQ 20,881263 in the postpartum period did not have signifi cant effects on blood pressure in a mixed group of women with hypertension.

Interest in the role of the RAS in preeclampsia has increased as the effects of angiotensin on responses other than blood pressure have been recognized.264 The activation of NADPH oxidase in several tissues by angiotensin II can generate oxidative stress.264-266 Hypoxia-inducing factors (HIFs) induce molecules responsible for many of the responses to hypoxia. These factors are upregulated in the placenta of a woman with preeclampsia267 and can be activated by angiotensin II.268 Anti-bodies to angiotensin II that activate angiotensin receptors and likely increase the sensitivity of these receptors to angiotensin II are present in women with preeclampsia.269

Studies indicate that no simple relationship exists between compo-nents of the RAS and preeclampsia. The signifi cance, however, of reduced plasma renin activity, plasma renin concentration, and angiotensin II concentration on blood pressure and sodium excretion in this group of women—who show apparent volume constriction and who are exquisitely sensitive to angiotensin II—deserves elucidation.

Atrial Natriuretic Factor. Atrial natriuretic factor (ANF), a peptide produced in response to atrial stretch with hypervolemia, regu-lates intravascular volume by several mechanisms. ANF increases sodium excretion and the egress of fl uid from the intravascular com-partment. Although the reduced plasma volume of preeclampsia pre-dicts reduced ANF concentration, the concentration is increased,270 and the increase precedes clinical disease.271 The stimulus for this increase is unclear, but the paradoxical fi nding of increased circulating ANF levels and reduced renin concentration with reduced plasma volume in preeclamptic women suggests that the reduced plasma volume is increased relative to the constricted vascular compartment.

Changes in Sodium Excretion. Sodium retention has long been considered an integral part of the pathophysiology of preeclampsia. Women with eclampsia and severe preeclampsia have very little chlo-ride and sodium in the urine.272 After delivery, however, chloride excretion increases dramatically. Infusion of hypertonic saline into preeclamptic women results in excretion of the infused sodium at about one half of the rate seen in normal pregnant women.167 Similar results occur in women with glomeruloendotheliosis identifi ed on renal biopsy.273 Most studies of exchangeable sodium have indicated an increase in total body sodium in preeclamptic patients.274,275

The cause of sodium retention in preeclamptic women is diffi cult to determine because of the enormous number of factors that infl u-ence sodium excretion in normal pregnancy and because of the many demonstrated anomalies of renal function in preeclampsia that can cause sodium retention (Table 35-5). Any or all of the demonstrated changes in plasma volume, angiotensin sensitivity, and renal function may act on several of the factors listed in Table 35-5 to cause sodium retention.

Several investigators have considered the increased sodium reten-tion to be a primary factor inciting the pathogenetic changes in pre-

TABLE 35-5 FACTORS AFFECTING SODIUM BALANCE IN NORMAL PREGNANCY

Factors Affecting Glomerular Filtration

Blood pressure in critical areas of the kidneyRelative tonus of afferent and efferent glomerular arteriolesPlasma oncotic pressureIntrarenal redistribution of blood fl owCentral nervous system effects

Factors Affecting Tubular Reabsorption

AldosteroneProgesterone (an aldosterone antagonist)Renal vascular resistancePerfusion pressure in peritubular capillariesOncotic pressure in peritubular capillariesNon-reabsorbable anions in the fi ltrateVelocity of fl ow in tubulesReabsorptive capacity of tubulesEstrogens (stimulate sodium reabsorption, possibly indirectly, by

effects on vascular permeability)Plasma sodium concentrationHematocrit (viscosity effects)Changes of plasma volumeAngiotensinSympathetic nervous systemPossibly a natriuretic hormone (“third factor”)

Modifi ed from Chesley LC: Hypertensive Disorders in Pregnancy. New

York, Appleton-Century-Crofts, 1978.

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eclampsia. Although this possibility cannot be defi nitely excluded, it is not likely for several reasons:

1. Angiotensin sensitivity precedes obvious fl uid retention by months.

2. Thiocyanate space, an indicator of sodium space, does not reliably predict preeclampsia.276

3. Restriction of dietary sodium or increasing sodium excretion with diuretics does not affect the occurrence of preeclampsia.277-279

SUMMARY OF RENAL FUNCTION CHANGESRenal function changes in preeclampsia are consistent and charac-

teristic. Changes in tubular function precede the more widely appreci-ated changes in glomerular function. These functional changes return to normal within weeks to months after the conclusion of pregnancy. Prospective, sequential studies of renal function indicate that some of these changes antedate the clinical diagnosis of preeclampsia, but they do not necessarily antedate other indicators of preeclampsia such as changes in coagulation and plasma volume. They are therefore unlikely to be causal abnormalities. Although the cause of renal functional changes is not clear, they may be explained by systemic or regional abnormalities of renal perfusion.

Immunologic Changes and Activation of

Infl ammatory ResponsesEpidemiologic and laboratory observations suggest that fetal-maternal immunologic interactions may be etiologically important in the patho-genesis of preeclampsia. The increased incidence of preeclampsia in fi rst pregnancies and the protective effect even of miscarriage suggest that maternal exposure to fetal antigens may be protective, an effect that appears to be lost if the father is not the same man who fathered the prior pregnancy.280,281 The increased risk of preeclampsia with a new father is affected by the interpregnancy interval, which tends to be longer in pregnancies with new fathers. This fi nding is compatible with an immunoprotective effect of antigen exposure, which is also lost when antigen exposure is minimal for a prolonged period.282 Exposure to paternal components of fetal antigen through sexual activity with the potential father before the fi rst pregnancy is also associated with reduced risk of preeclampsia.283,284 The pathologic changes in decidual vessels at the placental site in preeclampsia are similar to the vascular changes of acute immunologic rejection.140

Several immunologic mechanisms have been suggested.285,286 Pre-eclampsia may be an immune complex disease. There is an effl ux of fetal antigen into the maternal circulation during pregnancy. If the maternal antibody response is adequate, the complexes are cleared by the reticuloendothelial system, and no damage occurs. If the antibody response or clearance mechanisms are inadequate,287 the pathologic immune complexes formed can cause vasculitis, glomerular damage, and activation of the coagulation system. An inadequate maternal anti-body response also can be suggested by HLA typing that demonstrates an increased concordance of the major histocompatibility antigens in maternal-paternal pairs that result in preeclamptic pregnancies.286 However, preeclampsia is less common in consanguineous marriages, a fi nding incompatible with this concept.288 Alternatively, the maternal antibody system may be overwhelmed by an excess of fetal antigen, a theory supported by the increased incidence of preeclampsia when trophoblastic tissue is increased (e.g., twins, hydatidiform mole, hydropic placenta). Few data support this concept.

Actual measurements of immune complexes in women with pre-eclampsia are inconsistent because of broadly different methodologies and defi nitions of preeclampsia. Increased immune complexes are a

feature of normal pregnancy, with further increases in women with mild preeclampsia and signifi cant elevations observed in women with severe preeclampsia.289

Another hypothesis about the immunologic cause of preeclampsia is that vascular changes in the spiral arterioles of the placental implan-tation site are the result of an allograft rejection between mother and fetus. However, who is rejecting whom?286 Should the spiral arteries lined with trophoblast be thought of as fetal vessels, with the fetus rejecting the mother, or as maternal vessels, with the mother rejecting the fetus?

If preeclampsia represents a rejection of the fetus by the mother, the protective effect of previous exposure to antigen indicates that the preeclamptic mother has a defi cit of blocking antibodies or of suppres-sor cell function. The recognition of a unique HLA antigen, HLA-G, on the trophoblast290 suggests other possible causes of rejection of the fetus. HLA-G is a class I antigen present almost exclusively on the cytotrophoblast with minimal heterogeneity. Unlike classic HLA anti-gens, which exhibit numerous epitopes, fetal HLA-G in the trophoblast is likely to be identical in most fetuses, and the fetus would exhibit the same antigen as that expressed by the mother during her fetal life. Because an immune cell (i.e., natural killer lymphocyte) found in maternal decidua in high numbers is postulated to destroy cells not bearing HLA antigens, a reduced level of HLA-G may render the fetus a target for these cells. Unusual epitopes of HLA-G also can activate maternal immune defenses. Although there are suggestions that poly-morphisms of HLA-G may be more common in preeclampsia,291 the data are minimal, and fi ndings are not universally accepted.292

If preeclampsia represents a rejection of the mother by the fetus, the preeclamptic mother would have to be defi cient in the capacity to destroy fetal immune cells. These alternative hypotheses—one requiring active intervention and the other passive intervention by the maternal immune system—should give disparate results in in vitro testing of maternal immune function. The experimental evidence available is not consistent enough to confi rm or to contradict either hypothesis.

The innate immune response system may also play a role.293 Normal pregnancy is associated with an activation of infl ammatory response that is similar to that seen in sepsis. This infl ammatory response is further increased in preeclampsia.294 Materials released from the pla-centa, perhaps microvillus particles associated with aponecrosis, inter-act with maternal immune cells to produce infl ammatory activation.295 Increased release of these materials in preeclampsia is posited to augment the immune response with secondary pathogenetic effects of this infl ammatory activation.

An immunologic cause of preeclampsia is consistent with much that is known about the disorder. Increased delineation of the changes in the immunologic activity in preeclampsia may provide insight into the cause of preeclampsia and normal fetal-maternal compatibility during pregnancy.

