Chapter 35Pregnancy-Related Hypertension James M. Roberts, MD, and Edmund F. Funai, MD mination. Because of the discrepancy between random protein deter- minations and 24-hour urine protein values in women withClassiﬁcation of preeclampsia (which can be higher or lower),7-9 the diagnosis shouldHypertensive Disorders be based on a 24-hour urine specimen or on a timed collection corrected for creatinine excretion if a 24-hour collection is notInterpreting epidemiologic studies of the hypertensive disorders of feasible.3pregnancy is difﬁcult because the terminology is inconsistent.1 Several Preeclampsia occurs as a spectrum but is arbitrarily divided intosystems of nomenclature are in use around the world. The system mild and severe forms. This terminology is useful for descriptive pur-prepared by the National Institutes of Health (NIH) Working Group poses but does not indicate speciﬁc diseases, nor should it indicateon Hypertension in Pregnancy,2 although imperfect, has the advantage arbitrary cutoff points for therapy. The diagnosis of severe preeclamp-of clarity and is available in published form for investigators through- sia is conﬁrmed when any of the following criteria are met10:out the world. The NIH system has four main classes: chronic hyper-tension, preeclampsia and eclampsia, preeclampsia superimposed on Blood pressure of 160 mm Hg systolic or higher or 110 mm Hgchronic hypertension, and gestational hypertension. 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+Chronic Hypertension or greater on two random urine samples collected at least 4Chronic hypertension is deﬁned as hypertension that is observable hours apartbefore pregnancy or that is diagnosed before the 20th week of gesta- Oliguria of less than 500 mL in 24 hourstion. Hypertension is deﬁned as a persistent blood pressure greater Cerebral or visual disturbancesthan 140/90 mm Hg. Hypertension for which a diagnosis is conﬁrmed Pulmonary edema or cyanosisfor the ﬁrst time during pregnancy and that persists beyond the 84th Epigastric or right upper quadrant painday after delivery is also classiﬁed as chronic hypertension. Impaired liver function Thrombocytopenia Fetal growth restrictionPreeclampsia and EclampsiaThe diagnosis of preeclampsia is determined by increased blood pres- Eclampsia is the occurrence of seizures that cannot be attributed tosure accompanied by proteinuria. The diagnosis requires a systolic other causes in a woman with preeclampsia.pressure of 140 mm Hg or higher or a diastolic pressure of 90 mm Hg Edema occurs in too many normal pregnant women to be discrimi-or higher. Diastolic blood pressure is deﬁned as the Korotkoff phase V nant and has been abandoned as a marker in preeclampsia by thevalue (i.e., disappearance of sounds). Gestational blood pressure eleva- National High Blood Pressure Education Program and by other clas-tion should be determined by at least two measurements, with the siﬁcation schemes.11,12 Edema of the hands and face occurs in 10% torepeat blood pressure performed in a manner that reduces the likeli- 15% of women whose blood pressure remains normal throughouthood of artifact and patient anxiety.3 Absent from the diagnostic cri- pregnancy.13 Edema can be massive in women with severe preeclamp-teria is the former inclusion of an increment of 30 mm Hg in systolic sia, rendering the patient virtually unrecognizable (Fig. 35-1).or 15 mm Hg in diastolic blood pressure, even when absolute valuesare below 140/90 mm Hg. This deﬁnition was excluded because avail-able evidence shows that women in this group are not likely to suffer Preeclampsia Superimposed onincreased adverse outcomes.4,5 Nonetheless, women who have an Chronic Hypertensionincrease of 30 mm Hg in systolic or 15 mm Hg in diastolic blood pres- There is ample evidence that preeclampsia can occur in women whosure warrant close observation, especially if proteinuria and hyperuri- are already hypertensive and that the prognosis for mother and fetuscemia (i.e., uric acid ≥ 5.5 mg/dL)6 are also present.3 is much worse with both conditions than with either alone. Distin- Proteinuria is deﬁned as the urinary excretion of at least 300 mg of guishing superimposed preeclampsia from worsening chronic hyper-protein in a 24-hour specimen. This usually correlates with 30 mg/dL tension tests the skills of the clinician. For clinical management, theof protein (i.e., 1+ dipstick reading) or more in a random urine deter- principles of high sensitivity and unavoidable overdiagnosis are appro-
652 CHAPTER 35 Pregnancy-Related Hypertension 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).priate, especially with advancing gestational age. The suspicion of be assigned. If blood pressure elevation persists, the diagnosis is chronicsuperimposed preeclampsia mandates close observation, with delivery hypertension. The diagnosis of gestational hypertension is used duringindicated by the overall assessment of maternal and fetal well-being pregnancy only until a more speciﬁc diagnosis can be assigned afterrather than by any ﬁxed end point. The diagnosis of superimposed delivery.3preeclampsia is highly likely with the following ﬁndings:1. In women with documented hypertension and no proteinuria Problems with Classiﬁcation before 20 weeks’ gestation The degree of blood pressure elevation that constitutes gestational New-onset proteinuria, deﬁned as the urinary excretion of 0.3 g hypertension is controversial. Because average blood pressure in of protein or more in a 24-hour specimen women younger than 30 years is 120/60 mm Hg, the standard deﬁni-2. In women with hypertension and proteinuria before 20 weeks’ tion of hypertension (i.e., blood pressure >140/90 mm Hg) is judged gestation by some to be too high,14 resulting in the suggestion that women with A sudden increase in proteinuria blood pressure increases greater than 30 mm Hg systolic or 15 mm Hg A sudden increase in blood pressure in a woman whose blood diastolic should be observed closely even if absolute blood pressure has pressure has previously been well controlled not exceeded 140/90 mm Hg.3 Objective evidence of involvement of multiple organ systems, Blood pressures measured in early pregnancy to diagnose chronic such as thrombocytopenia (platelet count < 100,000/mm3), an hypertension are problematic. Blood pressure usually decreases early increase in liver transaminases to abnormal levels,3 or sudden in pregnancy, reaching its nadir at about the time women often present worsening of renal function 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-Gestational Hypertension sequent return of blood pressure to pre-pregnant levels in late gesta-A woman who has no proteinuria and a blood pressure elevation tion may satisfy criteria for a diagnosis of preeclampsia. Women withdetected for the ﬁrst time during pregnancy is classiﬁed as having ges- hypertension before pregnancy have a greater decrease in blood pres-tational hypertension. This is a provisional diagnosis that includes sure in early pregnancy than do normotensive women,15 and they arewomen with preeclampsia who have not yet manifested proteinuria more likely to be misdiagnosed as preeclamptic according to bloodand women who do not have preeclampsia. The hypertension may be pressure criteria.accompanied by other concerning signs or symptoms that can inﬂu- The diagnosis of chronic hypertension based on the failure of bloodence management. A ﬁnal determination that the woman does not pressure to return to normal by 84 days after delivery can be in error.have preeclampsia can be made only after delivery. If preeclampsia has In a long-range, prospective study by Chesley,16 many women whonot developed and blood pressure has returned to normal by 12 weeks remained hypertensive 6 weeks after delivery were normotensive atafter delivery, the diagnosis of transient hypertension of pregnancy can long-term follow-up. Neither proteinuria nor hypertension is speciﬁc
