Acute Complications of Preeclampsia

Home , Complication (medicine), Eclampsia

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ERROL R. NORWITZ, MD, PhD,* CHAUR-DONG HSU, MD, MPH,† and JOHN T. REPKE, MD† Departments of Obstetrics & Gynecology, *Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts, and †University of Nebraska Medical Center, University of Nebraska Medical School, Omaha, Nebraska

Preeclampsia is an idiopathic multisystem clinically as preeclampsia. Although attrac- disorder specific to human pregnancy and tive, this hypothesis remains to be validated. the puerperium.1 More precisely, it is a dis- Preeclampsia is a clinical diagnosis. The ease of the placenta, because it has also been classic definition of preeclampsia encom- described in pregnancies where there is tro- passes three elements: new-onset hyperten- phoblast but no fetal tissue (complete molar sion (defined as a sustained sitting blood pregnancies). Although the pathophysiol- pressure Ն140/90 mm Hg in a previously ogy of preeclampsia is poorly understood, it normotensive woman); new-onset protein- is clear that the blueprint for its development uria (defined as >300 mg/24 hours or Ն2+ is laid down early in pregnancy. It has been on a clean-catch urinalysis in the absence of suggested that the pathologic hallmark is a urinary tract infection); and new-onset sig- complete or partial failure of the second 1 nificant nondependent edema. However, wave of trophoblast invasion from 16 to 20 more recent consensus reports have sug- weeks’ gestation, which is responsible in gested eliminating edema as a criterion for normal pregnancies for destruction of the 3 muscularis layer of the spiral arterioles.2 As the diagnosis. pregnancy progresses, the metabolic de- A more extensive synopsis of preeclamp- mands of the fetoplacental unit increase. sia is beyond the scope of this discussion. However, because of the abnormally shal- This monograph serves to review in detail low invasion of the placenta, the spiral arte- the diagnosis and management of several rioles are unable to dilate to accommodate acute maternal complications of preeclamp- the required increase in blood flow, result- sia: eclampsia, HELLP (hemolysis, elevated ing in “placental dysfunction” that manifests liver enzymes, low platelets) syndrome, liver rupture, pulmonary edema, renal failure, disseminated intravascular coagulopa- Correspondence: Errol R. Norwitz, MD, PhD, Depart- thy (DIC), hypertensive emergency, and hy- ment of Obstetrics & Gynecology, Brigham & Women’s Hospital, Harvard Medical School, 75 Francis Street, pertensive encephalopathy and cortical Boston, MA 02115. E-mail: [email protected] blindness.

CLINICAL OBSTETRICS AND GYNECOLOGY / VOLUME 45 / NUMBER 2 / JUNE 2002

308 Acute Complications of Preeclampsia 309 Eclampsia ditions. Eclamptic seizures are almost al- Eclampsia refers to the occurrence of one or ways self-limiting and seldom last longer more generalized convulsions and/or coma than 3 to 4 minutes. Eclamptic seizures are in the setting of preeclampsia and in the ab- clinically and electroencephalographically sence of other neurologic conditions.1 In indistinguishable from other generalized the past, eclampsia was thought to be the tonic-clonic seizures. In general, women end result of preeclampsia, hence the no- with typical eclamptic seizures who do not menclature. However, it is now clear that have focal neurologic deficits or prolonged coma do not require either electroencepha- seizures are only one of several clinical 9 manifestation of “severe” preeclampsia. lographic or cerebral imaging studies. The precise cause of seizures in women Clinical conditions other than eclampsia that with eclampsia is not known. Proposed eti- should be considered when evaluating a ologies include cerebral vasospasm with pregnant woman who has had a seizure are local ischemia, hypertensive encephalopa- listed in Table 1. thy with hyperperfusion, vasogenic edema, Approximately half of all cases of 4 eclampsia occur before term, with more than and endothelial damage. Despite recent 7 advances in detection and management, 20% occurring before 31 weeks’ gestation. preeclampsia/eclampsia remains the second Three quarters of the remaining cases occur most common cause of maternal death in the at term, developing intrapartum or within 48 United States (after thromboembolic