Oxidative StressOxidative stress occurs when there is an excess of active oxygen prod-ucts beyond the capacity of buffering mechanisms, antioxidants, and antioxidant enzymes. This phenomenon can occur with excess produc-tion of reactive oxygen products or with defi ciency of antioxidant mechanisms.296 Reactive oxygen products can damage proteins, lipids, and DNA, and the endothelium is particularly vulnerable. Levels of lipid markers of oxidative stress are increased in women with pre-eclampsia.297,298 Lipid oxidation products, protein products of oxida-tion, protein carbonyls,299 and nitrotyrosine are present in the circulation, blood vessels,219 and placenta218 of preeclamptic women

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and their fetuses. Reduced levels of antioxidants300,301 and increased levels of antibodies to oxidized LDL cholesterol302 are found in excess in women with preeclampsia. These changes are not likely the result of preeclampsia, because reduced antioxidants and increased lipid peroxidation products are present in women destined to develop preeclampsia.303,304

The excess oxidative species relevant to preeclampsia have several origins. Transition metals such as iron catalyze the formation of reac-tive oxygen species, and free iron and redox active copper305 are increased in the blood of women with preeclampsia.306 Reduced tissue perfusion suffi cient to result in hypoxia and followed by restored per-fusion and reoxygenation leads to the formation of reactive oxygen species.307 This mechanism is compatible with pregnancy and pre-eclampsia. Uterine and placental blood fl ow is not privileged, and fl ow is reduced when blood is shunted to other organs during exercise, eating, and other normal activities. In late pregnancy, uterine and pla-cental blood fl ow is reduced profoundly by postural effects on uterine perfusion. All of these changes are reversible and are followed by restored perfusion. In normal pregnancy, reduced placental perfusion as described is not suffi cient to generate free radicals. In preeclampsia, however, free radicals are generated in the intervillous space.218,308 Reduced placental perfusion may result in maternal systemic disease as the products of oxidative stress are transferred to the maternal circulation.309

Genetics of PreeclampsiaThe tendency of preeclampsia and eclampsia to occur in daughters and sisters of women with preeclampsia is frequently overlooked. In Aber-deen, Scotland, the incidence of proteinuric preeclampsia was increased fourfold among sisters of women who had preeclampsia in their fi rst pregnancy compared with sisters of women who did not.310 The inci-dence of preeclampsia was 15% among mothers but only 4% among mothers-in-law of preeclamptic women.311 Chesley and Cooper312 evaluated preeclampsia in the fi rst pregnancy of sisters, daughters, granddaughters, and daughters-in-law of women who had been eclamptic. The incidence of preeclampsia was 37% among sisters, 26% among daughters, and 16% among granddaughters. The incidence was 6% among daughters-in-law. The fetal genome is also related to the occurrence of preeclampsia. Men who have fathered preeclamptic pregnancies are more likely to father preeclamptic pregnancies with new partners than are men who have never been fathers in preeclamp-tic pregnancies.313 Men born to preeclamptic pregnancies are more likely to be fathers of preeclamptic pregnancies than are men who are born of non-preeclamptic pregnancies.314

What is inherited in preeclampsia? Possibilities include immuno-logic differences, features that compromise implantation, and an increased response to the systemic insult caused by reduced placental perfusion. Examinations of candidate genes support all possibilities. In some populations, certain HLA types are more common in the mother and the fetus from preeclamptic pregnancies.315,316 A variant of the angiotensinogen gene—reported to be more common in some studies317-319—is speculated to infl uence blood pressure and spiral artery remodeling.320 Gene variants potentially leading to aberrations of endothelial function are more common in preeclamptic women.321-323 Mutations leading to increased risk factors for later-life cardiovascular disease, including function-perturbing mutations of lipoprotein lipase genes88 and methylene tetrahydrofolate reductase (MTHFR, an enzyme abnormality associated with increased circulating homocysteine),322 are associated with preeclampsia. As is common in studies of genetic polymorphisms, the results vary according to the population studied.324

Although these and other studies325 support the genetic heterogeneity of preeclampsia,174 the literature may be underpowered and subject to publication bias.326

In the Genetics of Preeclampsia study of 1000 paternal, maternal, and fetal triads, none of the usual candidates was related to preeclamp-sia.326 The results of linkage analyses to perform hypothesis-free testing of genetic associations have varied. Associations of preeclampsia have been found with loci on chromosomes 2p,327,328 2q,327,328 4q,325,329 9,329 and 10330 in different populations. A novel study from the Nether-lands330 combined physical localization of a candidate gene with a search for functionally relevant genes in this chromosomal region. This methodology identifi ed STOX1, a paternally imprinted gene involved in trophoblast differentiation. As a paternally imprinted gene, STOX1 is active only when coming from the mother. A mutated version of this gene was consistently present in affected sisters in preeclamptic pedi-grees. Although STOX1 was localized to chromosome 10 in the Netherlands study, a paralogue of this gene, STOX2, is located on chromosome 4q, close to the suggestive region identifi ed in genome-wide searches in Finland and Australia. The use of high-throughput genetic and gene expression and proteomic studies is just beginning to be applied to the study of preeclampsia.326

Management of Preeclampsia

Philosophy of ManagementThe optimal philosophy of management is a product of the current knowledge about the pathophysiologic changes of and prognosis for preeclampsia. Three principles can be applied.

First, delivery is always appropriate therapy for the mother but may not be so for the fetus. Because we do not understand its cause, attempts to prevent preeclampsia by conventional medical approaches have been understandably unsuccessful. The primary goal of therapy is to prevent maternal morbidity and mortality. Preeclampsia is progressive at variable rates, and careful antepartum observation can identify the woman at risk. Preeclampsia is completely reversible and begins to abate with delivery. If only maternal well-being were considered, deliv-ery of all preeclamptic women, regardless of severity of process or stage of gestation, would be appropriate. Expectant management is appro-priate in some circumstances to attain an optimal outcome for the fetus. The goal of any therapy for preeclampsia other than delivery must be improved rates of perinatal and long-term mortality and morbidity for the fetus, infant, and child.

Second, the signs and symptoms of preeclampsia are not pathoge-netically important. The pathologic and pathophysiologic changes of preeclampsia indicate that poor perfusion, caused at least in part by vasospasm, is the major factor leading to the derangement of maternal physiologic function and ultimately leading to perinatal mortality and morbidity. This same abnormality causes increased total peripheral resistance, with subsequent elevation of blood pressure and decreased renal perfusion leading to sodium retention and edema. The protein-uria of preeclampsia is at least partially explained by vasospasm and by reversible glomerular damage. Attempts to treat preeclampsia by natriuresis or by lowering blood pressure do not alleviate the impor-tant pathophysiologic changes. Natriuresis may be counterproductive and may adversely affect fetal outcome because the plasma volume is already reduced in preeclamptic women.

Third, the pathogenic changes of preeclampsia are present long before clinical criteria for diagnosis are evident. Changes in vascular reactivity, plasma volume, and renal function antedate—in some cases by months—the increases in blood pressure, protein excretion,

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and sodium retention. Irreversible changes affecting fetal well-being therefore may be present before the clinical diagnosis is made. This likely explains the failure of dietary, pharmacologic, and postural therapy instituted after the recognition of clinical disease to reduce perinatal morbidity and mortality. The only rationale for therapy other than immediate delivery is to palliate the maternal condition to allow fetal maturation, and even this rationale is controversial.

DeliveryDelivery is the defi nitive treatment for preeclampsia.

DELIVERY REMOTE FROM TERMDelivery in the setting of severe preeclampsia usually is chosen for

the maternal and fetal indications described previously. Fetal indica-tions for intervention include the following:

� Non-reassuring fetal test results� Estimated fetal weight less than the 5th percentile for

gestational age� Oligohydramnios (i.e., amniotic fl uid index below 5.0 cm or

maximal vertical pocket of fl uid less than 2.0 cm)� Persistent absent or reversed diastolic fl ow on umbilical artery

Doppler velocimetry in a growth-restricted fetus

Delivery should be considered for all women with severe preeclampsia who have reached a favorable gestational age, which usually is defi ned as more than 32 to 34 weeks’ gestation.

DELIVERY AT OR NEAR TERMThe treatment of choice for preeclampsia at term is delivery. Expect-

ant management may be considered when preeclampsia is diagnosed at less than 32 to 34 weeks’ gestation, even if disease is severe. However, as gestational age approaches 34 weeks, short- and long-term neonatal outcomes are excellent, and the potential benefi ts of expectant man-agement become less compelling. At 34 to 37 weeks, decisions regard-ing delivery are not guided by good evidence, and clinical judgment must consider the neonatal prognosis, severity of maternal disease, and the wishes of the patient.

ROUTE OF DELIVERYDelivery is usually accomplished by the vaginal route, with cesarean

delivery reserved for obstetric indications. The decision to expedite delivery in the setting of severe preeclampsia does not mandate imme-diate cesarean birth.331 Cervical ripening agents may be used if the cervix is not favorable before induction332 and if the fetus can be satis-factorily monitored; however, a prolonged induction is best avoided, especially in the presence of IUGR or oligohydramnios. The rate of vaginal delivery after labor induction decreases to about 33% at less than 28 to 34 weeks’ gestation because of the high frequency of non-reassuring fetal heart rate tracings and failure of induction.333 Some physicians recommend scheduled cesarean delivery for women with severe preeclampsia with a pregnancy of less than 30 weeks’ gestation and with an unfavorable Bishop score.334

After the decision for delivery is made, induction should be carried out aggressively and expeditiously. Cesarean delivery should be reserved for obstetric indications. Because the probability of fetal compromise in preeclampsia is high, it is mandatory in all vaginal deliveries that the fetus be monitored adequately. When feasible, internal monitoring is preferable to allow determination of variability; however, external monitoring, if technically good, is adequate until internal monitoring

is possible. Magnesium sulfate may reduce fetal heart rate variability,335 but if normal variability was never evident, fetal scalp blood sampling may be necessary to ensure that decreased variability is not related to fetal compromise. For the woman with marked hepatic capsular dis-tention, cesarean delivery is indicated if vaginal delivery is not immi-nent. Even several extra hours can threaten the life of the mother, and liver rupture is diffi cult to predict and to treat. In some cases of severe preeclampsia, especially those with HELLP syndrome, rapidly worsen-ing thrombocytopenia or other signs of maternal instability may pre-clude a trial of labor.

Regional anesthesia offers its usual advantages for vaginal and cesarean delivery but does carry the possibility of extensive sympa-tholysis with consequent decreased cardiac output, hypotension, and impairment of already compromised uteroplacental perfusion. This problem can be avoided by meticulous attention to anesthetic tech-nique and volume expansion. Regional anesthesia is not a rational means of lowering blood pressure because it does so at the expense of cardiac output. Similarly, although analgesia with narcotics is not con-traindicated and may be used when necessary, attempting to manage or prevent eclampsia with profound maternal sedation has been inef-fective and even dangerous.

Antepartum ManagementWhen preeclampsia is suspected, a careful evaluation of mother and fetus is essential. Maternal blood pressure, laboratory values, and fetal well-being should be assessed. If the diagnosis of preeclampsia is con-fi rmed, maternal seizure prophylaxis should be considered, blood pres-sure should be controlled to a level that minimizes risk of maternal stroke, and plans for delivery should be made according to the gesta-tional age.

ASSESSMENT AND MONITORING OF THE

MOTHER AND FETUSMaternal Monitoring. There are two goals for antepartum moni-

toring of the mother:

� Recognizing the condition early, because infants of mothers with even mild preeclampsia are at increased risk for adverse outcomes.