CHAPTER 35 Pregnancy-Related Hypertension 653 gresses at various rates. In most cases, progression is slow, and the mm Hg disorder may remain mild. In others, the disease can progress rapidly, 125 changing from mild to severe over days to weeks or, in fulminant cases, Systolic progressing in days or hours. 120 PARA 0 In a series of eclamptic women analyzed by Chesley,18 25% had evidence of only mild preeclampsia in the days preceding convulsions. 115 PARA 1+ For purposes of clinical management, overdiagnosis must be accepted because prevention of the serious complications of preeclampsia and 110 eclampsia requires increased sensitivity and early treatment, primarily through the timing of delivery. For this reason, studies of preeclampsia 75 are necessarily confounded by inclusion of women diagnosed as pre- Diastolic eclamptic who have another cardiovascular or renal disorder. 70 PARA 0 65 PARA 1+ HELLP Syndrome The pathophysiologic changes of preeclampsia can occur in the absence 60 of hypertension and proteinuria. This is not surprising, because the 16 20 24 28 32 36 40 traditional diagnostic criteria have more historical than pathophysio- Gestational age (weeks) logic relevance.18 This situation presents a challenge to clinicians and demands that they remain alert to the possibility of preeclampsia inFIGURE 35-2 Blood pressure correlated with gestational age. The pregnant women with signs and symptoms that may be explained bymean blood pressure was plotted against gestational age for 6000 reduced organ perfusion. One clear setting in which this occurs is thewhite women between the ages of 25 and 34 years who delivered HELLP syndrome (hemolysis, elevated liver enzymes, and low plate-singleton term infants. (From Christianson R, Page EW: Studies on lets), a combination of ﬁndings that deﬁnes a reasonably consistentblood pressure during pregnancy: Inﬂuence of parity and age. Am J syndrome.19Obstet Gynecol 125:509, 1976. Courtesy of the American College ofObstetricians and Gynecologists.) 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 TABLE 35-1 RENAL BIOPSY FINDINGS IN preeclamptic women. Not all women with HELLP have hypertension.20 PATIENTS WITH A CLINICAL From a pathophysiologic perspective, changes in the renin-angiotensin DIAGNOSIS OF PREECLAMPSIA system characteristic of preeclampsia are not present in HELLP.21 Nonetheless, progression of the disease and its termination with deliv- Primigravidas Multigravidas ery argue for an observation and management strategy similar to that Biopsy Findings (n = 62) (n = 152) for preeclampsia. Glomeruloendotheliosis with 70% 14% or without nephrosclerosis Normal histology Chronic renal disease, chronic 5% 25% 53% 21% Preeclampsia and Eclampsia glomerulonephritis, or chronic pyelonephritis Epidemiology of Preeclampsia Arteriolar nephrosclerosis 0% 12% and Eclampsia Despite the difﬁculties in clinical diagnosis, there exists a disorder Modiﬁed from McCartney CP: Pathological anatomy of acute hypertension of pregnancy. Circulation 30(Suppl II):37, 1964; by unique to pregnancy characterized by poor perfusion of many vital permission of the American Heart Association, Inc. organs (including the fetoplacental unit) that is completely rever- sible with the termination of pregnancy. Pathologic, pathophysiologic, and prognostic ﬁndings indicate that preeclampsia is not merelyto preeclampsia, and their presence in pregnancy can have other an unmasking of preexisting, underlying hypertension. Although theexplanations. unique nature of preeclampsia has been well documented for many Renal biopsy specimens from women with preeclampsia demon- years, controversies in therapy persist because of management strate-strate these diagnostic difﬁculties (Table 35-1).17 Of 62 women with a gies based on principles used to treat hypertension in nonpregnantdiagnosis of preeclampsia in their ﬁrst pregnancies, 70% had a glo- individuals. The successful management of preeclampsia requires anmerular lesion believed to be characteristic of the disorder, but 24% understanding of the pathophysiologic changes in this condition andhad evidence of chronic renal disease that was not previously sus- recognition that the signs of preeclampsia (i.e., increased blood pres-pected. Renal biopsy specimens of multiparous women with a clinical sure and proteinuria) are only signs and do not cause the other featuresdiagnosis of superimposed preeclampsia also demonstrate the uncer- of preeclampsia.tainty of diagnosis. Of 152 subjects, only 3% had the characteristicglomerular lesion, but 43% had evidence of preexisting renal or vas- Women at Riskcular disease. Preeclampsia occurs in about 4% of pregnancies that continue past Preeclampsia has a clinical spectrum ranging from mild to severe the ﬁrst trimester. Nulliparity is the most common feature of womenforms. The illness in affected women does not begin with eclampsia or who develop preeclampsia. At least two thirds of cases occur in thethe severe manifestations of preeclampsia. Rather, the disease pro- ﬁrst pregnancy that progresses beyond the ﬁrst trimester. Other risk
654 CHAPTER 35 Pregnancy-Related Hypertensionfactors for preeclampsia are similar in nulliparous and parous Obesity is a risk factor for preeclampsia.28,51 In the National Insti-women.22 tute of Child Health and Human Development (NICHD) study of Although preeclampsia was thought to be more common among aspirin to prevent preeclampsia in low-risk pregnancies,31 the inci-women of lower socioeconomic status, this impression may be a con- dence of preeclampsia increased with maternal body mass index. Evensequence of the associations of preeclampsia with age, race, and parity. in women of normal weight, there is a linear relationship betweenStudies of pregnant women in Scotland23 from Aberdeen,24 Finland,25 pre-pregnancy body mass index and the frequency of preeclampsia.52and Israel26 found that preeclampsia was not related to socioeconomic The mechanism may be related to increased insulin resistance, becausestatus. Eclampsia, in contrast, is clearly more common in women of preeclampsia is more common in another setting of increased insulinlower socioeconomic status,23,25,26 related to the lack of availability of resistance: gestational diabetes.53 With a threefold increased risk forquality obstetric care for indigent women. Remarkably, preeclampsia obese women and with 35% to 50% of women of reproductive age inand eclampsia were once thought to occur more frequently in women the United States being obese, obesity has become a major attributableof higher socioeconomic status.18 risk factor for preeclampsia, which is associated with more than one There is a relationship between the extremes of childbearing age third of cases of preeclampsia.and the incidence of eclampsia and preeclampsia. Because most ﬁrst Certain conditions of pregnancy increase the risk of preeclampsia.pregnancies occur in young women, most cases of preeclampsia and The incidence is increased among parous and nulliparous women witheclampsia occur in this age group, but the association with young multiple gestations, although to a larger degree in the latter.36,54 In amaternal age is lost when parity is considered. In the studies cited,23,25,26 study of 34,374 pregnancies with singleton, twin, triplet, or quadrupleta higher incidence of preeclampsia was found in older women inde- pregnancies, the incidence of preeclampsia increased with each addi-pendent of parity. tional fetus. The incidences were 6.7%, 12.7%, 20.0%, and 19.6%, The relationship of preeclampsia and eclampsia to race is compli- respectively.55 The disease process may be initiated earlier and may becated by the higher prevalence of chronic hypertension in African more severe in these cases.54Americans and the difﬁculty in differentiating preeclampsia from Preeclampsia affects 70% of women with large, rapidly growingunrecognized preexisting chronic hypertension. Some studies indicate hydatidiform moles and occurs earlier than usual during gestation.56a relationship.26,27 In a small case-control study of carefully deﬁned In cases of preeclampsia occurring before 24 weeks’ gestation, hyda-preeclampsia, black race was a signiﬁcant risk factor only in nullipa- tidiform mole should be suspected and sought.rous women (odds ratio [OR] = 12.3; 95% conﬁdence interval [CI], An interesting variant of preeclampsia is the mirror syndrome, in1.6 to 100.8).28 Other studies support a more modest increased risk in which the mother’s peripheral edema mirrors the fetal hydrops. ItAfrican-American women.29,30 Studies that include the more severe occurs with fetal hydrops, although not with erythroblastosis uncom-forms of preeclampsia more often suggest an increased incidence plicated by hydrops. The incidence approaches 50% of pregnanciesamong African-American women.28 complicated by hydrops. The mirror syndrome is not conﬁned to In contrast, the incidence of rigorously deﬁned preeclampsia did hydrops resulting from isoimmunization. In one series, mirror syn-not differ by race after other risk factors were controlled in two large, drome occurred in 9 of 11 pregnancies with hydropic infants of non-prospective trials of medical prophylaxis that enrolled 294731 and immune origin.57 This condition can manifest early in pregnancy with431432 nulliparous women. Maternal nonwhite race appears to be severe signs and symptoms of preeclampsia, and it has resolved withrelated more to the severity than the incidence of disease. treatment of the underlying process.58-60 Proteinuria is massive, and A diverse array of medical disorders that often coexist with preg- blood pressure elevation