dis- hours of delivery. Seizures due to eclampsia ease), accounting for 15% of all maternal always resolve postpartum, often within a deaths.5 It is estimated that eclampsia ac- few hours to days. Diuresis (>4 L/day) is be- counts for 50,000 maternal deaths per year lieved to be the most accurate clinical indi- worldwide.6 cator of resolution of preeclampsia/eclampsia, but it is not a guarantee against the development of seizures.10 Indeed, late postpartum EPIDEMIOLOGY AND INCIDENCE eclampsia (eclamptic seizures developing Eclampsia is most common in nonwhite, >48 hours postpartum but <4 weeks postpar- nulliparous women from lower socioeco- nomic backgrounds. Peak incidence is in the TABLE 1. Differential Diagnosis of teenage years and early 20s, but there is also Eclampsia an increased prevalence in women older than 35. Eclampsia before 20 weeks’ gesta- Cerebrovascular accident tion is rare; this should raise the possibility Intracerebral hemorrhage of an underlying molar pregnancy or anti- Cerebral arterial or venous thrombosis Hypertensive diseases phospholipid antibody syndrome. Hypertensive encephalopathy The overall incidence of eclampsia is Pheochromocytoma relatively stable, at 4 to 5 cases per 10,000 Space-occupying lesions of the central nervous live births in developed countries.7 In devel- system oping countries, however, the incidence var- Brain tumor Abscess ies widely from 6 to 100 per 10,000 live Metabolic disorders 8 births. Hypoglycemia Uremia Inappropriate antidiuretic hormone secretion CLINICAL MANIFESTATIONS AND resulting in water intoxication DIAGNOSIS Infectious etiology Eclampsia is a clinical diagnosis based on Meningitis evidence of one or more generalized convul- Encephalitis sions and/or coma in a preeclamptic woman Thrombotic thrombocytopenic purpura Idiopathic epilepsy and in the absence of other neurologic con- 310 NORWITZ ET AL tum) accounts for 25% of postpartum cases system, where it achieves anticonvulsant and up to 16% of all cases of eclampsia.10,11 levels within 1 minute, and it will control seizures in greater than 80% of patients MANAGEMENT within 5 minutes.13 However, most investi- A number of management strategies have gators recommend avoiding benzodiaz- been developed to prevent maternal and fe- epines because of the potentially profound tal complications resulting from eclampsia depressant effects on the fetus. This effect during the peripartum period. The immedi- becomes clinically significant when the total ate issues in caring for an eclamptic woman maternal dose of diazepam exceeds 30 mg. include maintenance of maternal vital func- tions, control of convulsions and blood pres- Treatment of Hypertension sure, prevention of recurrent seizures, and Cerebrovascular accident accounts for 15– evaluation for delivery. If the seizure is wit- 20% of deaths from eclampsia. The risk of nessed, maintenance of airway patency and hemorrhagic stroke correlates directly with prevention of aspiration should be the first the degree of elevation in systolic blood responsibilities of management. The partu- pressure and is less related to, but not inde- rient should be rolled onto her left side and a pendent of, the diastolic pressure.14 It is not padded tongue blade placed in her mouth, if clear whether there is a threshold pressure possible. above which emergent therapy should be in- stituted.14 Most investigators recommend Control of Convulsions aggressive antihypertensive therapy for sus- Although eclamptic seizures usually resolve tained diastolic pressures of more than 105 without treatment within 3 to 4 minutes, an to 110 mm Hg and systolic blood pressures anticonvulsant can be administered to of 160 mmHg or greater,3 although these achieve resolution of an ongoing convul- thresholds have not been tested prospec- sion. The treatment of choice is magnesium tively. The cerebral vasculature of women sulfate. In women already receiving magne- with underlying chronic hypertension can sium seizure prophylaxis, a serum magne- probably tolerate higher systolic pressures sium level should be obtained immediately without injury, whereas adolescents with and a rapid intravenous infusion of 1 to 2 g normally low blood pressures may benefit administered while awaiting the results. In from starting treatment at lower levels. Per- women not receiving seizure prophylaxis, sistent, severe