� Gauging the rate of progression of the condition to prevent severe morbidity by delivery and to determine whether fetal well-being can be monitored safely by the usual intermittent observations

Ideally, identifi cation of early changes allows intervention before the advent of clinical symptoms. Although many hemodynamic, volume, and metabolic changes antedate the diagnostic clinical signs in women destined to develop preeclampsia, none is sensitive enough to be clinically useful.7,33,112,167,235,336-338 The increased blood pressure response to angiotensin II172,339,340 in women destined to have elevated blood pressure in late pregnancy was once the gold standard against which other predictors were judged, but a large study failed to confi rm the predictive value of the test,112,173 and it is neither simple nor safe enough for extensive clinical use. Abnormal uterine artery Doppler velocimetry in the second trimester has a positive predictive value for preeclampsia of about 20%. Although useful for research identifi cation of subjects, the low sensitivity and positive predictive value limit its use in clinical care.341 The role of Doppler velocimetry in patient manage-ment remains uncertain. Other suggested markers include angio-genic and antiangiogenic factors, but clinical use awaits additional evaluation.342

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Clinical management is dictated by the overt clinical signs of pre-eclampsia. Proteinuria—the most valid clinical indicator of preeclamp-sia—is often a late change, sometimes even preceded by seizures, and it is therefore not useful for early recognition of disease. Although rapid weight gain and edema of the hands and face suggest fl uid and sodium retention characteristic of preeclampsia, they are not univer-sally present in or uniquely characteristic of preeclampsia. These signs are at most a reason for close observation of blood pressure and urinary protein levels. Early recognition of preeclampsia is necessarily based primarily on diagnostic blood pressure increases in the late second and early third trimesters compared with pressures in early pregnancy. Blood pressure changes without proteinuria undoubtedly occur in some normal women and in some with underlying renal or vascular disease. Because the goal of early diagnosis is to identify patients requiring more careful observation, overdiagnosis is prefera-ble to underdiagnosis.

After blood pressure changes diagnostic of preeclampsia occur, evi-dence of multiorgan involvement should be sought through laboratory assessment. A 24-hour or timed urine specimen should be collected,343 regardless of fi ndings on urine dipstick evaluation.9 Because of the hectic protein excretion characteristic of the disorder,344 24-hour urine collections may reveal excretion of more than 300 mg of protein, even with only trace proteinuria identifi ed on the dipstick evaluation.9 Platelet count and liver enzyme tests should also be obtained.2 To rule out fulminant progression, repeated examination of pressure and urinary protein is suggested within 24 hours. The frequency of subse-quent observations is determined by these initial observations and the ensuing clinical progression. If the condition appears stable, once- or twice-weekly observations may be appropriate. Any evidence of pro-gression merits more frequent observations, perhaps in the hospital. The appearance of proteinuria is an especially important sign of pro-gression and requires frequent observation.

If deterioration in laboratory fi ndings, symptoms, or clinical signs occurs, the decision to continue the pregnancy is determined day by day. Subjective evidence of central nervous system involvement (i.e., headache, disorientation, and visual symptoms) and hepatic distention (i.e., abdominal pain and right upper quadrant or epigastric tender-ness) indicates worsening preeclampsia. Important clinical signs are blood pressure, urinary output, and fl uid retention as evidenced by daily weight increase.

Laboratory studies are performed at intervals of no less often than every 48 hours. Tests should include a platelet count and fi brin split products, urinary protein excretion and serum creatinine levels, and serum levels of transaminases.

Fetal Observation. Assessment of fetal well-being is required to determine whether continuing the pregnancy is safe (see Chapter 21). With the diagnosis of gestational hypertension, fetal assessment for size by sonography and for function by nonstress testing is indicated. After the diagnosis of preeclampsia is made, it is mandatory to monitor the fetal condition. Ultrasound evaluation of fetal weight and amniotic fl uid volume and a nonstress test of the fetal heart rate should be per-formed. Alternatively, a complete biophysical profi le may be performed. Doppler velocimetry is not recommended unless fetal growth restric-tion is identifi ed.

As long as the maternal condition is mild and stable, weekly moni-toring of the fetus appears to be adequate. Unfortunately, no test of fetal well-being is satisfactory when the mother’s condition is unstable, and testing should be repeated whenever the maternal status changes. Management of fetal growth restriction, a common complication of preeclampsia, is discussed in Chapter 34. Amniotic fl uid testing for fetal lung maturity (see Chapter 23) may aid the decision to deliver the

fetus with growth restriction. Fetal jeopardy, rather than lung maturity, is the fetal criterion to determine delivery when preeclampsia occurs remote from term.

Expectant Management of Severe

Preeclampsia Remote from TermProlonged expectant antepartum management of women with severe preeclampsia is not practiced in most centers. With improvements in neonatal care, many clinicians regard delivery of women with severe preeclampsia beyond 32 to 34 weeks’ gestation to be in the best inter-ests of the mother and fetus. When gestational age is critical (<32 weeks), the physician may consider control of maternal blood pressure along with meticulous observation of maternal and fetal conditions. This approach requires personnel and facilities for very close assess-ment of both patients.

The initial evaluation and management of a woman suspected to have severe preeclampsia between 24 and 32 to 34 weeks’ gestation includes the following components:

� The pregnant woman is admitted to the hospital.� A course of antenatal corticosteroids is administered (see

Chapter 23). Barring rapid deterioration of the maternal or fetal status, reasonable efforts should be made to delay delivery for 48 hours to complete a full course of antenatal corticosteroids. Neonates from preeclamptic pregnancies may have a reduced incidence of respiratory distress syndrome, but this does not justify withholding antenatal corticosteroid therapy.345,346

� Seizure prophylaxis is undertaken with magnesium sulfate.� Blood pressure is monitored at least every 1 to 2 hours.� Fluid intake and urine output are strictly monitored.� A 24-hour urine collection is used to determine protein

excretion and creatinine clearance.� Laboratory studies include a complete blood cell count with a

platelet count and smear and determinations of electrolytes, creatinine, ALT, AST, lactic acid dehydrogenase (LDH), uric acid, and albumin. A coagulopathy profi le (i.e., prothrombin time [PT], partial thromboplastin time [PTT], and fi brinogen) should be obtained if the ALT and AST values are more than twice normal or if the platelet count is less than 100,000 cells/μL.

� Assessment of fetal well-being includes a nonstress test, amniotic fl uid volume determination, and estimation of fetal size. If growth restriction is recognized, umbilical artery Doppler velocimetry is suggested.

After the complete assessment of the fetus and mother, the safety and potential utility of expectant management should be reassessed daily. Several factors mandate delivery regardless of gestational age. Under these circumstances, the initial dose of antenatal steroids should be administered, but pregnancy should not be unnecessarily prolonged to give the second dose.

CONTRAINDICATIONS TO

EXPECTANT MANAGEMENTImmediate delivery should be considered if any of the following

conditions are present:

� Maternal hemodynamic instability (e.g., shock)� Non-reassuring fetal test results (e.g., persistently abnormal

fetal heart rate testing, estimated fetal weight less than the 5th percentile for gestational age, oligohydramnios with amniotic

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fl uid index <5.0 cm or maximal vertical pocket <2.0 cm, persistent absent or reversed diastolic fl ow on umbilical artery Doppler velocimetry in a growth-restricted fetus)

� Persistent, severe hypertension unresponsive to medical therapy� Persistent headache, visual aberrations, or epigastric or right

upper quadrant pain� Eclampsia� Pulmonary edema� Renal failure with a marked rise in serum creatinine (i.e.,

serum creatinine concentration increased by 1 mg/dL over baseline) or urine output less than 0.5 mL/kg/hr for 2 hours that is unresponsive to hydration with two intravenous boluses of 500 mL of fl uid

� Laboratory abnormalities (e.g., rapid increase in aminotransferases that exceeds twice the upper limit of normal, progressive decrease in the platelet count to less than 100,000 cells/μL, coagulopathy in the absence of an alternative explanation) that worsen over a period of 6 to 12 hours

� Abruptio placentae� Gestational age more than 34 weeks� HELLP syndrome (Some studies have reported that serious

maternal complications in the setting of expectant management of HELLP syndrome are uncommon with careful maternal monitoring.347,348 However, the aim of expectant management is to improve neonatal morbidity and mortality, and it has not been shown that overall perinatal outcome is improved with expectant management compared with pregnancies delivered after a course of corticosteroids. Expectant management remains an investigational approach.349,350)

� Patient who does not want to undergo risks of expectant management

If the fetus and mother have none of these signs or symptoms and the informed woman agrees, expectant management may be considered.

CANDIDATES FOR EXPECTANT MANAGEMENTIn women with severe preeclampsia remote from term, the decision

to continue pregnancy beyond that required for corticosteroids depends on the results of frequent maternal and fetal assessment and continual review of the ongoing risks of conservative management versus the benefi t of further fetal maturation. These women should be cared for in a hospital setting and cared for by or in consultation with a maternal-fetal medicine specialist. In this environment, expectant management of severe preeclampsia remote from term may be consid-ered in four circumstances.

The fi rst is transient abnormal laboratory test results. Asymptom-atic women before 34 weeks’ gestation with severe preeclampsia on the basis of laboratory abnormalities that improve or resolve within 24 to 48 hours after hospitalization may be managed expectantly.351,352 If initial laboratory abnormalities include elevated liver function test results (e.g., ALT, AST) less than twice the upper limit of normal, a platelet count of less than 100,000 cells/μL but greater than 75,000 cells/μL, and coagulopathy in the absence of an alternative explanation, it is reasonable to delay delivery, administer antenatal corticosteroids, and repeat laboratory tests every 6 to 12 hours. If the laboratory values show a trend toward improvement, or if they resolve, expectant man-agement may be continued until a more favorable gestational age. Delivery is warranted if liver function test values or platelet counts deteriorate or coagulopathy occurs.

The second reason to consider expectant management of severe preeclampsia remote from term is severe preeclampsia based solely on

proteinuria. In the absence of other features of severe preeclampsia, proteinuria greater than 5 g in 24 hours is not an indication for delivery. Several clinical studies have shown that neither the rate of increase nor the amount of proteinuria affects maternal or perinatal outcome in the setting of preeclampsia.353,354 For this reason, after the threshold of 300 mg in 24 hours for the diagnosis of preeclampsia has been exceeded, 24-hour urinary protein estimations do not bear repeating.