and edema are marked. Eclampsia occursnancy, including diabetes, chronic hypertension, chronic renal disor- rarely (see Chapter 26).ders, and rheumatologic conditions, have been associated withpreeclampsia. The existence and severity of diabetes have beenassociated with an increased risk for preeclampsia, and diabetic Short-Term Prognosis for Preeclampsiamicrovascular disease further increases this risk. This relationship PERINATAL MORTALITYhas been found in Sweden33 and in the United States.34 Both The perinatal mortality rate is increased in infants of preeclampticstudies33,34 demonstrated that the risk of preeclampsia was approxi- women.61-63 In a study that examined 10,614,679 singleton pregnanciesmately 20% and 21% in 491 and 462 pregnancies, respectively. This in the United States from 1995 to 1997 after 24 weeks’ gestation, theestimate is far more modest than the 50% incidence reported in his- relative risk for fetal death was 1.4 for infants born to women with anytorical cohorts.18 The preeclampsia risk increased according to the of the gestational hypertensive disorders and 2.7 for those born toseverity of disease, with an 11% to 12% risk among women with class women with chronic hypertensive disorders compared with low-riskB diabetes and 21% to 23% with class C and D diabetes. Microvascular controls. Causes of perinatal death are placental insufﬁciency anddisease increased this risk to 36% to 54% in diabetics with class F or abruptio placentae,64 which cause intrauterine death before or duringR disease.33,34 labor, and prematurity. Predictably, the mortality rate is higher for Chronic renal insufﬁciency and hypertension are well-recognized infants of women with more severe forms of the disorder. At any levelrisk factors. Of women with hypertension antedating pregnancy, 25% of disease severity, the perinatal mortality rate is greatest for womendevelop preeclampsia.35,36 Renal insufﬁciency with33,37 and without dia- with preeclampsia superimposed on preexisting vascular disease.betes38-40 also is an important risk factor.38,40 The stillbirth rate attributable to preeclampsia has declined dra- Connective tissue disorders such as systemic lupus erythe- matically in the past 35 years. However, infants born of preeclampticmatosus41,42 and antiphospholipid antibody syndrome43-45 have been pregnancies continue to have an approximately twofold increased riskreported as risk factors for preeclampsia. With lupus, the risk is par- for neonatal death.65 Although neonatal survival rates have improvedticularly elevated with hypertension or nephropathy.46,47 However, dramatically, delivery before 34 weeks’ gestation continues to be associ-data concerning an association between isolated antiphospholipid ated with an increased risk of long-range neurologic disability (seeantibodies and preeclampsia have been conﬂicting, with some Chapter 58).studies demonstrating no relationship48,49 and others conﬁrming the Growth restriction is more common in infants born to preeclamp-association.44,50 tic women (see Chapter 34) and more pronounced with increasing
CHAPTER 35 Pregnancy-Related Hypertension 655severity and earlier diagnosis.66 As with perinatal mortality, intrauter- To determine the subsequent pregnancy outcomes of women whoine growth restriction (IUGR) is more common in infants of chroni- clearly had preeclampsia, Chesley and colleagues74 followed 270 womencally hypertensive women with superimposed preeclampsia.67 with eclampsia for more than 40 years; only two were lost to follow-up. The dramatic decrease in perinatal mortality rate among infants of Among 187 women who had eclampsia in the ﬁrst pregnancy, 33% hadpreeclamptic women is the result in part of improved medical and a hypertensive disorder in any subsequent pregnancy. In most, theobstetric management, including improved assessment of fetal well- condition was not severe, but 5% had recurrent eclampsia. Twentybeing in the antepartum and intrapartum periods. The primary effect women with eclampsia as multiparas had recurrent hypertension inon the perinatal mortality rate, however, has come from improvements 50% of subsequent pregnancies.in neonatal care. Women with a clinical diagnosis of preeclampsia have increased risk for hypertensive disorders in subsequent pregnancies. The chances MATERNAL MORTALITY of recurrence decrease as the likelihood of true preeclampsia increases. Maternal death associated with preeclampsia predominantly re- If the condition does recur, it will usually not be worse, and if pre-sults from complications of abruptio placentae, hepatic rupture, and eclampsia truly arose de novo, it probably will be less severe in subse-eclampsia. Historically, the mortality rate of eclamptic women was quent pregnancies. Some women, however, are normotensive betweenmost effectively reduced by avoiding iatrogenic complications related pregnancies but have recurrent preeclampsia. The risk of such recur-to overmedication and overzealous attempts at vaginal delivery. In rence is increased when preeclampsia occurs in the late second orseries from the late 19th century, when immediate delivery was the early third trimester.73 The recurrence of severe preeclampsia orpractice, the mortality rate of eclamptic women was 20% to 30%. eclampsia in one pregnancy predicts its likely recurrence in subsequentExpectant management with profound maternal sedation with narcot- pregnancies.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 Preeclampsia and Cardiovascular Diseasein the 1920s and 1930s resulted in a maternal mortality rate of 5%. in Later LifeAlthough magnesium was undoubtedly helpful, the primary factor Evidence that preeclampsia is associated with long-term maternalresponsible for improved mortality was decreased maternal sedation.18 health consequences is based on the work of Chesley and coworkers,74The currently used combination of magnesium sulfate (MgSO4) and who followed a cohort of white women with eclampsia in their ﬁrstantihypertensive drugs as sole pharmacologic agents, followed by pregnancy and reported no increased risk of subsequent chronictimely delivery, has produced a maternal mortality rate of almost hypertension. However, mortality was twofold to ﬁvefold higher overzero68,69 because of an appreciation of the profound pathophysiologic the next 35 years among women with eclampsia in any pregnancy afterabnormalities of preeclampsia, careful cardiopulmonary monitoring, the ﬁrst (Fig. 35-3). The ﬁndings of Chesley and colleagues74 led toand limitation of unproven interventions. speculation that multiparous women with preeclampsia or eclampsia were more likely to have had unrecognized underlying chronic hyper- RECURRENCE IN SUBSEQUENT PREGNANCIES tension and that this, not preeclampsia, caused the subsequent increase Data from classic series indicate that the likelihood of recurrent in mortality. Sibai and associates71 also found that women with recur-preeclampsia is inﬂuenced by the certainty of the clinical diagnosis in rent preeclampsia were more likely to develop chronic hypertension.the ﬁrst pregnancy. Of 225 women with hypertension during preg- These studies are the basis for a statement by The National High Bloodnancy chosen for study without regard to parity, 70% had a recurrence Pressure Education Program’s Working Group on High Blood Pressureof preeclampsia in their next pregnancy.70 In a study of primiparas with during Pregnancy that recurrent hypertension in pregnancy, pre-severe preeclampsia, the recurrence rate was 45% .71 Because the diag- eclampsia in a multipara, and early-onset disease in any pregnancy maynosis in these studies was based solely on clinical ﬁndings, these groups all herald increased future health risks.2probably included patients with unrecognized preexisting blood pres- Women with idiopathic preeclampsia (i.e., preeclampsia occurringsure elevation or underlying renal or cardiovascular disease. in nulliparous women without underlying renal or cardiovascular Recurrence rates were reported in 2006 for 896 parous women in disease, including chronic hypertension) were not thought to haveIceland according to standardized diagnostic criteria in both pregnan- increased risk of later vascular disease until a report from Norway75cies (i.e., National High Blood Pressure Criteria3). The rates of recur- found modest (1.65-fold) increased cardiovascular mortality for nul-rence differed substantially by the diagnosis in the ﬁrst pregnancy, as liparous women with preeclampsia at term and an eightfold increasedseen in Table 35-2.72 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 Second Pregnancy* Gestational Chronic Superimposed All First Pregnancy Normal Hypertension Preeclampsia Hypertension Preeclampsia 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.