elevation in blood pressure magnesium should be given as a rapid intra- (Ն160/110 mm Hg) should be treated to pre- venous infusion of 2 g repeated every 15 vent cerebrovascular accident. Initial treat- minutes to a maximum of 6 g. This loading ment options include hydralazine (5 mg in- dose may be given safely even in the pres- travenous push followed by 5- to 10-mg bo- ence of renal insufficiency. Exactly how luses as needed q 20 minutes) or labetalol magnesium acts as an anticonvulsant in (10–20 mg intravenous push, repeat q 10–20 eclampsia is not known. Several mecha- minutes with doubling doses not to exceed nisms have been proposed, including selec- 80 mg in any single dose, for a maximum tive vasodilatation of the cerebral vascula- total cumulative dose of 300 mg). Women ture, protection of endothelial cells from who do not improve rapidly after control of damage by free radicals, prevention of cal- seizures and hypertension or those who de- cium ion entry into ischemic cells, and/or as velop localizing neurologic signs should be a competitive antagonist to the glutamate N- evaluated further. methyl-D-aspartate receptor (which is epi- leptogenic).12 Benzodiazepines have been Prevention of Subsequent Seizures used in the past for eclamptic seizures. Di- Approximately 10% of eclamptic women azepam rapidly enters the central nervous will have repeated seizures if managed ex- Acute Complications of Preeclampsia 311 pectantly.15 There is universal agreement ministration (cardiac monitoring is not re- that women with eclampsia require anticon- quired), and less sedation than diazepam and vulsant therapy to prevent further seizures phenytoin. Magnesium also appears to se- and the possible complications of repeated lectively increase cerebral blood flow and seizure activity: neuronal death, rhabdomy- oxygen consumption in women with pre- olysis, metabolic acidosis, aspiration pneu- eclampsia18; this is not true for phenytoin.19 monitis, neurogenic pulmonary edema, and The maintenance dose of magnesium sul- respiratory failure. However, the choice of fate is 2 to 3 g/h administered as a continu- agent is controversial. Obstetricians have ous intravenous infusion. The maintenance long favored magnesium sulfate as the phase is given only if a patellar reflex is pres- drug of choice for prevention of recurrent ent (loss of deep tendon reflexes is the first eclamptic seizures, whereas neurologists fa- manifestation of symptomatic hypermagne- vor anticonvulsants traditionally used in semia), respirations are greater than 12 per nonpregnant individuals, such as phenytoin minute, and urine output is greater than 100 or diazepam. This dispute appears to have mL in 4 hours. Following serum magnesium been resolved by a number of recent clinical levels is not required if the woman’s clinical studies: status is closely monitored for evidence of potential magnesium toxicity. There also ● The Eclampsia Trial Collaborative Group does not appear to be a clear threshold con- conducted a prospective trial in which 905 centration for ensuring the prevention of eclamptic women were randomly assigned to convulsions, although a range of 4.8 to 8.4 receive either magnesium or diazepam and 20 775 eclamptic women were randomly as- mg/dL has been recommended. The dose signed to receive either magnesium or phe- should be adjusted according to the clinical nytoin.16 Primary measures of outcome were response of the patient (Table 2). recurrence of seizures and maternal death. Women allocated to magnesium therapy had Evaluation for Delivery half the rate of recurrent convulsions com- The definitive treatment of eclampsia is pared with those allocated to diazepam (13% prompt delivery, irrespective of gestational and 28%, respectively). There were no sig- age, to prevent potential maternal and fetal nificant differences in maternal or perinatal complications. However, this does not nec- death or complication rates between the two essarily preclude induction of labor.21 After groups. Similarly, women administered mag- maternal stabilization, several factors nesium had one-third the rate of recurrent seizures of those taking phenytoin (6% vs. 17%). should be considered before determining the In this arm of the study, women who received most appropriate route of delivery. These in- magnesium were 8% less likely to be admit- clude gestational age, Bishop score, and fe- ted to an intensive care facility, 8% less likely tal condition and position. In general, less to require ventilatory support, and 5% less than one third of women with severe likely to develop pneumonia compared with preeclampsia/eclampsia remote from term women given phenytoin. There were no sig- (<32 weeks’ gestation) with an unfavorable nificant differences in the maternal death rate cervix will have a successful vaginal deliv- or perinatal outcome. 