The third reason is severe preeclampsia based solely on fetal growth restriction. Women with severe preeclampsia based only on the pres-ence of IUGR in the setting of preeclampsia may be managed expec-tantly if they meet the following criteria355:

� Mild IUGR, defi ned as an estimated fetal weight between the 5th and 10th percentile for gestational age (see Chapter 34)

� Gestational age less than 32 weeks� Reassuring fetal test results, defi ned as a reassuring nonstress

test result, adequate amniotic fl uid volume (AFI > 5.0 cm or maximal vertical pocket >2.0 cm), and no persistent absent or reversed diastolic fl ow on umbilical artery Doppler velocimetry (see Chapter 21)

These women should be admitted to the hospital for close maternal surveillance and daily fetal testing.356 The admission-to-delivery interval in such pregnancies averages only 3 days, and more than 85% of these women require delivery within 1 week of presentation.350,355

The fourth reason to consider expectant management is severe preeclampsia based solely on blood pressure criteria. Two studies have established a precedent for expectant management of patients with severe preeclampsia by blood pressure criteria alone in pregnancies less than 32 weeks with reassuring fetal testing.351,352

COMPONENTS OF EXPECTANT MANAGEMENTExpectant management of severe preeclampsia is not associated

with any direct maternal benefi ts. The mother is assuming a small but signifi cant risk to her own health to delay delivery until a more favor-able gestational age is reached for her child.

If the contraindications to expectant management described previ-ously are absent, the following protocol may minimize the risk of maternal and fetal complications:

� Close supervision of the mother and fetus is crucial because it is impossible to predict the clinical course the disease will take after admission.349

� The mother is hospitalized until delivery.� The patient is kept on bed rest with bathroom privileges.� Blood pressure is monitored every 2 to 4 hours while the

patient is awake.� Maternal symptoms are assessed every 2 to 4 hours while she is

awake.� Fluid intake and urine output are strictly recorded.� Complete blood cell count, electrolyte determinations, and

liver and renal function tests are performed at least twice weekly, if not daily.

� The mother is given antenatal corticosteroids, if not previously given.

� Regular assessment of fetal well-being (at least daily nonstress tests with a biophysical profi le if nonreactive)3

� Delivery occurs after 32 to 34 weeks’ gestation, depending on the clinical scenario.

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If abnormal laboratory test results are obtained on admission, tests should be repeated every 6 to 12 hours. Delivery should be considered if there is no trend toward improvement within 12 hours of admission or if the condition worsens after an initial improvement.

There is no standardized protocol for fetal assessment in this setting. We perform fetal kick counts and nonstress tests at least daily, ultra-sound assessment of amniotic fl uid volume once or twice per week, ultrasound estimation of fetal growth every 10 to 14 days, and weekly Doppler velocimetry of the umbilical artery if the fetus is growth restricted.

Several management strategies with no proven benefi t in the setting of severe preeclampsia are often recommended, but they are best avoided. They include the routine use of continuous fetal heart rate monitoring, routine initiation of antihypertensive therapy (antihyper-tensive therapy should be avoided, with the exception of women with chronic hypertension and those being managed according to standard protocols for severe preeclampsia by blood pressure criteria only remote from term),352 prolonged (>48 hours) antepartum administra-tion of magnesium sulfate for seizure prophylaxis, serial 24-hour urine collections for protein quantitation, and routine assessment of fetal lung maturity. However, the latter may be useful between 30 and 34 weeks when there is contradictory or equivocal evidence of maternal or fetal deterioration.

Postpartum administration of intravenous dexamethasone does not reduce the severity or duration of disease. The serendipitous obser-vation that women who had received antepartum steroids appeared to evidence improvement in the HELLP syndrome357 stimulated several retrospective and observational studies.358-363 These studies and a small, randomized, controlled trial364 suggest improvement in laboratory fi ndings and prolongation of pregnancy. The determination of appro-priate dosing and whether the benefi t of therapy exceeds risks await larger, randomized, controlled trials. Its benefi t for patients with HELLP syndrome remains controversial.365

OUTCOMES OF EXPECTANT MANAGEMENTSeveral studies have shown that with close monitoring, pregnancies

complicated by severe preeclampsia could be managed expectantly and extended by 5 to 19 days, on average, with good maternal and neonatal outcomes. However, pregnancies with a growth-restricted fetus typi-cally deliver in 3 to 5 days.351,352,366,367

Intrapartum ManagementThe intrapartum management of women with preeclampsia tests the obstetric and medical skills of the health care team. The patient with severe preeclampsia or eclampsia is acutely ill, with functional derange-ments of many organ systems.368 Improved appreciation of the gravity of this situation and enhanced methods of maternal monitoring have reduced mortality rates. One study from the United Kingdom demon-strated a signifi cant reduction in maternal death due to eclampsia from 15.1% in the 1940s to less than 3.9% after 1950.368 Failure to recognize and appropriately manage this grave condition probably accounts for most deaths. Even mildly preeclamptic women can experience an acceleration of disease during labor.

Baseline information should be obtained to determine renal func-tion, coagulation status, and liver function. Determination of the serum protein concentration informs the choice of appropriate fl uid administration. Some investigators advocate the use of intensive car-diovascular monitoring, with Swan-Ganz catheters or with central venous pressure catheters in all women with severe preeclampsia or eclampsia (see Chapter 57). Such a practice is probably indicated in oliguric patients whose urinary output does not improve with a modest

fl uid challenge. The major problems to be managed are those of high blood pressure, intravascular volume, and convulsions. Less commonly, patients with DIC and myocardial dysfunction require treatment.

SEIZURE PROPHYLAXIS AND TREATMENTMost seizures occur during the intrapartum and postpartum

periods, when the preeclamptic process is most likely to accelerate. In the Magpie study, 10,000 preeclamptic women were randomized to receive magnesium sulfate or placebo. Magnesium sulfate clearly reduced the risk of eclampsia in this trial,369 and it was shown in sepa-rate trials to be superior for this purpose to other prophylactic medica-tions, including phenytoin370,371 and diazepam.372,373

Despite the demonstrated effi cacy of magnesium sulfate, it is diffi -cult to select preeclamptic women for whom the risks of seizure exceed the risk of prophylaxis. In the Magpie study, treatment was effective and safe even in developing countries, but most of these women had signifi cant disease. Twenty-fi ve percent were defi ned as having severe preeclampsia, and 75% required antihypertensive therapy. Although the use of magnesium prophylaxis in so-called mild preeclampsia is controversial, the incidence of eclampsia increased by 50% in a large obstetric service when magnesium prophylaxis was limited to women with severe disease.374 A review of eclamptic patients from another large U.S. center indicates the diffi culty in selecting preeclamptic women with disease severe enough to warrant therapy. None of the clinical signs and symptoms considered to be prognostic of seizures was absolutely reliable. Seventeen percent of women who had seizures did not have headache, 80% did not have epigastric pain, and 20% had normal deep tendon refl exes (Table 35-6). The lack of absolute correla-tion with proteinuria is consistent with the observations by Chesley and Chesley276 more than 50 years ago that 24% of patients do not have proteinuria before seizures.

Most U.S. investigators recommend prophylactic anticonvulsant therapy for all women with a blood pressure elevation diagnostic of preeclampsia, regardless of whether other signs and symptoms, includ-ing proteinuria, are present. This approach includes women for whom the risks of treatment may exceed the risks from seizures. The fi rst requirement for anticonvulsant prophylaxis is that the agent and dosage schedule must be extremely safe for the mother. Safety for the fetus and neonate is the next criterion.

Magnesium Sulfate. Magnesium sulfate offers considerable advantages for prophylaxis in women with preeclampsia. Its pharma-cokinetic processes during pregnancy are well established, as are its effi cacy and safety for the mother and fetus.

TABLE 35-6 FREQUENCY OF SYMPTOMS PRECEDING ECLAMPSIA

Symptom Frequency (%)

Headache 83Hyperrefl exia 80Proteinuria 80Edema 60Clonus 46Visual signs 45Epigastric pain 20

Adapted from Sibai BM, Lipshitz J, Anderson GD, Dilts PV Jr:

Reassessment of intravenous MgSO4 therapy in preeclampsia-

eclampsia. Obstet Gynecol 57:199-202, 1981; with permission from the

American College of Obstetricians and Gynecologists.

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The volume of distribution of magnesium is greater than that of sucrose, indicating that the distribution of this ion goes beyond extra-cellular fl uid and enters bones and cells.375 Magnesium circulates largely unbound to protein and is almost exclusively excreted in urine. It is reabsorbed in the proximal tubule by a process limited by trans-port maximum (Tmax), and its excretion increases as the fi ltered load increases above the Tmax.

376 In women with normal renal function, the half-time for excretion is about 4 hours.375 Because excretion depends on delivery of a fi ltered load of magnesium that exceeds the Tmax, the half-time of excretion is prolonged in women with a decreased GFR.

The clinically relevant effects of elevated serum magnesium concentrations are related primarily to the membrane effects. Magnesium slows or blocks neuromuscular and cardiac conducting system transmission, decreases smooth muscle contractility, and depresses central nervous system irritability. These actions produce the desired anticonvulsant effect and cause decreased uterine and myocardial contractility, depressed respirations, and interference with cardiac conduction. These effects occur at different serum mag-nesium concentrations (Table 35-7). Doses of magnesium sulfate suffi cient for anticonvulsant therapy cause little change in blood pressure.

Depression of deep tendon refl exes occurs at serum concentrations lower than those associated with adverse cardiac and respiratory effects. The presence of deep tendon refl exes indicates that the serum magne-sium concentration is not dangerously high. If deep tendon refl exes are lost, the serum magnesium concentration may be greater than 10 mEq/L, but brisk deep tendon refl exes do not signify inadequate magnesium dosage. Any attempt to titrate magnesium therapy until deep tendon refl exes are eliminated is irrational and dangerous.

In the United States, magnesium sulfate is routinely given intrave-nously, rather than by more painful intramuscular injections. A typical loading dose is 4 to 6 g given intravenously over about 15 to 30 minutes, followed by 1 to 2 g/hr as a continuous infusion. Magnesium is admin-istered by continuous infusion because intermittent bolus infusions result in only transient elevations of magnesium level. To ensure con-sistent infusion and to avoid inadvertent administration of large doses of magnesium, mechanically controlled infusion is mandatory. In all patients, deep tendon refl exes should be checked regularly (at least every 2 hours) to make sure they remain present, and the respiratory rate must be monitored.