656 CHAPTER 35 Pregnancy-Related Hypertension 100 TABLE 35-3 SIGNS AND SYMPTOMS OF PREECLAMPSIA OR ECLAMPSIA 90 Cerebral Blurred vision Headache Amaurosis 80 Percentages surviving Dizziness Gastrointestinal Tinnitus Nausea 70 Drowsiness Vomiting Change in respiratory rate Epigastric pain 60 Tachycardia Hematemesis Fever Renal 50 Visual Oliguria Diplopia Anuria 40 Scotomata Hematuria Hemoglobinuria 30 dyslipidemia,92 altered angiogenic factors,93 and increased antibodies 10 20 30 40 45 to the angiotensin-2 receptor.94 These data may explain the common Years risk factors for preeclampsia and cardiovascular disease, but alternativeFIGURE 35-3 Eclampsia survivorship. Survival times are plotted explanations, such as that preeclampsia causes vascular injury thatfor women with eclampsia in the ﬁrst pregnancy (solid line) and those increases cardiovascular risk or that normal pregnancies have a protec-with eclampsia in a later pregnancy (dashed line). Survival of women tive effect, cannot be excluded.with ﬁrst-pregnancy eclampsia was not different from survival of acontrol group. (From Chesley LC, Annitto JE, Cosgrove RA: Theremote prognosis of eclamptic women: Sixth periodic report. Am J Clinical PresentationObstet Gynecol 124:446, 1976, Courtesy of the American College of Preeclampsia can manifest with a wide spectrum of disease, rangingObstetricians and Gynecologists.) from life-threatening neurologic, renal, hepatic, and coagulation abnormalities to mild ﬁndings of preeclampsia with minimal end- organ involvement. The fetus may be severely compromised by theScottish investigators reported a fourfold increased risk of subsequent maternal condition and by extreme preterm delivery or only minimallyhypertension in nulliparous women with preeclampsia2,76,77 (OR = affected. These variations have puzzled clinicians and researchers for3.98; CI, 2.82 to 5.61). Funai and colleagues78 described excess long- many years. An understanding of the pathophysiology of the disorderterm mortality in women with prior preeclampsia that was largely provides insight into the diverse clinical presentations.attributed to a threefold increase in deaths due to cardiovasculardisease. Other reports support a link between preeclampsia and mater- Symptomsnal ischemic heart disease,79,80 which is sometimes evident 20 years Most women with early preeclampsia are asymptomatic. The absenceafter the preeclamptic pregnancy and coincident with the onset of of symptoms is the rationale for frequent obstetric visits in late preg-menopause.78,80 A family history of cardiovascular disease increases the nancy. In most cases, signs such as increased blood pressure and pro-association between preeclampsia and cardiovascular outcomes.81 teinuria antedate overt symptoms.Obesity is a known risk factor for preeclampsia and cardiovascular The various symptoms associated with preeclampsia, especiallydisease. Although controlling for obesity attenuates the increased risk preeclampsia of increasing severity, are listed in Table 35-3. Becauseof death for postmenopausal women, this risk is not fully explained by preeclampsia is a disease of generalized poor perfusion, the diversityobesity alone.82 of symptoms related to many organ systems is not surprising. Symp- The relationships among obesity, insulin resistance, and preeclamp- toms suggesting hepatic, neurologic, and visual involvement are par-sia are part of an interesting relationship of preeclampsia to the meta- ticularly worrisome. They include epigastric pain, “stomach upset,” andbolic or insulin resistance syndrome.83 This syndrome predisposes to pain penetrating to the back. Headache and mental confusion indicatecardiovascular disease in later life and consists of obesity, hypertension, poor cerebral perfusion and may be precursors of convulsions. Visualdyslipidemia (i.e., increased low-density lipoprotein [LDL] cholesterol, symptoms ranging from scotomata to blindness indicate retinal arte-decreased high-density lipoprotein [HDL] cholesterol, and increased rial spasm and edema. Symptoms suggesting congestive heart failuretriglycerides), and increased uric acid, all of which are found in women or abruptio placentae also represent signiﬁcant complications of pre-with preeclampsia.83 Other conditions predisposing to later-life cardio- eclampsia. Other symptoms, such as tightness of hands and feet andvascular disease—including elevated levels of homocysteine,84 evidence paresthesias resulting from medial or ulnar nerve compression, mayof androgen excess (including polycystic ovarian syndrome),85 elevated alarm the patient but have little prognostic signiﬁcance.testosterone levels,86 male fat distribution (i.e., increased waist-to-hipratio),87 and lipoprotein lipase mutations88—are also linked to an Signsincreased risk for preeclampsia. Signs of preeclampsia usually antedate symptoms. The most common Women who appear normal years after a preeclamptic pregnancy sequence is increased blood pressure followed by proteinuria.18may nevertheless demonstrate subtle metabolic and cardiovascularabnormalities. Compared with women with uncomplicated pregnan- BLOOD PRESSURE CHANGEcies, formerly preeclamptic women have evidence of endothelial dys- An increase in blood pressure is required for the diagnosis offunction,89,90 higher blood pressures,89 increased insulin resistance,91 preeclampsia. Blood pressure variation in normal pregnancy can
CHAPTER 35 Pregnancy-Related Hypertension 657lead to misdiagnosis. In clinical practice, the serious effects of pre- HYPERREFLEXIAeclampsia on the mother and fetus warrant such overdiagnosis. The Although hyperreﬂexia is given much clinical attention and deepprimary pathophysiologic alteration, poor tissue perfusion resulting tendon reﬂexes are increased in many women before seizures, convul-from vasospasm, is revealed more by blood pressure changes than by sions can occur in the absence of hyperreﬂexia,68 and many pregnantabsolute blood pressure levels. Although a diagnosis of preeclampsia women are consistently hyperreﬂexic without being preeclamptic.is not made without absolute blood pressure increases to 140 mm Hg Changes, or lack thereof, in deep tendon reﬂexes are not part of thesystolic or 90 mm Hg diastolic, women who reach this level from a low diagnosis of preeclampsia.early pregnancy value typically manifest more vasospasm than thosefor whom 140/90 mm Hg represents a smaller increase. OTHER SIGNS Although maternal and fetal risks rise with increasing blood pres- Other signs that occur less commonly in preeclampsia are indica-sure,95 serious complications can occur in women who experience only tors of involvement of speciﬁc organs in the preeclamptic process.modest blood pressure elevation. In two series, 20% of women with Women with marked edema may have ascites and hydrothorax, andeclampsia never had a systolic blood pressure above 140 mm Hg.18,96 those with congestive heart failure display increased neck vein disten-In a large, prospective study from the United Kingdom, there were 383 tion, gallop rhythm, and pulmonary rales. Hepatic capsular distention,conﬁrmed cases of eclampsia, of which 77% were hospitalized before manifested by hepatic enlargement and tenderness, is a particularseizures occurred. Of these, 38% of the cases were not preceded by concern, as is disseminated intravascular coagulation (DIC) sufﬁcientdocumented proteinuria or hypertension.97 Others have noticed similar to cause petechiae or generalized bruising and bleeding.ﬁndings.98,99 Laboratory Findings PROTEINURIA Major changes revealed by laboratory studies occur in severe pre- Among the diagnostic signs of preeclampsia, proteinuria in the eclampsia and eclampsia. In the patient with mild preeclampsia,presence of hypertension is the most reliable indicator of fetal jeopardy. changes in most of these indicators may be minimal or absent.In two studies of preeclampsia, the perinatal mortality rate tripled forwomen with proteinuria,100 and the amount of proteinuria correlated RENAL FUNCTION STUDIESwith increased perinatal mortality rate and the number of growth- Serum Uric Acid Concentration and Urate Clearance. Uricrestricted infants.101 A later study demonstrated that the risk for acid is the most sensitive laboratory indicator of preeclampsia availabledelivering a small-for-gestational-age fetus was higher in women with to clinicians. A decrease in uric acid clearance precedes a measurablehypertension and proteinuria (52%) compared with women with new- decrease in the glomerular ﬁltration rate (GFR). Hypertension withonset gestational hypertension (15%) or chronic hypertension (12%). hyperuricemia but without proteinuria was associated with growthThe perinatal mortality rate was fourfold higher with proteinuria restriction as commonly as hypertension and proteinuria without ele-and hypertension than in pregnancies complicated by hypertension vated uric acid in one series.105 Although increased serum uric acidalone.102 concentration is often attributed to altered renal function, an alterna- tive view favors increased production caused by oxidative stress.106 An RETINAL CHANGES elevated uric acid level may itself have pathogenic effects.107 Table 35-4 Retinal vascular changes on funduscopic examination occur in shows normal uric acid levels during gestation and levels associatedretinal arterioles in at least 50% of women with preeclampsia, and they with preeclampsia.are important because they correlate best with renal biopsy-proven Serum Creatinine Concentration and Creatinine Clearance.changes of preeclampsia.103 Localized retinal vascular narrowing is Creatinine clearance is decreased in most patients with severe pre-visualized as segmental spasm, and the generalized narrowing is indi- eclampsia, but it can be normal in women with mild disease. Serialcated by a decrease in the ratio of arteriolar-venous diameter from serum creatinine determinations may indicate decreased clearance, butthe usual 3 : 5 to 1 : 2 or even 1 : 3. It can occur in all vessels or, in early single values are not helpful unless markedly elevated because of thestages, in single vessels.104 Preeclampsia does not cause chronic arterio- wide range of normal values. The serum creatinine concentrationlar changes; the presence of arteriolar sclerosis detected by increased varies as a geometric function of creatinine clearance so that smalllight reﬂex, copper wiring, or arteriovenous nicking indicates preexist- changes in glomerular ﬁltration are best determined by measurementsing vascular disease. of creatinine clearance. TABLE 35-4 PLASMA URATE CONCENTRATIONS IN NORMOTENSIVE AND HYPERTENSIVE PREGNANT WOMEN Normotensive Patients Hypertensive Patients Weeks of Gestation mmol/L SD* mg/dL mmol/L SD* mg/dL 24-28 0.18 (20%) 3.02 0.24 (20%) 4.03 29-32 0.18 (35%) 3.02 0.28 (25%) 4.7 33-36 0.20 (30%) 3.36 0.30 (20%) 5.04 37-40 0.26 (20%) 4.4 0.31 (23%) 5.28 41-42 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). Modiﬁed from Shuster E, Weppelman B: Plasma urate measurements and fetal outcome in preeclampsia. Gynecol Obstet Invest 12:162, 1981.