22–24 17 ery. Cervical ripening agents can be ● A Cochrane review reported that magne- used to improve the Bishop score; however, sium sulfate was safer and better than “lytic long inductions should be avoided. cocktail” (containing promethazine hydro- chloride, chlorpromazine, and meperidine hy- Fetal bradycardia lasting at least 3 to 5 drochloride) for the prevention of repeat sei- minutes is a common finding during and im- zures in eclamptic women. mediately after an eclamptic seizure and does not necessitate emergent cesarean de- Additional advantages of magnesium sul- livery. Maneuvers to stabilize the mother fate therapy include lower cost, ease of ad- may help the fetus recover in utero from the 312 NORWITZ ET AL

TABLE 2. Prevention of Recurrent Seizures in Patients With Eclampsia Drug Loading Dose Maintenance Dose Therapeutic Level Recommended first-line therapy Magnesium sulfate 4–6 g IV over 10–20 min 2–3 g/h IV infusion 4–8 mEq/L* 10 g IM (5 g into each buttock) 5 g IM every 4 h As above Recommended therapy in women refractory to magnesium sulfate Phenytoin 1–1.5 g IV over 1 h (depending on 250–500 mg q 10–12 h 10–20 µg/mL body weight) orally or IV Diazepam – 10 mg/h IV infusion – Chlormethiazole† 40–100 mL of 0.8% over 20 min 60 mL/h IV infusion –

* Not tested prospectively † Not available in the United States effects of maternal hypoxia, hypercarbia, found that the brains of more than 50% of and uterine hyperstimulation. Resolution of the women who died within 2 days of sei- maternal seizure activity is often associated zures displayed cerebral hemorrhages and with compensatory fetal tachycardia and softening.31 Petechial cortical hemorrhages even with transient fetal heart rate decelera- were most common, especially involving tions, which typically resolve within 20 to the occipital lobe. Diffuse cerebral edema 30 minutes.25 and gross hemorrhage were noted less frequently. Cerebral venous thrombosis was PROGNOSIS common in woman with postpartum Maternal complications occur in up to 70% eclampsia. of women with eclampsia and include DIC, The perinatal death rate in eclamptic 7,26 acute renal failure, hepatocellular injury, pregnancies is 9–23% and is closely re- liver rupture, intracerebral hemorrhage, car- lated to gestational age. For example, the diorespiratory arrest, aspiration pneumoni- perinatal death rate in one series of 54 par- tis, acute pulmonary edema, and postpartum turients with eclampsia before 28 weeks’ 26 hemorrhage.26,27 Hepatocellular damage, gestation was 93% ; this rate was only 9% renal dysfunction, coagulopathy, hyperten- in another study in which the mean gesta- 32 sion, and neurologic abnormalities typically tional age at birth was 32 weeks. Perinatal resolve after delivery. However, cerebro- deaths are primarily the result of premature vascular damage from hemorrhage or ische- delivery, abruptio placentae, and intrauter- mia may result in permanent neurologic se- ine asphyxia. quelae.28 Maternal death rates of 0–13.9% have FUTURE PREGNANCIES been reported.7,26,28 One retrospective Eclampsia can recur in a subsequent preg- analysis of 990 cases of eclampsia found an nancy.33,34 The risk appears to be reduced overall maternal death rate of 13.9% by close maternal monitoring and timely in- (138/990). The highest risk (12/54 [22%]) tervention if preeclampsia develops.35 How- was observed in a subgroup of women with ever, there is as yet no effective way to preeclampsia previous to 28 weeks’ gestation. vent preeclampsia.36 The rate of recurrent Maternal death and severe complication eclampsia is estimated to be around 2%.37 rates are lowest among women receiving Subsequent pregnancies in women with a regular prenatal care who are managed by history of severe preeclampsia/eclampsia experienced physicians in tertiary cen- are also at increased risk of other obstetric ters.29,30 An autopsy study performed