The rate of infusion is modifi ed for patients with compromised renal function. If the maternal creatinine level is greater than 1.0 mg/dL, serum magnesium levels should be obtained and the infusion rate limited to no more than 1 g/hr if there is further evidence of renal impairment. If overdosage occurs, especially with apnea, calcium glu-conate (10 mL of a 10% solution injected intravenously over 3 minutes) is an effective antidote. The “therapeutic concentrations” of magne-sium have been empirically determined and are the levels attained with

dosages found to be usually effective and safe (Table 35-8). No study has compared magnesium concentrations in patients successfully or unsuccessfully treated with MgSO4 · 7 H2O. We do not recommend titrating levels to any specifi c therapeutic range, and there is no evi-dence that levels greater than 6 mEq/L increase effi cacy. Magnesium is not a perfect anticonvulsant, and some women have convulsions even with high serum concentrations.377

Based on extensive experience, intravenous administration of mag-nesium at doses up to 2 g/hr appears to be safe if renal function is normal. In the Magpie study, doses of 1 g/hr given intravenously were effective without serious complications in 5000 treated women; some were treated in underdeveloped nations.

Magnesium sulfate therapy at effective anticonvulsant doses is safe for the fetus and neonate. Neonatal serum magnesium concentrations are almost identical to those of the mother.378 Although amniotic fl uid magnesium concentrations increase with prolonged infusion because of fetal renal excretion, fetal serum magnesium levels do not increase, and there is no evidence of cumulative effects on the neonate of pro-longed magnesium administration for seizure prophylaxis.

In a study of 118 infants of mothers treated with magnesium sulfate, the average serum magnesium concentration was 3.7 mEq/L. There was no correlation of magnesium levels with Apgar scores.379 Administration of magnesium to the mother may have additional ben-efi cial effects for the fetus, which are being tested in controlled trials (see Chapter 29).

Phenytoin. Phenytoin is an effective anticonvulsant with pharma-cologic effects that would not be predicted to produce adverse effects on the fetus or neonate. In several small studies, there were no obvious adverse fetal or maternal effects.380,381 Although phenytoin is not as effective as magnesium for prophylaxis or treatment of eclampsia,372,382 it can be used safely when magnesium is inappropriate, such as in women with myasthenia gravis or markedly compromised renal func-tion. Phenytoin nonetheless does have potential severe adverse effects that may be magnifi ed by unfamiliarity of obstetric personnel with its use.

Anticonvulsant Therapy. Magnesium is more effective than phenytoin or benzodiazepam to treat eclamptic seizures.372 An initial infusion of 4 g can be administered safely intravenously over as little as 5 minutes, and intravenous MgSO4 can be administered at 1 to 2 g/hr to maintain therapeutic serum magnesium levels. If a patient already receiving magnesium has an eclamptic seizure, it is safer to terminate seizures with another agent, such as 5 to 10 mg of diazepam (Valium), 4 mg of lorazepam (over 2 to 5 minutes),383 or a short-acting barbitu-rate, such as pentobarbital (125 mg given intravenously). If these measures fail, general anesthesia may be necessary to terminate the seizures.

TABLE 35-7 EFFECTS ASSOCIATED WITH VARIOUS SERUM MAGNESIUM LEVELS

Effect Serum Level (mEq/L)

Anticonvulsant prophylaxis 4-6Electrocardiographic changes 5-10Loss of deep tendon refl exes 10Respiratory paralysis 15Cardiac arrest >25

TABLE 35-8 SAFETY AND EFFICACY OF INTRAVENOUS MAGNESIUM SULFATE THERAPY

Factor Number (%)

Number of women treated 1870Number of women with seizures 11 (0.6)Number with seizure morbidity 1 (0.05)Number with morbidity from treatment 0 (0)

Adapted from Sibai BM, Lipshitz J, Anderson GD, Dilts PV Jr:

Reassessment of intravenous MgSO4 therapy in preeclampsia-

eclampsia. Obstet Gynecol 57:199-202, 1981; with permission from the

American College of Obstetricians and Gynecologists.

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Most seizures terminate spontaneously within 1 to 2 minutes. The most important measures for any seizure before pharmacologic therapy is initiated are prevention of injury and protection of the airway to prevent aspiration.

ANTIHYPERTENSIVE THERAPYAntihypertensive agents are not administered routinely to women

with preeclampsia. There is no evidence that administration of these agents has benefi cial fetal effects. The suggestion that lowering blood pressure reduces the risk of seizures has not been tested. The goal of antihypertensive treatment is prevention of intracranial bleeding and stroke.

Therapy is reserved for women in whom blood pressure is elevated to more than 160 mm Hg systolic or more than 105 to 110 mm Hg diastolic, which are the levels associated with intracranial bleeding or stroke.384,385 The goal of blood pressure control is not to attain normal blood pressure but merely to reduce blood pressure to a level that can provide a margin of maternal safety (i.e., 135 to 145 mm Hg systolic and 95 to 100 mm Hg diastolic) without compromising adequate uterine perfusion. These patients have elevated blood pressure with reduced plasma volume. Overly aggressive treatment lowers maternal cardiac output and uterine perfusion and may result in iatrogenic fetal distress.

Several agents available for reducing blood pressure rapidly are described in Table 35-9. Not listed in this table are potent diuretic agents that lower blood pressure rapidly by depleting plasma volume, because the use of these agents in the plasma volume–depleted patient may reduce maternal cardiac output and uterine perfusion.

Hydralazine. The agent most widely used to reduce blood pres-sure in women with severe preeclampsia is hydralazine. As a direct vasodilator, it offers two major advantages. First, vasodilation with hydralazine results in a refl ex increase in cardiac output and increased uterine blood fl ow as blood pressure decreases. Second, the increase in cardiac output blunts the hypotensive effect and makes it diffi cult to overdose the patient. The important side effects of hydralazine are headache and epigastric pain, which may be confused with worsening preeclampsia.

The pharmacokinetic profi le of hydralazine is outlined in Table 35-9. The onset of action occurs in 10 to 20 minutes, and peak action occurs 20 minutes after administration, even when the agent is given intravenously. The duration of action is 3 to 8 hours. The use of con-tinuous intravenous infusions of hydralazine is not sensible because minute-to-minute control cannot be attained. An alternative approach is to administer the drug as a bolus infusion, repeated at 20-minute intervals until the desired control is attained and then repeated as

necessary. A test dose of 1 mg is given over 1 minute, and blood pres-sure is determined to avoid idiosyncratic hypotensive effects; 4 mg is then infused over 2 to 4 minutes. After 20 minutes, the blood pressure is determined, and the following criteria for action are taken into account:

� If there was no effect from the fi rst dose of hydralazine, the dose is repeated.

� If a suboptimal effect was obtained, a second, smaller dose is given.

� If diastolic blood pressure is between 90 and 100 mm Hg, therapy is not repeated until diastolic blood pressure increases to 105 mm Hg.

Other Drugs. In rare instances, hydralazine may not effectively lower blood pressure to the desired level. If blood pressure control is not adequate after the administration of 20 mg of hydralazine, other hypotensive agents must be used.

The calcium entry blocker nifedipine has been taken orally in doses of 10 mg, which may be repeated after 30 minutes if needed to lower blood pressure rapidly. For maintenance dosing, 10 to 20 mg can then be given every 3 to 6 hours as needed. It is quite effective and well toler-ated; headache is the most common side effect.386

Labetalol, a mixed α-adrenergic and β-adrenergic antagonist, also is useful for reducing blood pressure acutely. It is given intravenously as a bolus infusion, beginning with 10 mg and followed by repeated doses that may be increased up to twofold (e.g., 20 mg, 40 mg, 80 mg), with doubling every 10 minutes as needed (up to 300 mg) for blood pressure control.387 The major reservation about the use of labetalol is that, unlike the vasodilators hydralazine and nifedipine, it does not reduce afterload. There are theoretical disadvantages with using labet-alol for managing cardiac failure associated with the hypertension of preeclampsia.

Methyldopa (formerly designated α-methyldopa) is a safe and well-tested drug. However, its delayed onset of action (4 to 6 hours), even when administered intravenously, limits its usefulness for hypertensive emergencies. On the basis of side effects and experience, nifedipine or labetalol are preferred when hydralazine is ineffective.

MANAGEMENT OF OLIGURIAIn preeclamptic women, oliguria can have a prerenal or renal origin

(see Chapters 44 and 57). Even though plasma volume is decreased in preeclamptic patients, the use of fl uids is controversial. Excessive fl uid infusion can lead to congestive heart failure and perhaps cerebral edema388; nevertheless, oliguria can be corrected in many patients by fl uid infusion.

TABLE 35-9 DRUGS FOR TREATMENT OF HYPERTENSIVE EMERGENCIES

Drug

Time Course of ActionIntramuscular

Dosage Intravenous Dosage

Interval

between Doses MechanismOnset Maximum Duration

Hydralazine 10-20 min 20-40 min 3-8 hr 10-50 mg 5-25 mg 3-6 hr Direct dilatation of arterioles

Sodium nitroprusside

0.52-2 min 1-2 min 3-5 min — IV solution: 0.01 g/L; IV infusion rate: 3-4 μg/kg/min

Direct dilatation of arterioles and veins

Labetalol 1-2 min 10 min 6-16 hr — 20-50 mg 3-6 hr α- and β-Adrenergic blocker

Nifedipine 5-10 min 10-20 min 4-8 hr — 10 mg orally 4-8 hr Calcium channel blocker

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To avoid complications, the physician should not prescribe hypo-tonic fl uids. They worsen the dilutional decreases in serum osmolality that may occur with any of the following: oliguria from renal causes, elevated antidiuretic hormone (ADH) level in response to stress, and oxytocin treatment.

Fluids must be administered with the understanding that oliguria may have a renal origin and that the patient is at risk for fl uid overload-ing. Because acute renal failure resulting in permanent renal damage is rare in pregnancy (whereas pulmonary edema is a common event on some obstetric services), oliguria should be defi ned conservatively as less than 20 to 30 mL/hr for 2 hours.

If there are no clinical signs or history suggesting congestive heart failure, 1000 mL of isotonic crystalloid can safely be infused in 1 hour. If urine output increases, fl uid infusion is maintained at 100 mL of isotonic crystalloid per hour. If the oliguria does not resolve, further fl uid infusion should be guided by central venous or, preferably, pul-monary wedge pressures (see Chapter 57).

Relatively small amounts of intrapartum and postpartum blood loss can result in profound hypovolemia and shock in patients who already have compromised blood volumes. A large peripheral line should be in place at all times in case rapid replacement of blood volume becomes necessary.