658 CHAPTER 35 Pregnancy-Related Hypertension LIVER FUNCTION TESTS Although most tests of liver function are not highly predictive ofseverity of preeclampsia,18 the association between microangiopathicanemia and elevations in aspartate aminotransferase (AST) and alanineaminotransferase (ALT) carries an especially disturbing prognosis forthe mother and infant.19,108 These ﬁndings usually correlate with theseverity of disease and, when associated with hepatic enlargement, maybe a sign of impending hepatic rupture. COAGULATION FACTORS Although overt DIC is rare, subtle evidence of activation of thecoagulation cascade occurs in many women with preeclampsia. Theaverage platelet count in the patient with mild preeclampsia is similarto the platelet count in normal pregnant women.109 However, carefulplatelet counts performed sequentially may reveal decreased plateletsin many patients.110 Highly sensitive indicators of activation of theclotting system, reduced serum concentrations of antithrombin III,111a decrease in the ratio of factor VIII bioactivity to factor VIII antigen,112and subtle indicators of platelet dysfunction, including alteration of FIGURE 35-4 Hemorrhagic hepatic lesions in eclampsia.turnover,6 activation,113 size,114 and content,115 exist in even mild pre- Hemorrhage into the periportal area occurred with crescenticeclampsia and may antedate clinically evident disease. compression of liver cells. (From Sheehan HL, Lynch JB: Pathology of Toxemia in Pregnancy. London, Churchill Livingstone, 1973.) METABOLIC CHANGES Preeclampsia is characterized by an increase in the insulin resis-tance of normal pregnancy. Signs of the insulin resistance syndromeare exaggerated.110 Levels of circulating lipids already elevated innormal pregnancy116 are accentuated in women with preeclampsia.117Triglycerides and fatty acid levels are elevated, changes that antedateclinically evident disease by weeks to months.118,119 Levels of the car-dioprotective HDL cholesterol are reduced in preeclamptic women,120whereas levels of a variant of LDL cholesterol (i.e., small, dense cho-lesterol that is strongly associated with cardiovascular disease) areincreased.121,122 These changes resolve after delivery.Pathologic Changes in PreeclampsiaThe pathologic changes found in organs of women dying of eclampsiaand in biopsy specimens from women with preeclampsia providestrong evidence that preeclampsia is not merely an unmasking ofessential hypertension or a variant of malignant hypertension. Theseﬁndings also indicate that the elevation of blood pressure probablydoes not have primary pathogenetic importance.Brain FIGURE 35-5 Hepatic infarction in eclampsia. Hepatic infarction caused by intense vasospasm manifests as small to large areasCerebral edema, once thought to be a common ﬁnding in women beginning near the sinusoids and extending into the area near thedying of eclampsia, was uncommon among postmortem examinations portal vessels. (From Sheehan HL, Lynch JB: Pathology of Toxemia inperformed within 2 to 3 hours of death.123 However, studies using Pregnancy. London, Churchill Livingstone, 1973.)computed tomography again raised the possibility that cerebral edemais an important pathophysiologic event in some women with pre-eclampsia.124 Noninvasive studies of cerebral blood ﬂow and resistance results from vasodilatation of arterioles, producing dislocation andsuggest that vascular barotrauma and loss of cerebral vascular auto- deformation of the hepatocytes in their stromal sleeves (Fig. 35-4).regulation contribute to the pathogenesis of cerebral vascular pathol- Later, intense vasospasm causes hepatic infarction, ranging from smallogy in cases of preeclampsia or eclampsia.125 to large areas beginning near the sinusoids and extending into the area near the portal vessels (Fig. 35-5). Hemorrhagic changes are present inLiver 66% and necrotic changes in 40% of eclamptic women and in aboutGross lesions of the liver are visible in about 60% of women dying of one half as many preeclamptic women. Hyalinization and thrombosiseclampsia, and one third of the remaining livers are microscopically of hepatic vessels have been cited as evidence of DIC, but they may beabnormal. Many early investigators thought that the hepatic changes the result of hemorrhage.were pathognomonic for eclampsia,126 but similar changes have beendescribed in women dying of abruptio placentae.127 Kidney Two temporally and etiologically distinct hepatic lesions have been The pathologic renal changes of preeclampsia and eclampsia are clearlydescribed.123 Initially, hemorrhage into the hepatic cellular columns different from those seen in other hypertensive or renal disorders.
CHAPTER 35 Pregnancy-Related Hypertension 659 EN BM RFIGURE 35-6 Glomerular changes in preeclampsia are identiﬁed Aby light microscopy. The enlarged glomerulus completely ﬁllsBowman’s capsule. Diffuse edema of the glomerular wall is indicated Ep Cyby the vacuolated appearance. The visible capillary loops areextremely narrow, and there are virtually no red blood cells in thecapillary tuft. EnGlomerular, tubular, and arteriolar changes have been described. Theglomerular lesion is considered by some to be pathognomonic of pre-eclampsia and eclampsia, but identical changes have been seen in pla- BS Rcental abruption without evident preeclampsia.128 This change is not Enseen in any other form of hypertension. Ep GLOMERULAR CHANGES Changes 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 Pthe glomerular capillary lumen is decreased and contains few bloodcells. The endothelial-mesangial cells have increased cytoplasmic Bvolume and can contain lipoid droplets (Fig. 35-6). Electron microscopic examination of glomeruli provides more evi- FIGURE 35-7 Electron photomicrographs of renal glomeruli.dence that the primary pathologic change occurs in endothelial cells, A, Normal anatomy. B, Biopsy specimen from a preeclamptic woman.which are greatly increased in size and can occlude the capillary lumen; Endothelial cells (En) are markedly enlarged, obstruct the capillarytheir cytoplasm contains electron-dense material.129 The basement lumen, and contain electron-dense inclusions. The basementmembrane bordering the epithelial cell may be slightly thickened, and membrane (BM) is slightly thickened with inclusions, but theit also contains electron-dense material. The epithelial cell podocytes epithelial foot processes (EP) are normal. BM, basement membrane;are not altered (Fig. 35-7). These changes are collectively called glo- BS, Bowman’s space; Cy, cytoplasmic inclusions; EN, capillary endothelial cells that line the glomeruli; Ep, renal epithelial cells; L,merular capillary endotheliosis. capillary lumen containing red blood cells; P, podocytes; R, red blood Characteristic glomerular changes occur in 70% of primiparas cell. (From McCartney CP: Pathological anatomy of acutebut in only 14% of multiparas with a diagnosis of preeclampsia.17 The hypertension of pregnancy. Circulation 30[Suppl II]:37, 1964. Bymore likely the diagnosis of preeclampsia, the more common the glo- permission of the American Heart Association, Inc.)merular lesion. As the clinical condition worsens, the magnitude of theglomerular lesion increases. The glomerular lesions are reversible afterdelivery and are not present in subsequent biopsy specimens obtained5 to 10 weeks later.103 NONGLOMERULAR CHANGES The glomerular changes correlate more consistently with protein- Pathologic changes in renal tubules include dilatation of proximaluria than with hypertension, suggesting that proteins identiﬁed immu- tubules with thinning of the epithelium,123 tubular necrosis,103 enlarge-nohistochemically may be trapped in the glomerulus. These staining ment of the juxtaglomerular apparatus,131 and hyaline deposition inpatterns are not found in other renal disorders with proteinuria. The renal tubules.123 Fat deposition in women with prolonged heavy pro-glomerular changes of preeclampsia can be mimicked in animal studies teinuria has been reported.123 Necrosis of the loop of Henle, a changeby reducing the renal concentration of vascular endothelial growth that correlates with the degree of hyperuricemia, has also beenfactor (VEGF), which usually exists in high concentration in this tissue described.131by increasing the synthesis of the VEGF antagonist soluble Fms-like Thickening of renal arterioles may be seen in preeclampsia, espe-tyrosine kinase 1 (sFlt1).130 cially in women with preexisting hypertension. Unlike the glomerular
660 CHAPTER 35 Pregnancy-Related Hypertension SpinalEndometrium Basal Radial ArcuateMyometrium AFIGURE 35-8 Schematic representation of uterine arteries. Thecharacteristic changes occur in the decidual vessels supplying theplacental site in a normal pregnancy. (From Okkels H, Engle ET:Studies of the ﬁner structure of the uterine vessels of the Macacusmonkey. Acta Pathol Microbiol Scand 15:150, 1938.)lesion, it does not regress after delivery,103 suggesting that the arteriolarchange results from coincident disease, not preeclampsia. BVascular Changes in the Placental Site FIGURE 35-9 Spiral arterial changes in normal pregnancy. A, InThe characteristic changes in the decidual vessels supplying the pla- the section of spiral arterioles at the junction of the endometrium andcental site in normal pregnancy are depicted in Figure 35-8. In normal myometrium in a nonpregnant woman, notice the inner elastic laminapregnancy, the spiral arteries (Fig. 35-9) increase greatly in diameter.132 and smooth muscle. B, In a section of a spiral arteriole at the sameMorphologically, the endothelium is replaced by trophoblast, and the scale and from the same location during pregnancy, notice theinternal elastic lamina and smooth muscle of the media are replaced markedly increased diameter and absence of inner elastic lamina andby trophoblast and an amorphous matrix-containing ﬁbrin (see smooth muscle. (From Sheppard BL, Bonnar J: UteroplacentalFig. 35-9).133 These changes occur originally in the decidual portion of arteries and hypertensive pregnancy. In Bonnar J, MacGillivray I, Symonds G [eds]: Pregnancy Hypertension. Baltimore, University Parkthe spiral arteries but extend into the myometrium as pregnancy Press, 1980, p 205.)advances and can even involve the distal portion of the uterine radialartery. The basal arteries are not affected. These morphologic changesare considered to be a vascular reaction to the trophoblast, occurringdirectly or humorally, that results in increased perfusion of the placen-tal site. In placental-site vessels of women with preeclampsia, the normalphysiologic changes do not occur, or they are limited to the decidualportion of the vessels. Myometrial segments of spiral arteries retain thenonpregnant 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 Fradial arterioles may become necrotic, with components of the normalvessel wall replaced by amorphous material and foam cells, a changecalled acute atherosis (Fig. 35-10).135 This lesion is best seen in the basalarteries because they do not undergo the normal changes of pregnancy.It is also present in decidual and myometrial spiral arteries and canprogress to vessel obliteration. The obliterated vessels correspond toareas of placental infarction. Failed vascular remodeling and atherotic changes may be seenwith fetal growth restriction in women without clinical evidence of FIGURE 35-10 Atherosis. Numerous lipid-laden cells (L) and ﬁbrinpreeclampsia. Atherotic changes occur in decidual vessels of some dia- deposition (F) are present in the media of this occluded decidualbetic women,136 and failed vascular remodeling is present in about vessel. (From Sheppard BL, Bonnar J: Uteroplacental arteries andone third of women who experience preterm labor.137 It appears hypertensive pregnancy. In Bonnar J, MacGillivray I, Symonds Gthat abnormal invasion may be necessary but is not sufﬁcient to cause [eds]: Pregnancy Hypertension. Baltimore, University Park Press,preeclampsia. 1980, p 205.)