complications compared with women with shortly after death in eclamptic women no such history, including placental abrup- Acute Complications of Preeclampsia 313 tion (2.5–6.5% vs. 0.8%), preterm delivery tered to parturients at high risk can prevent a (15–21% vs. 7–8%), intrauterine growth re- first seizure in women with severe pre- striction (12–23% vs. 10%), and an in- eclampsia. Two large studies have demon- creased perinatal death rate (4.6–16.5% vs. strated the superiority of magnesium sulfate 1–3%).32,33,38,39 Women with a history of over phenytoin for the prevention of preeclampsia/eclampsia remote from term eclampsia.43,44 The Parkland Hospital (<28 weeks’ gestation) are at highest risk for group, for example, randomly assigned developing these complications.38,39 This 2,138 preeclamptic women to receive either risk appears to be the same whether they had magnesium or phenytoin.43 Eclamptic sei- severe preeclampsia or eclampsia. zures developed in 10 of 1,089 women assigned to phenytoin compared with none of CAN ECLAMPSIA BE PREDICTED? 1,049 women assigned to magnesium (P = The relationship between hypertension, 0.004). Maternal and neonatal outcomes signs and symptoms of cortical irritability were similar in both groups. These data are (headache, visual aberrations, nausea, vom- supported by a recent study performed in iting, fever, hyperreflexia), and seizures re- South Africa in which 685 women with se- mains unclear. A retrospective analysis of vere preeclampsia were randomly assigned 383 cases of eclampsia in the United King- to seizure prophylaxis with magnesium sul- dom found that only 59% of eclamptic fate therapy or placebo.45 Progression to women experienced one or more prodromal eclampsia was lower in the magnesium symptoms—headache, visual disturbance group (0.3% vs. 3.2% [P = 0.003]). (scotomata, amaurosis, blurred vision, dip- Anticonvulsant therapy is generally initi- lopia, homonymous hemianopsia), or epi- ated during labor or while administering an- gastric pain—before their eclamptic sei- tenatal corticosteroid therapy or cervical rip- zure.7 Moreover, the magnitude of blood ening agents previous to planned delivery in pressure elevation does not appear to be pre- women with severe preeclampsia. Treat- dictive of eclampsia, although it does corre- ment should be continued until 24 to 48 late well with the incidence of cerebrovas- hours postpartum, when the risk of seizures cular accident. Retrospective analysis is low. The most common magnesium sul- shows that eclampsia was the first manifes- fate regimen is a loading dose of 4 to 6 g tation of pregnancy-related hypertensive given intravenously over 20 minutes, fol- disease in 20–38% of cases.7,28 Similar find- lowed by 2 to 3 g/h as a continuous infusion. ings were reported in studies from Sweden, It is unclear whether all women with pre- Scotland, and the United States.40–42 In one eclampsia require prophylaxis to prevent of the latter reviews, the factors found to be seizures in a small number of patients (0.6– at least partially responsible for failure to 3.2%46). Moreover in women with nonpro- prevent eclampsia (179 consecutive cases) teinuric hypertension, the incidence of sei- were physician error (36%), magnesium zures is so low (<0.1%45) that it may be safe failure (13%), late postpartum onset (12%), to withhold seizure prophylaxis in such women. early onset before 21 weeks (3%), abrupt onset (18%), and lack of prenatal care (19%).41 Therefore, many cases of eclampsia appear HELLP Syndrome not to be preventable, even among women HELLP syndrome (hemolysis, elevated receiving regular prenatal care. liver enzymes, low platelets) is a serious complication of preeclampsia that was first 47 PREVENTION OF FIRST ECLAMPTIC described by Pritchard et al in 1954, al- SEIZURE though the term HELLP syndrome was Although not all cases of eclampsia can be coined by Weinstein in 1982.48 Among predicted, anticonvulsant therapy adminis- women with severe preeclampsia, 6% will 314 NORWITZ ET AL manifest with one abnormality suggestive of count 50,000 to 100,000/mm3, and class 3 as HELLP syndrome (usually elevated liver a platelet count more than 100,000/mm3. Al- enzymes or low platelets), 12% will develop though this classification does appear to cor- two abnormalities, and about 10% will relate to some degree with the prognosis and manifest