MANAGEMENT OF LESS COMMON PROBLEMSDisseminated Intravascular Coagulation. Evidence of DIC is

an important indicator of severity and progression of preeclampsia. DIC is measurable by the usual clinical tests in 20% of severely pre-eclamptic and eclamptic women and is suffi cient to cause coagulation problems in less than 10%.

Defi nitive therapy for DIC is removal of the inciting factor. In pre-eclampsia, whether the cause of the coagulation disorder is endothelial cell damage, release of thromboplastic materials, vasospasm with attendant microangiopathic changes, or local consumption of pro-coagulants in the choriodecidual space, the inciting factor is pregnancy related, and defi nitive therapy is termination of the pregnancy. The long-range follow-up of women with preeclampsia indicates that all organ system functions return to normal. It is unlikely that occlusion of the microvasculature by thrombi in mild forms of DIC causes per-manent damage.

Evidence of early DIC is not by itself an absolute indication for immediate delivery. With rapidly deteriorating renal or hepatic func-tion or DIC complicated by spontaneous hemorrhage, however, deliv-ery should be expeditious.

The experience with heparin anticoagulation, which has been used to maintain pregnancies in women with symptomatic DIC or as a prophylactic measure to prevent DIC, indicates that these approaches are not effective.389 The use of heparin during labor in women in whom DIC necessitates delivery has not been studied extensively. The experi-ences already cited, however, indicate that the approach may be dangerous.

If procoagulants decrease to a level associated with spontaneous hemorrhage, appropriate procoagulant therapy should be given before delivery. This should be done whether the anticipated mode of delivery is vaginal or cesarean (see Chapter 40).

Pulmonary Edema. Pulmonary edema occurs in a small number of women with preeclampsia. In the past, this complication was associ-ated with high rates of maternal mortality. The pathogenesis of pul-monary edema often is iatrogenic fl uid overload, but it can be cardiogenic or involve transudation of fl uid into alveoli. The noncar-diogenic variety results from decreased colloid oncotic pressure or a pulmonary vascular leakage, and it can occur in the antepartum, intra-

partum, or postpartum period. Delayed onset of pulmonary edema requires special awareness because the edema usually occurs during postpartum diuresis, when most concerns about the complications of preeclampsia are diminishing.

Management of pulmonary edema requires intensive monitoring, with the capability to assess pulmonary and cardiac function accu-rately and to perform mechanical ventilation as needed (see Chapter 57). With accurate assessment of cardiopulmonary function and aggressive treatment, the mortality resulting from pulmonary edema in preeclampsia has been greatly reduced.390

Postpartum Management in PreeclampsiaDelivery does not immediately reverse the pathophysiologic changes of preeclampsia, and it is necessary to continue palliative therapy for various periods. Some of the constraints on therapy, however, are eliminated by delivery of the fetus. Approximately one third of convulsions occur in the postpartum period, most within 24 hours and virtually all within 48 hours, although there are rare exceptions. Most physicians advocate continuing anticonvulsant therapy for 24 hours after delivery. For simplicity, magnesium sulfate therapy is usually continued, but because there is no need to consider fetal effects, any safe anticonvulsant regimen is reasonable at this time.

Anticonvulsant effi cacy rather than sedation is the goal, and barbi-turate anticonvulsants in usual therapeutic doses require days to achieve effective levels. Similarly, phenytoin must be administered intravenously in large doses to achieve therapeutic levels within hours, with the attendant dangers of cardiac arrhythmia. Serum magnesium concentrations decrease with increased urinary output, and with puer-peral diuresis, it is extremely unlikely that the serum magnesium concentration is therapeutic at usual doses. Despite this drawback, convulsions rarely occur in the postpartum period, suggesting that rapid diuresis indicates resolution of the preeclamptic process and that therapy may no longer be required.

On the basis of these considerations, it appears reasonable to dis-continue magnesium sulfate therapy when diuresis occurs before 24 hours after delivery. Some investigators recommend continuing mag-nesium sulfate administration for longer than 24 hours in selected patients, but it is diffi cult to determine the basis on which this selection can be made. In one randomized trial limited to women with mild preeclampsia, there was no difference in seizure risk when magnesium was discontinued after only 12 hours.391 Unfortunately, this study was limited by a relatively small sample, and it is likely that any future studies will be similarly underpowered because of the rarity of the outcome.

Hypertension may take considerably longer than 24 to 48 hours to resolve. Women who are hypertensive 6 weeks after delivery may be normotensive at long-term follow-up.74 The indications for therapy are similar to those for the antepartum period. The patient with blood pressure greater than 160 mm Hg systolic or 105 mm Hg diastolic after delivery should be treated; the fetus no longer infl uences therapeutic choices. If rapid blood pressure control is necessary, sodium nitroprus-side is more effective and better tolerated than hydralazine. Diuretics and conventional oral antihypertensive agents can be started to achieve smooth control. The woman who remains hypertensive (>100 mm Hg diastolic pressure) should be sent home with continued antihyperten-sive therapy.

Patients with lesser elevations require no therapy. The choice of drugs is based on the usual step method of antihypertensive therapy. The patient sent home with a therapeutic regimen must be warned about symptoms of hypotension, and she must be seen at weekly

Ch035-X4224.indd 674 8/26/2008 4:05:45 PM


intervals, because the need for therapy diminishes rapidly in some cases.

Therapies No Longer RecommendedStrict sodium restriction and diuretic therapy have no role in the pre-vention or treatment of preeclampsia. In women with marked sodium retention as manifested by signifi cant edema, modest sodium restric-tion may not alter the course of the disease but can reduce discomfort. Diuretics should not be given because plasma volume is already decreased, and further volume depletion can affect the fetus adversely. Attempts to modify the progression of the disease by volume expan-sion have not been conclusively shown to be helpful and require more thorough evaluation before being used in routine management of preeclampsia.392

Sodium nitroprusside is a potent, short-acting, direct vasodilator that allows excellent moment-to-moment blood pressure control. However, because elevated fetal concentrations of serum cyanide, sometimes to toxic levels, have been reported in animal studies,393 this agent is rarely used in humans.

Diazoxide is a thiazide analogue that has no diuretic effect, but it is an extremely potent antihypertensive agent, acting as a direct vaso-dilator. It is rarely used because of effects on maternal and fetal carbo-hydrate metabolism and its profound and slowly reversible effect on blood pressure.

There is little evidence that therapeutic efforts alter the underlying pathophysiology of preeclampsia. Therapeutic intervention for clini-cally evident preeclampsia is palliative. At best, it may slow the progres-sion of the condition, but it is more likely to allow continuation of the pregnancy. Bed rest is a usual and reasonable recommendation for the woman with mild preeclampsia, although its effi cacy is not clearly established.394 Prophylactic hospitalization with increased bed rest may reduce the incidence of preeclampsia for women at high risk identifi ed by increased angiotensin sensitivity.395 It is unclear, however, which of the several behavioral modifi cations involved in hospital residence is important. Anecdotal reports of clinical improvement with bed rest must be tempered by the recognition of the unpredictable course of preeclampsia.

Follow-up Assessment for PreeclampsiaBecause the early recognition and treatment of signifi cant blood pres-sure elevation reduce morbidity, all women with a clinical diagnosis of preeclampsia deserve long-range follow-up. Decisions for evaluation and treatment should be deferred until 12 weeks after delivery because some women who are hypertensive at 6 weeks are normotensive years later. The woman who is normotensive 12 weeks after delivery should be advised of her increased risk for hypertension in later life77 and should be counseled to have her blood pressure checked at least yearly. Because of the association between preeclampsia and later cardiovas-cular disease,78 formal assessment of cardiovascular risk factors in such patients is prudent.

Prevention of PreeclampsiaSince the preeclamptic syndrome was fi rst recognized, prevention has been attempted. Sodium restriction and nutrient supplements have been unsuccessful.18 Randomized, controlled trials based on several hypotheses for preventing preeclampsia have been performed. The sequence of studies for each intervention has been similar, with initial small, single-center studies suggesting benefi t and subsequent larger, well-powered studies fi nding no signifi cant benefi t.36,396-398

Aspirin trials to prevent preeclampsia are a prototype. More than 35,000 women have been included in randomized, controlled trials of various sizes and quality to determine the benefi t of aspirin.399 Small, single-center studies suggested benefi t,400-402 but larger, multicenter trials showed no effect.36,403 One potential explanation is publication bias in favor of positive results. Results also might have varied because of the heterogeneity of preeclampsia, with benefi t of therapy evident in only a subset.

A meta-analysis of trials that enrolled a large number of pregnant women found benefi t for antiplatelet treatment (i.e., aspirin) to reduce the frequency of the diagnosis of preeclampsia, preterm delivery, and growth-restricted infants.399,404 There was a modest reduction of the incidence of preeclampsia (17%), with 72 women needing treatment to prevent one case of preeclampsia. There was a 14% reduction in the rate of fetal and neonatal deaths, with a number needed to treat of 243 to prevent one death. The investigators concluded that antiplatelet agents such as aspirin have moderate benefi ts when used for preven-tion of preeclampsia and its consequences.