CHAPTER 35 Pregnancy-Related Hypertension 661 Changes characteristic of preeclampsia have been observed in the hypertension. Second, the pathologic ﬁndings indicate that the primarydecidual vessels of one in seven primiparous women and in a lower pathology is poor tissue perfusion, not blood pressure elevation. Thepercentage of multiparous women at the time of ﬁrst-trimester abor- histologic data support the clinical impression that the poor perfusiontion.138,139 These ﬁndings suggest that disordered placentation precedes results from profound vasospasm, which increases total peripheralthe clinical presentation of preeclampsia. The cause of the decidual resistance and blood pressure.vascular lesions is unknown. The appearance of the atherotic vesselsresembles vessels in transplanted kidneys that have undergone rejec-tion, suggesting an immunologic cause, which is consistent with ﬁnd- Pathophysiologic Changesings of a study that demonstrated components of complement (e.g., in PreeclampsiaC3) in decidual vessels with the lesion.140 Preeclampsia can cause changes in virtually all organ systems. Several The vascular remodeling of spiral arteries supplying the intervillous organ systems are consistently and characteristically involved, andspace is intimately related to normal trophoblast invasion.141 The these are discussed in the following sections.expression of adhesion molecules and their receptors that characterizesimplantation is abnormal in preeclampsia.142 The trophoblast that lines Cardiovascular Changesthe decidual vessels of normal pregnant women begins to express Blood pressure is the product of cardiac output and systemic vascularmolecules usually present only on endothelium,143 a phenomenon that resistance. Cardiac output is increased by up to 50% in normal preg-does not occur in preeclampsia.144 Potential mechanisms responsible nancy, but blood pressure does not usually increase, indicating thatfor the normal and abnormal changes include decidually produced systemic vascular resistance decreases. Blood pressure is lower in thecytokines145-147 and local oxygen tension.148,149 There may be interac- ﬁrst half of pregnancy than in the postpartum period, when cardiactions of speciﬁc molecules on trophoblast and maternal decidual cells output returns to nonpregnant levels (see Fig. 35-2). Some womenthat drive invasion. Invasive cytotrophoblasts express a human leuko- destined to develop preeclampsia have a higher cardiac output beforecyte antigen (HLA) molecule (HLA-C) that is minimally hetero- clinically evident disease. However, cardiac output is reduced to pre-geneous. Interaction of this molecule with a receptor on maternal pregnancy levels with the onset of clinical preeclampsia.157,158 Althoughdecidual cells, killer immunoglobulin receptors (KIRs), causes various some studies suggest increased cardiac output,159 most have founddegrees of activation of the trophoblast cell, depending on the combi- normal or slightly reduced cardiac output in women with untreatednation of KIR and HLA-C subtypes. Mothers with the minimally acti- preeclampsia.160 Increased systemic vascular resistance is the mecha-vating KIR subtype who have a fetus with a speciﬁc HLA-C subtype nism for the increase in blood pressure in clinical preeclampsia.(HLA-C2) have an increased frequency of preeclampsia. This is not an There is substantial evidence that arteriolar narrowing occurs inimmune interaction because the relationship persists regardless of preeclampsia. Changes in the caliber of retinal arterioles correlate withmaternal HLA-C subtype. Researchers propose that this combination the clinical severity of the disorder and with renal biopsy-conﬁrmeddoes not favor trophoblast invasion and vascular remodeling. Popula- diagnosis of preeclampsia.103 Similar ﬁndings occur in vessels of thetion studies indicate that populations in which HLA-C2 is common nail bed and conjunctiva. Measurements of forearm blood ﬂow indi-have a reduced frequency of the speciﬁc inhibitory KIR subtype and cate higher resistance in preeclamptic than in normal pregnantvice versa.150 women.161,162 It is unlikely that this effect is determined by the auto- nomic nervous system. Although normal pregnant women are exqui-Placental Pathologic Changes sitely sensitive to the interruption of autonomic neurotransmission byUltrastructural examination of placentas from women with pre- ganglionic blockade and high spinal anesthesia, preeclamptic womeneclampsia reveals an abnormal syncytiotrophoblast containing areas of are less sensitive.163 This ﬁnding suggests that the arteriolar constric-cell death and degeneration. Viable-appearing syncytiotrophoblast is tion of preeclampsia is not maintained by the autonomic nervousalso abnormal, with decreased density of microvilli, dilated endoplas- system and that humoral factors are implicated. The increased sympa-mic reticulum, and decreased pinocytotic and secretory activity. The thetic activity in preeclampsia, however, raises questions about thesecells of the villous cytotrophoblast cells are increased in number and older ﬁndings.164 Assays of concentrations of recognized endogenoushave higher mitotic activity. The basement membrane of the tropho- vasoconstrictors are limited to determinations of catecholamines andblast is irregularly thickened, with ﬁne ﬁbrillary inclusions.151 angiotensin II. Results suggest minimal or no change in catechol- The changes may be caused by local hypoxia. Similar syncytiotro- amines, whereas circulating angiotensin II concentrations are lower inphoblastic changes are present in placental segments maintained under preeclamptic women.165hypoxic conditions in vitro.152 The cytotrophoblastic alterations are Levels of endothelin-1, a vasoconstrictor produced by endothelialalso consistent with hypoxia. The cytotrophoblasts comprise the stem cells, are increased in the blood of preeclamptic women166 at concen-cells of the trophoblast and responds to damage by proliferation. The trations much lower than those necessary to stimulate vascular smoothtrophoblast of the preeclamptic placenta is characterized by increased muscle contraction in vitro. It is not clear whether these circulatingapoptosis and necrosis,153,154 possibly caused by hypoxia or hypoxia concentrations reﬂect endothelial production sufﬁcient to stimulatereperfusion injury,155 and this may be the origin of the increased cir- local vasoconstriction or low concentrations of endothelin potentiateculating syncytiotrophoblast microparticles in preeclampsia.156 contractile responses to other agonists. As indicated by the older term toxemia, early investigators sus-Summary of Pathologic Changes pected that preeclampsia was caused by circulating humors. Earlyin Preeclampsia reports suggesting etiologic agents such as pressor substances in blood,Structural changes associated with preeclampsia and eclampsia lead to decidual extracts, placental extracts, and amniotic ﬂuid of preeclamp-two important conclusions. First, preeclampsia is not an alternate form tic patients have not been replicated. The explanation for the pressorof malignant hypertension. The renal changes in preeclamptic and effects was, in some studies, normal endogenous pressors; in others,eclamptic women and the structural changes in other organs of women the explanation was faulty methodology and failure to recognize thedying of eclampsia differ from the alterations caused by malignant immunologic difference between the source of the extract and the