Using another analytical strategy, meta-analysis of individual patient data, the Perinatal Antiplatelet Review of International Studies (PARIS) Collaborative Group attempted to differentiate the success of aspirin in subsets according to maternal diagnosis, dosage of aspirin, and time when therapy was initiated. Although the group did confi rm a reduction in preterm birth and the incidence of preeclampsia by 10% with aspirin, they did not identify any particular subgroups for whom aspirin was more effective. There was no difference in perinatal death for women treated with prophylactic aspirin.405

The estimated number of women to treat to prevent one case of preterm birth in this study was 500 for low-risk pregnancies (incidence of 2%) and 50 for high-risk pregnancies when the estimated incidence of preeclampsia was 20%. Decisions about the choice of aspirin with this degree of effi cacy must consider the short-term adverse effects on the mother and infant, which have not been evident in the large number of women treated, and the long-term outcome, which is largely unknown.406

Calcium supplementation to prevent preeclampsia was initiated with similar enthusiasm. Calcium was tested in a large, randomized, controlled trial in the United States396 based on initial studies and meta-analyses.407 The conclusion of this study was unequivocal, fi nding no evidence that 2 g of supplemental calcium administered to preg-nant women from early gestation onward reduced the incidence of preeclampsia, altered blood pressure, or affected fetal weight. A review of published studies concluded that any benefi t of calcium was related to low calcium intake before pregnancy in some women.408 Based on this rationale, the World Health Organization conducted a trial of calcium supplementation in populations with low calcium intake. Treatment did not reduce the diagnosis of preeclampsia but did reduce adverse outcomes.409 Calcium administration has therefore been pro-posed as useful in low calcium consuming populations.410

Oxidative stress has been suggested as important in preeclampsia. The results of antioxidant therapy are similar to those with calcium and aspirin; an initial small trial of antioxidant vitamins C and E sug-gested benefi t,411 but a subsequent, larger trial did not.397 There was concern about the safety of this therapy for the fetus because an excess of low-birth-weight infants (but not IUGR or premature infants) occurred in the antioxidant-treated group. The largest trial of low-risk women is ongoing, with results expected in 2008. This study initiated antioxidant treatment far earlier in pregnancy than the other studies (start date at 9 to 16 weeks), with 40% of women enrolled before 12 weeks, whereas the other studies began at an average of 18 weeks. This may be relevant because oxidative stress is known to accompany the

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establishment of the intervillous circulation at 8 to 10 weeks’ gesta-tion.412 The primary outcome in this study is a composite outcome of maternal and fetal morbidity. Final decisions about effi cacy and safety await the conclusion of this trial.408

The results of these studies of prophylaxis raise several important points:

� Randomized clinical trials of appropriate population and size to achieve suffi cient power must guide clinical management. Nonetheless, the success in small trials and the failure in large, multicenter trials may be related to the heterogeneity of patients with preeclampsia.174 Prophylaxis may be effective in a specifi c subset of women (e.g., calcium supplementation in women with low average calcium intake).

� Because the diagnosis of preeclampsia is based on signs that usually have minimal causal signifi cance, prophylactic therapy should be aimed at the pathophysiology and judged by effects on perinatal outcome.

� The aspirin and calcium data suggest that initiation of therapy before disease is clinically evident may be successful if specifi c interventions can be applied to appropriately selected subjects.

Chronic HypertensionDifferentiation of chronic hypertension from preeclampsia is complex but essential. Even more important is the diffi cult discrimination between exacerbation of preexisting hypertension and the onset of superimposed preeclampsia. The rate of progression and the effect on the mother and fetus of these conditions are different in the two dis-eases. Management of hypertension in early pregnancy requires early recognition of blood pressure elevation, baseline testing to aid in the later diagnosis of superimposed preeclampsia, and meticulous mater-nal and fetal observation. If a decision is made to use antihypertensive therapy, antihypertensive drugs must be chosen on the basis of con-siderations specifi c to pregnancy.

EpidemiologyThe prevalence of chronic hypertension increases with advancing age. In whites, the risk increases from 0.6% (18 to 29 years old) to 4.6% (30 to 39 years old). In African-American women, the risks increased to 2% and 22.3%, respectively.413 Preeclampsia occurs in 25% of hyper-tensive women, compared with 4% in previously normotensive women.

Pathogenesis

Effects of Chronic Hypertension on the MotherBlood pressure elevation during pregnancy without the superimposi-tion of preeclampsia has the same impact as blood pressure increases in any other 10-month period. Systolic and diastolic blood pressures that exceed 160 and 105 mm Hg, respectively, increase the risk of mor-bidity even over this short period.

Maternal morbidity and mortality rates are greater among women with superimposed preeclampsia than among those with preeclampsia arising de novo. Blood pressure elevation with superimposed pre-eclampsia is also greater, increasing the possibility of intracranial bleeding. Two thirds of cases of eclampsia occur in fi rst pregnancies, but two thirds of maternal deaths due to eclampsia occur in pregnan-

cies other than the fi rst pregnancy, in which underlying hypertension is a more common predisposing factor.414

One review of 28 women with preeclampsia and stroke examined blood pressures before the event. The range of systolic values ranged from 159 to 198 mm Hg, and the range for diastolic values was much greater, from 81 to 133 mm Hg (mean, 98 mm Hg). Only fi ve women had diastolic values greater than 105 mm Hg.385 Morbidity is diffi cult to predict by blood pressure, although it seems to be signifi cantly increased when systolic pressures exceed 160 mm Hg and may be increased when diastolic pressures exceed 100 mm Hg.385 The National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy has recommended initiating therapy when systolic pressures exceed 150 to 160 mm Hg and diastolic pres-sures exceed 100 to 110 mm Hg.

Effects of Chronic Hypertension on the FetusThe perinatal mortality rate for infants born to hypertensive mothers increases as maternal blood pressure rises.101 Without antihypertensive therapy, a woman with a systolic pressure of 200 mm Hg or a diastolic pressure of 120 mm Hg had only a 50% chance of bearing a living infant. The perinatal mortality rate is strikingly higher in hypertensive women with proteinuria, indicating the impact of superimposed pre-eclampsia on the fetus.

The perinatal mortality rate for infants of women with superim-posed preeclampsia is greater than for infants of women in whom the condition arises de novo.415 There are two explanations for this difference.

First, the decidual vessels of women with even mild preexisting hypertension demonstrate vascular changes similar to the changes in renal arterioles seen in women with long-standing hypertension.416 Decreased uteroplacental perfusion resulting from this change may be additive and perhaps synergistic with the decidual vascular changes of preeclampsia. The decidual vascular changes likely explain the higher incidence of abruptio placentae among women with superimposed preeclampsia.

Second, preeclampsia appears earlier in pregnancies of hypertensive women than in those of normotensive women. Fetal growth restriction is common in infants of hypertensive women, and it increases in fre-quency and severity with increasing maternal blood pressure.101

Some investigators suggest that hypertension without preeclampsia has no adverse effect on the fetus,286,417 but this observation ignores the effects of growth restriction. In a study of almost 300 pregnancies of women with chronic hypertension, perinatal death occurred only in growth-restricted infants.418

DiagnosisChronic hypertension is defi ned as hypertension that is observable before pregnancy or that is diagnosed before the 20th week of gesta-tion. Hypertension is defi ned as a blood pressure greater than 140/90 mm Hg. If the diagnosis of hypertension is confi rmed for the fi rst time during pregnancy and it persists beyond the 84th day after delivery, it is classifi ed as chronic hypertension.

Pharmacologic Management of Hypertension

Antihypertensive Therapy in the Reduction of

Maternal and Fetal Morbidity and MortalityAntihypertensive therapy reduces maternal mortality as effectively during pregnancy as at any other time. Lowering of markedly elevated

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blood pressure (>100 mm Hg diastolic pressure) can reduce the risk of morbid events even over 10 months, whereas the impact of such reduc-tion on the minimal morbidity associated with less elevated pressures is unlikely. Antihypertensive therapy for women with mild to moderate hypertension can reduce the risk for severe hypertension in later pregnancy.419

It has been postulated that antihypertensive therapy for the mother and fetus might reduce the incidence of superimposed preeclampsia, but there has been no evidence of that effect in large trials of antihy-pertensive therapy administered during pregnancy. A Cochrane review indicates no effect of antihypertensive therapy on the perinatal mortal-ity rate, but antihypertensive therapy was begun in the fi rst trimester in only 2 of 46 studies included in the review.419 Because pathologic and pathophysiologic changes are present as early as 14 weeks’ gesta-tion, it is possible that therapy was begun too late to have any effect on preeclampsia or fetal outcomes. There is no evidence that antihy-pertensive therapy increased perinatal mortality rates in any of these studies.420,421 If therapy is indicated for maternal considerations (dia-stolic pressure >100 mm Hg), it is safe for the fetus if the choice of drug is appropriate.422

There is some suggestion that antihypertensive therapy may be associated with an increased risk of small infants. This increase is small and driven largely by therapy with β-blockers, specifi cally atenolol.423

Overview of Therapy for Hypertension

in PregnancyAntihypertensive therapy can be used safely in pregnancy when indi-cated by the maternal condition. Therapy reduces the maternal risks of markedly elevated pressures, and in women with mild to moderate hypertension, it prevents severe hypertension later in pregnancy. The decision to use antihypertensive therapy is based on maternal considerations.

Antihypertensive medication is reserved for women with diastolic pressures above 90 mm Hg. Women using hypertensive therapy when they become pregnant, regardless of pretreatment blood pressure, are best served by continuation of therapy. There is no evidence that anti-hypertensive therapy presents a substantial risk to the fetus, and dis-continuation of therapy may adversely affect long-range compliance with drug therapy, increasing the risk to the mother.

Perhaps in no other area of medicine is therapy with the potential for benefi t or danger to two individuals so poorly evaluated. There is virtually no information from large, randomized, controlled trials about the fetal and maternal benefi ts and risks of antihypertensive therapy for mild to moderate chronic hypertension in pregnancy.

Choice of Antihypertensive AgentsEFFECT ON THE FETUSFetal considerations, particularly teratogenic concerns, infl uence

the choice of antihypertensive agents (see Chapter 20). Few of the available antihypertensive agents have been associated with morpho-logic teratogenic effects; exceptions are the angiotensin-converting enzyme (ACE) inhibitors (discussed later). Because development does not end with gross organ development, long-term follow-up of infants and children treated in utero is needed. Such information is available only for methyldopa. Children of mothers treated with this agent during pregnancy showed no signs of neurologic or somatic abnor-malities when examined at age 7 years.424

Maternal drug therapy can have pharmacologic effects on the fetus. For example, maternal treatment with propranolol reduced fetal and maternal cardiac output in animal studies.425 Because of the potential pharmacokinetic differences between mother and fetus, appropriate

dosage for the mother may be excessive for the fetus.426 Drug effects of minimal importance to the mother and fetus may be of great impor-tance to the infant.

EFFECT ON UTERINE BLOOD FLOWMaternal medication may affect fetal well-being by altering uterine

blood fl ow. Antihypertensive drugs act by reducing cardiac output or systemic vascular resistance, which may affect blood fl ow to the uterus. Optimal drug choice in pregnancy avoids agents that reduce uterine and therefore uteroplacental blood fl ow. Agents that reduce cardiac output are best avoided because they almost inevitably reduce uterine blood fl ow. Antihypertensive drugs that act on total peripheral resis-tance may increase, decrease, or have no effect on uterine perfusion, depending on the pattern of blood fl ow redistribution.

Reliable information on the effects of antihypertensive drugs on human uterine blood fl ow is scant. Data on the potential effects of these drugs are based on studies in pregnant animals in which it was assumed that humans and sheep respond identically or in which blood fl ow to the kidney—an exquisitely autoregulated organ that usually receives 10% of cardiac output—was compared with blood fl ow to the uterus, an organ whose perfusion increases 500-fold over several months. With these limitations, Table 35-10 outlines the available information about antihypertensive agents used in pregnancy.