662 CHAPTER 35 Pregnancy-Related Hypertension 50 50 Preeclampsia Preeclampsia Nonpregnant Nonpregnant 40 Normal pregnancy MBP, mm Hg Normal pregnancy 40 MBP, mm Hg 30 30 20 20 10 10 5 10 15 25 50 100 200 5 10 15 25 50 100 200 Dose, ng/kg Dose, ng/kgFIGURE 35-11 Mean dose-response graphs for norepinephrine. FIGURE 35-12 Mean dose-response graphs for angiotensin.Women with preeclampsia have an increased sensitivity to all Preeclamptic women are much more sensitive to angiotensin II thanendogenous pressors. MBP, mean blood pressure. (From Talledo OE, normal pregnant and nonpregnant women. MBP, mean bloodChesley LC, Zuspan FP: Renin-angiotensin system in normal and pressure. (From Talledo OE, Chesley LC, Zuspan FP: Renin-toxemic pregnancies. III. Differential sensitivity to angiotensin II and angiotensin system in normal and toxemic pregnancies. III.norepinephrine in toxemia of pregnancy. Am J Obstet Gynecol Differential sensitivity to angiotensin II and norepinephrine in toxemia100:218, 1968. Courtesy of the American College of Obstetricians of pregnancy. Am J Obstet Gynecol 100:218, 1968. Courtesy of theand Gynecologists.) American College of Obstetricians and Gynecologists.)animals tested. In other experiments, no defect is obvious. The hypoth- 16esis 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 isincreased response to normal concentrations of endogenous pressors.Women with preeclampsia have higher sensitivity to all the endoge- 12nous pressors that have been tested. They are exquisitely sensitive to ng/kg/minvasopressin.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 8 Nonpregnant meanstriking difference is seen in the sensitivity of the preeclamptic womanto angiotensin II. Normal pregnant women are less sensitive to angio- P<.01tensin II than nonpregnant women, requiring approximately 2.5 times P<.05 P<.1 P<.001as much angiotensin to raise the blood pressure by a similar incre- 4ment.171 In contrast, preeclamptic women are much more sensitive to 10 14 18 22 26 28 30 32 34 36 38 40angiotensin II than are normal pregnant and nonpregnant women Weeks of gestation(Fig. 35-12).170 In a classic study, angiotensin II sensitivity was signiﬁcantly FIGURE 35-13 Angiotensin sensitivity throughout pregnancy. Theincreased many weeks before the development of elevated blood pres- dose of angiotensin II necessary to increase diastolic blood pressuresure (Fig. 35-13).172 Although resistance to angiotensin II does not 20 mm Hg in women who developed elevated blood pressure in latedecrease to nonpregnant levels until 32 weeks’ gestation, signiﬁcant pregnancy (blue line, open circles) was compared with the dose for those who remained normotensive (red line, solid circles). The graphdifferences in sensitivity between women who later become hyperten- demonstrates that a signiﬁcantly lower dose was required in thesive and those who remain normotensive have been observed as early former group as early as 10 to 14 weeks’ gestation. (From Gant NF,as 14 weeks. However, a large British study did not conﬁrm this classic Daley GL, Chand S, et al: A study of angiotensin II pressor responseﬁnding,173 perhaps reﬂecting the heterogeneity of preeclampsia.174 throughout primigravid pregnancy. J Clin Invest 49:82, 1973. With The decreased sensitivity of normal pregnant women to angioten- permission of the American Society for Clinical Investigation.)sin II and the lower systemic vascular resistance in normal pregnancysuggest that arteriolar narrowing in preeclamptic women may resultfrom decreased levels of circulating or local vasodilator substances, coagulation system manifests as the intravascular disappearance ofrather than from increased levels of circulating pressors. This attractive procoagulants, intravascular appearance of degradation products ofhypothesis, however, is not consistent with the unchanged sensitivi- ﬁbrin, and end-organ damage from the formation of microthrombi.176ties to norepinephrine, epinephrine, and vasopressin in normal In the most advanced form of DIC, procoagulants—especially ﬁbrino-pregnancy.168-170 gen and platelets—decrease to a degree sufﬁcient to produce spontane- ous hemorrhage. In milder forms, only highly sensitive indicators ofCoagulation Changes clotting system activation are present. Decreasing platelet concentra-The syndrome of DIC occurs in preeclampsia and has been suggested tions is such a sign but may be evident only by serial observations.96as a primary pathogenetic factor175 (see Chapter 40). Activation of the Sensitive indicators of intravascular coagulation, such as an elevated
CHAPTER 35 Pregnancy-Related Hypertension 663level of ﬁbrin degradation products; increased platelet turnover,6 thelium. Vessels from preeclamptic women and the umbilical vesselsvolume,114 and activation177; reduced platelet content178; increased of their neonates generate less prostacyclin than similar vessels fromplatelet content in plasma179; reduced levels of antithrombin III111; and normal pregnant women.202-204 If potent inhibitors preventing the syn-a reduced ratio of factor VIII activity to factor VIII antigen,180 are thesis of all prostaglandins (including prostacyclin) are administeredcommon when concentrations of procoagulants remain normal. Subtle to pregnant women, the usual resistance to the vasoconstrictor effectsigns of platelet dysfunction,6,114,177-179 reduced antithrombin III,111 and of angiotensin II is abolished.205 Conversely, if aspirin is used as anreduction in the ratio of factor VIII bioactivity to factor VIII antigen112 inhibitor of prostaglandin synthesis in a manner determined to speciﬁ-are present in women with mild preeclampsia and may precede its cally reduce contractile prostanoids (e.g., thromboxane A2) much moreclinical signs. than prostacyclin, the increased angiotensin II sensitivity of preeclamp- Abnormalities of blood coagulation sufﬁcient to make a diagnosis tic women is reduced.206of DIC are present in approximately 10% of women with severe pre- Nitric oxide (NO) is another bioactive material produced by normaleclampsia or eclampsia.181 Results of highly sensitive assays of coagula- endothelium.207 Its release is stimulated by several hormones and neu-tion activation suggest, however, that abnormalities of the coagulation rotransmitters and by hydrodynamic shear stress. NO is quite labilesystem are present in many patients with mild to moderate preeclamp- and acts synergistically with prostacyclin as a local vasodilator andsia. Coagulation changes are thought to be secondary rather than inhibitor of platelet aggregation. Current thinking favors NO as anprimary pathogenetic factors182 because levels of procoagulants are endogenous vasodilator of pregnancy. Administration of inhibitors ofusually normal, and another early sign of preeclampsia—increased NO synthesis reduces blood ﬂow much more strikingly in pregnantserum uric acid—may precede changes in coagulation.110 than in nonpregnant women.208 Production of NO is reduced with The cause of the change in coagulation factors is uncertain. Vascu- endothelial cell injury. Information about NO production in pre-lar damage resulting from vasospasm may initiate DIC182 and probably eclampsia is conﬂicting,209-214 in part because of the use of blood con-contributes to activation of the clotting system in severe preeclampsia. centrations of NO metabolites to determine production in the settingSigns of endothelial dysfunction also antedate clinical disease,183 and of the reduced renal function of preeclampsia.215 Two studies haveactivation of platelets and other components of the coagulation cascade documented reduced urinary NO excretion in preeclampsia,212,216 andis a well-recognized consequence of endothelial dysfunction.184 Vascu- another found increased excretion.217 Perhaps the most compellinglar changes in the implantation site that appear to antedate blood data are from estimates of the tissue concentrations of nitrotyrosinepressure elevation may be pathogenetically important. (i.e., product of the interaction of NO and superoxide). Nitrotyrosine Whether coagulation changes measured in preeclamptic patients residues are increased in the placenta218 and vessels219 of women withrepresent true DIC or a localized consumption of procoagulants in preeclampsia. It is posited that the placenta directly or indirectly pro-the intervillous space is not clear. Microthrombi and the presence of duces factors that alter endothelial function. Candidate moleculesﬁbrin antigen have been inconsistently observed in liver, placenta, and include the following:kidney.185-187 Early coagulation changes such as factor VIII activity-antigen ratios and platelet count correlate better with the fetal outcome Cytokines220 (with increasing evidence that endothelialas measured by mortality and growth restriction rates than with the dysfunction is part of a generalized increased inﬂammatoryclinical severity of preeclampsia. Identical coagulation changes occur response221)in normotensive women with growth-restricted fetuses,188 suggesting Placental fragments (i.e., syncytiotrophoblast microvillousthat localized coagulation in the intervillous space is important. Simi- membranes)222larly, an increased concentration of ﬁbrin antigen has been reported in Free radicalsthe placentas of preeclamptic patients.185 Reactive oxygen species223Endothelial Cell Dysfunction The latter hypothesis—that oxidative stress causes endothelialThere is increasing support for endothelial dysfunction as a patho- dysfunction—is especially interesting in view of the similarities ofphysiologic component of preeclampsia.183,189,190 Alterations of glo- the lipid changes of preeclampsia to those of atherosclerosis,118 anmerular endothelial cells are a consistent feature of preeclampsia. endothelial disorder in which oxidative stress is thought to play a keyLevels of cellular ﬁbronectin,191,192 growth factors,193 vascular cell adhe- role.224sion molecule 1 (VCAM-1),194 factor VIII antigen, and peptides released The information available indicates that endothelial cell dysfunc-from injured endothelial cells are increased in preeclamptic women tion can alter vascular responses and intravascular coagulation in abefore the appearance of clinical disease.112 Examination showed that manner consistent with the pathophysiologic abnormalities of pre-the endothelial function of vessels of preeclamptic women was impaired eclampsia. Evidence is accumulating that endothelial injury may playin vitro.195,196 a central role in the pathogenesis of preeclampsia. The endothelium is a complex tissue with many important func-tions. Prevention of coagulation and modulation of vascular tone have Renal Function Changesspecial relevance to preeclampsia. Intact vascular endothelium is resis- Renal function changes characteristic of women with preeclampsia ortant to thrombus formation.197 With vascular injury, endothelial cells eclampsia include decreased glomerular ﬁltration and proteinuria.can initiate coagulation by the intrinsic pathway (i.e., contact activa- Changes in components of the renin-angiotensin system probablytion)198 or by the extrinsic pathway (i.e., tissue factor).199 Platelet adhe- differ from those of normal pregnancy. Sodium excretion is decreased,sion can also occur after injury with exposure of subendothelial resulting in ﬂuid retention and edema.components, such as collagen200 and microﬁbrils. Endothelium profoundly inﬂuences the response of vascular GLOMERULAR FUNCTIONAL CHANGESsmooth muscle to vasoactive agents. The response to some agents201 Glomerular Filtration Rate. Decreased glomerular ﬁltration fre-can change from dilation to constriction with the removal of endothe- quently complicates preeclampsia, and it is explained only partially bylium. Prostacyclin, a highly potent vasodilator, is produced by endo- decreased renal plasma ﬂow (RPF). The ﬁltration fraction (GFR/RPF)
664 CHAPTER 35 Pregnancy-Related Hypertensionmay be decreased18 because of intrarenal redistribution of blood In summary, uric acid clearance changes earlier in preeclampticﬂow.225 A more obvious explanation is glomeruloendotheliosis, in pregnancy than does the GFR, suggesting a tubular rather than a glo-which the occlusion of glomerular capillaries by swollen endothelial merular functional explanation. Although the exact mechanism for thecells probably renders many glomeruli nonfunctional. urate clearance change is not established, the common feature in the Protein Leakage. The pathogenesis of proteinuria in preeclamp- suggested mechanisms is decreased renal perfusion; however, increasedsia is primarily explained by glomerular changes. The normal absence production by poorly perfused tissue cannot be excluded.106,240of protein in urine results from a relative impermeability of glomeruli Urinary Concentrating Capacity. Although the issue is not fullyto large protein molecules and from the tubular resorption of smaller settled, the tubular concentrating capacity is probably unchanged inproteins that cross the glomeruli. As glomerular damage occurs, per- normal pregnancies.241 Assali and associates242 suggested that urinarymeability to proteins increases. As damage increases, so does the size concentrating ability is decreased in hypertensive women. The limita-of the protein molecule that can cross the glomerular membrane. tions of these studies include the failure to account for parallel changesIncreased permeability results in decreased selectivity. With minimal in the concentrating capacity and GFR243 and the use of speciﬁcglomerular damage or tubular dysfunction, only small protein mole- gravity—an unreliable estimate of osmolality—as the measure ofcules are excreted, but with greater damage, large and small proteins concentration.18are present in urine. Normal pregnant women were found to have decreased capacity to In women with preeclampsia, selectivity is low, indicating increased concentrate urine (measured as osmolar concentration and correctedpermeability and glomerular damage.226 The well-known clinical for the GFR) in response to vasopressin administration, a decreaseobservation that the magnitude of proteinuria in preeclamptic women similar to that seen in pregnant women who were or later becamevaries greatly over time was quantitated by Chesley,227 who noticed hypertensive.244 Conﬂicting study results suggesting that tubular con-hourly variation in the urinary creatinine-to-protein ratio in women centrating capacity is unchanged in normal pregnancy are confoundedwith preeclampsia that was not present in the urine of individuals with by a failure to correct for the increased GFR of normal pregnancy,other proteinuric conditions. which concomitantly increases concentrating capacity.243 Because structural glomerular changes are constant, proteinuria in Excretion of Phenolsulfonphthalein. Because phenolsulfon-preeclamptic women must in part depend on a varying functional phthalein is secreted by proximal tubular cells, its excretion can be usedcause (e.g., a variation in the intensity of the renal vascular spasm). as an indicator of proximal tubular function.235 However, phenolsul-That vascular spasm can cause proteinuria has been demonstrated by fonphthalein excretion is altered independently of tubular secretorymeasuring urinary excretion of protein in individuals subjected to the capacity with increased245 or decreased246 renal plasma ﬂow or reducedcold pressor test. Immersing a patient’s hand in ice water for 60 seconds GFR247 and with increased urinary dead space (a problem pertinent inincreases blood pressure by more than 16 mm Hg (systolic and dia- pregnancy). When these factors are controlled, reduced phenolsulfon-stolic), and an increase in protein excretion almost invariably phthalein excretion precedes changes in the GFR and clinically evidentoccurs.228 disease in women with preeclampsia.235 Renin-Angiotensin-Aldosterone System. The renin-angiotensin- RENAL TUBULAR FUNCTIONAL CHANGES aldosterone system (RAAS) is important in pressure and volume regu- Uric Acid Clearance. Three separate processes are involved in the lation in normal pregnancy (Fig. 35-14).248 Dramatic changes occur inrenal excretion of urate. Urate is completely ﬁltered at the glomerulus. the RAAS during pregnancy.249 The following components areIt is not bound to plasma proteins under physiologic conditions,229 and increased:glomerular urate concentration is equal to renal arterial plasma con-centration. Urate is secreted and reabsorbed by renal tubules. Most Angiotensinogen (i.e., renin substrate)urate (98%) is reabsorbed, and about 80% of excreted urate is accounted Plasma renin activity250for by urate secretion. Both processes occur predominantly in theproximal 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 Juxtaglomerular apparatusa consistent phenomenon in preeclampsia231 and have been regarded STIMULATIONas a function of decreased glomerular ﬁltration.232 Several studieshave demonstrated the discrepancy between uric acid clearance andboth inulin clearance and creatinine clearance.233,234 Serial studies also Intravascular volume decreasedreveal that decreased uric acid clearance precedes decreases in the INHIBITION Sodium depletion ReninGFR.235 Urate clearance is decreased by hypovolemia, presumably as a resultof nonspeciﬁc stimulation of proximal tubular reabsorption.236 Plasma Sodium retention Renin substrate Angiotensin Ivolume depletion is coincident with urate clearance changes,237 sug- Volume expansiongesting that volume change may account for the abnormality in urateclearance. However, the correlation between the degree of volume Angiotensin IIdepletion and the decrease in urate clearance is poor.237 Stimulates Converting enzyme Angiotensin II infusion decreases urate clearance even in the pres- aldosterone secretion Pressorence of normal blood volume.238 The increase in angiotensin II sensi- effecttivity seen in preeclampsia may account for the change in renalfunction. Local effects of angiotensin II may also be important because FIGURE 35-14 Schematic representation of the renin-angiotensinthis substance can be produced locally,239 unassociated with increased system. The system regulates pressure and volume in normalcirculating angiotensin II. pregnancies, and abnormalities contribute to preeclampsia.