USE OF DRUGSTwo common classes of antihypertensive medications—diuretics

and β-adrenergic blockers—warrant comment.Diuretics. The indiscriminate use of diuretic agents during preg-

nancy has appropriately been condemned and is no longer common. In an epidemiologic assessment of 8000 pregnancies, a small but sig-nifi cant increase in perinatal mortality rate was demonstrated in women receiving continued or intermittent diuretic therapy, especially when the drug was begun late in pregnancy.427 Lack of expansion of intravascular volume during pregnancy also has adverse prognostic signifi cance.337,428 In women taking diuretics from early pregnancy onward, plasma volume does not expand as much as in normal preg-nancy.429,430 Because of this, some physicians have recommended that diuretics be avoided entirely during pregnancy.286,431 However, diuretics are used frequently in nonpregnant patients for antihypertensive therapy, and their effi cacy, safety, and infrequency of side effects are extensively documented.432 The combination of diuretics with other antihypertensive drugs allows the use of lower doses of the other agents by preventing sodium retention.

Despite these theoretical concerns, when continuous diuretic therapy is begun before 24 to 30 weeks’ gestation, there is no evidence of an increased perinatal mortality rate or decreased neonatal weights.277,279 However, diuretic therapy should never be instituted if there is any evidence of reduced uteroplacental perfusion, such as fetal growth restriction or preeclampsia. Diuretic therapy increases the serum concentration of uric acid and thereby renders uric acid deter-minations invalid for evaluating superimposed preeclampsia.

b-Adrenergic Antagonists. β-Adrenergic antagonists are the initial antihypertensive agents for nonpregnant patients in many set-tings. These agents lower blood pressure by reducing cardiac output and perhaps by interfering with renin release.

Infants born to women treated with β-blockers in pregnancy are more often growth restricted compared with infants born to women treated with placebo or other antihypertensive drugs.433,434 Most growth-restricted infants were born to women who received ateno-lol.423 β-Adrenergic antagonists vary according to their β1-adrenergic subtype-specifi c (e.g., metoprolol, atenolol) and lipid solubility. For

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example, atenolol more readily crosses the placenta compared with metoprolol. Some of the β-adrenergic antagonists, such as oxprenolol, also have β-agonist effects. The decision, both theoretical and empiric, about the safety and effi cacy of these drugs requires evaluation of the pharmacologic characteristics of each drug rather than consideration of them as a class.

Labetalol. Unlike atenolol, labetalol possesses both α-adrenergic and β-adrenergic antagonist activity. It is commonly used during preg-nancy for acute treatment of preeclampsia and as therapy for chronic hypertension. Although some reports have suggested potential growth restriction,433 other studies have not.435,436 Experience has not identifi ed it as a teratogen (see Pharmacologic Recommendations, later).

Hydralazine. Although hydralazine seems to be an ideal antihy-pertensive drug for pregnant women, side effects, including headache and palpitations caused by refl ex increase in cardiac output, usually prevent its use in effective dosages for chronic hypertension. Tachy-phylaxis has been described with hydralazine, making its use limited to short-term blood pressure control.

Methyldopa. Methyldopa, the drug used in the largest study and the only drug whose safety for infants has been demonstrated in long-range follow-up assessments, is the benchmark of antihypertensive therapy in pregnancy. It frequently causes drowsiness, however, espe-cially when used in the large doses necessary when diuretics are not used concomitantly, and occasionally to a degree that is incapacitating, particularly for ambulatory patients.437 In the original examination of

infants whose mothers received methyldopa, there was a small but statistically signifi cant decrease in head circumference, although this effect was not found in follow-up studies.424

Other Drugs. Several other antihypertensive drugs are available that may offer theoretical advantages for use in pregnancy. More data are required about the effi cacy and the immediate and long-range safety of these drugs in pregnancy.

One agent that is widely used in nonpregnant patients is enalapril, an ACE inhibitor. Unexplained fetal death in pregnant ewes and rabbit does treated with another ACE inhibitor, captopril, have been borne out by clinical experience. Although there are no reports of fetal death, renal agenesis and neonatal renal dysfunction have been reported.438 This class of drugs is now considered pregnancy category X. There is less experience with angiotensin II receptor blockers (ARBs) such as losartan and telmisartan, although case reports suggest problems similar to those with ACE inhibitors.439-441 ACE inhibitors and ARBs should be discontinued before pregnancy or as soon as pregnancy is detected.442

Pharmacologic RecommendationsACE inhibitors and ARBs should be discontinued during pregnancy. No other drugs are absolutely contraindicated.

The drug regimens suggested in the following paragraphs are preferred because of the available information regarding effi cacy, side effects, and long-term follow-up. If a woman has established

TABLE 35-10 ANTIHYPERTENSIVE AGENTS USED IN PREGNANCY

Agent Mechanism Cardiac Output Renal Blood Flow

Side Effects

Maternal Neonatal

Thiazide Initial: decreased plasma volume and cardiac output

Decreased Decreased Electrolyte depletion, serum uric acid increase, thrombocytopenia, hemorrhagic pancreatitis

Thrombocytopenia

Later: decreased total peripheral resistance

Unchanged Unchanged or increased

Methyldopa False neurotransmission, central nervous system effect

Unchanged Unchanged Lethargy, fever, hepatitis, hemolytic anemia, positive Coombs test result

Hydralazine Direct peripheral vasodilation Increased Unchanged or increased

Flushing, headache, tachycardia, palpitations, lupus syndrome

Prazosin Direct vasodilator and cardiac effects

Increased or unchanged

Unchanged Hypotension with fi rst dose; little information on use in pregnancy

Clonidine Central nervous system effects

Unchanged or increased

Unchanged Rebound hypertension; little information on use in pregnancy

Propranolol β-Adrenergic blockade Decreased Decreased Increased uterine tone with possible decrease in placental perfusion

Depressed respiration

Labetalol α- and β-Adrenergic blockade

Unchanged Unchanged Tremulousness, fl ushing, headache

See propranolol

Reserpine Depletion of norepinephrine from sympathetic nerve endings

Unchanged Unchanged Nasal stuffi ness, depression, increased sensitivity to seizures

Nasal congestion, increased respiratory tract secretions, cyanosis, anorexia

Enalapril Angiotensin-converting enzyme inhibitor

Unchanged Unchanged Hyperkalemia, dry cough Neonatal anuria

Nifedipine Calcium channel blocker Unchanged Unchanged Orthostatic hypotension, headache, tachycardia

None demonstrated in humans

Ch035-X4224.indd 678 8/26/2008 4:05:46 PM


excellent blood pressure control, however, especially after unsuccessful trials of other agents, she should continue the successful regimen on becoming pregnant. Women receiving atenolol should switch to another β-adrenergic antagonist of equivalent effi cacy, such as metoprolol.

The use of diuretic therapy is associated with few acute adverse effects and potentiates other drug effects. Although the use of diuretics from early pregnancy onward appears safe,277-279 theoretical concerns raised by the effects of these agents on plasma volume militate against their use as initial therapy. Diuretics are also contraindicated for women with evidence of decreased uterine perfusion manifested as IUGR or preeclampsia. If the pregnancy is less than 30 weeks’ gestation, these drugs appear safe despite theoretical concerns. The initial dose should be 25 mg of hydrochlorothiazide equivalent, increasing at 2- to 4-day intervals to 50 mg/day. Sodium restriction should be avoided, and dietary potassium should be supplemented when diuretics are used.

Because of its established effi cacy and fetal safety, methyldopa has for many years been chosen to initiate antihypertensive therapy in pregnancy. The initial dosage is 250 mg taken at night and then 250 mg twice daily, increasing to a maximum of 1 g twice daily. If the maximal dose is not tolerated or does not control blood pressure, another agent should be added (not substituted). The addition of a diuretic usually dramatically increases the effi cacy of methyldopa.

Labetalol or nifedipine is commonly added to methyldopa therapy when a second agent is required, and they are increasingly used as fi rst-line therapy. If three drugs appear to be necessary to control blood pressure, consultation with a cardiologist or nephrologist is prudent. Used as a primary or secondary agent, labetalol is begun at 100 mg taken twice each day; it is given up to 2.4 g per day in divided doses, but the typical maximal dosage is 400 to 600 mg twice each day. Nife-dipine may be given 10 to 30 mg three times each day or as 30 to 60 mg once each day in sustained-release form.

Obstetric Management of HypertensionObstetric management of the woman with chronic hypertension com-prises the following measures:

� Recognizing superimposed preeclampsia early in the pregnancy� Monitoring fetal well-being� Excluding pheochromocytoma

Early in pregnancy, studies of renal function (i.e., creatinine clear-ance and 24-hour protein excretion), a serum urate determination, and a platelet count should be performed. These baseline studies may aid in differentiating exaggeration of the usual blood pressure changes of pregnancy from superimposed preeclampsia later in pregnancy. Because preeclampsia occurs at earlier gestational ages in hypertensive women, these patients should be seen more frequently, such as every other week at 24 to 26 weeks’ gestation and weekly after 30 weeks.

Ultrasonographic evaluation of the fetus between 18 and 24 weeks’ gestation allows accurate dating and provides a baseline for determin-ing incremental growth when there is suspicion of growth restriction. Because precise knowledge of the gestational age may become critical if early delivery is needed, a fi rst-trimester ultrasound scan to establish accurately the due date is prudent.

Most hypertensive pregnant women have essential hypertension. Thorough evaluation for most secondary forms of hypertension is best reserved for the postpartum period because of the obfuscation of many

of these forms by physiologic changes of pregnancy and because of the risks of diagnostic procedures to the mother and fetus.

Pheochromocytoma is a potentially lethal complication, especially during the intrapartum period. This condition can be simply, accu-rately, and inexpensively diagnosed in many individuals with fi xed hypertension by determination of the serum or urinary catecholamine concentration. Hypertensive women in whom this analyte has not been measured in the past should undergo this determination in early pregnancy.

Coarctation of the aorta is a rare cause of hypertension in women of reproductive age. It can be detected readily by determination of a lag between radial and femoral pulses, which should be measured as part of the physical examination of hypertensive patients.

Extensive antenatal fetal surveillance should be employed for preg-nancies with preeclampsia or growth-restricted infants.3 Because of the controversy surrounding uncomplicated hypertension and perinatal mortality and because the origin of the increased mortality is placental insuffi ciency, many clinicians employ some form of antenatal surveil-lance for uncomplicated cases in the third trimester.

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