with all three abnormalities.49 speed of resolution, it is not widely ac- HELLP syndrome can manifest at any time cepted. during pregnancy and the puerperium but (like preeclampsia) is rare before 20 weeks’ ETIOLOGY AND PATHOPHYSIOLOGY gestation. One third of all cases of HELLP Like preeclampsia, endothelial dysfunction, syndrome occur postpartum, and only 80% with resultant activation of the intravascular of such patients were diagnosed with pre- coagulation cascade, has been proposed as eclampsia before delivery. the central pathogenesis of HELLP syndrome. However, unlike preeclampsia, CLINICAL MANIFESTATIONS AND HELLP syndrome occurs more often in DIAGNOSIS whites, in multipara, and in women older Although parturients with HELLP syn- than 35 years. Some investigators regard drome may be asymptomatic, 80% report HELLP syndrome as an entirely distinct dis- right upper quadrant pain and 50–60% pre- ease entity from preeclampsia. sent with excessive weight gain and worsen- When preeclampsia is complicated by ing edema. Not all women with HELLP syn- HELLP syndrome, the maternal and perina- drome have hypertension or proteinuria. tal death rates are significantly increased. Indeed, 20% of patients with HELLP syn- Reported maternal death rates are 0–24%; drome have a maximum blood pressure less death results most often from liver rupture, than 140/90 mm Hg, and 6% do not have DIC, acute renal failure, pulmonary edema, significant proteinuria at the time of diagno- carotid thrombosis, and cerebrovascular ac- sis.49 Other clinical conditions that should cident.51 Perinatal death is related most be considered in women with features sug- closely to complications of prematurity, fe- gestive of HELLP syndrome include hemo- tal growth restriction, and placental abrup- lytic uremic syndrome, thrombotic throm- tion. Reported perinatal death rates are 7.7– bocytopenic purpura, and acute fatty liver. 60%.51 Delayed diagnosis and delayed or in- The definitive laboratory criteria for the appropriate treatment are commonly cited as diagnosis of HELLP syndrome remain to be reasons for the poor overall prognosis asso- validated prospectively. However, the labo- ciated with HELLP syndrome. Early identi- ratory criteria most commonly used are fication of this syndrome, coupled with those defined by Sibai in 1990.49 In this re- prompt and appropriate intervention, can view, Sibai defined hemolysis as the pres- significantly reduce maternal and perinatal ence of an abnormal peripheral smear with death and complication rates. Accordingly, schistocytes, serum lactate dehydrogenase parturients with HELLP syndrome should (LDH) more than 600 U/L, and total biliru- ideally be managed in a tertiary care facility. bin more than 1.2 mg/dL; elevated liver enzymes as serum aspartate aminotransferase MANAGEMENT more than 70 U/L (>3 standard deviations Stabilization of the mother’s conditions and above norm) and LDH more than 600 U/L; assessment of fetal well-being are the first and low platelet count as less than responsibilities of management for parturi- 100,000/mm3. Based on the severity of the ents with HELLP syndrome. Seizure pro- thrombocytopenia, Martin et al50 further phylaxis should be administered in the form categorized HELLP syndrome into three of parenteral magnesium sulfate. If the preg- classes. Class 1 is defined as a platelet count nancy is less than 34 weeks, antenatal corti- less than 50,000/mm3, class 2 as a platelet costeroids should be given to enhance fetal Acute Complications of Preeclampsia 315 lung maturation. With few exceptions, im- methasone in the antepartum “treatment” of mediate delivery is indicated, irrespective of HELLP syndrome.53 Of note, the dose of gestational age. The decision of whether to dexamethasone recommended in these stud- delay delivery for 48 hours to complete a full ies for antepartum treatment of HELLP syn- course of antenatal corticosteroids should be drome (12 mg q12h until delivery) is signifi- individualized. Immediate delivery does not cantly higher than that recommended by the necessarily mean cesarean delivery. How- National Institutes of Health54 or the Ameri- ever, if the pregnancy is remote from term can College of Obstetricians and Gynecolo- (<32 weeks) and the cervix is unfavorable, gists (ACOG) for promotion of fetal lung an elective cesarean delivery is a reasonable maturity (6 mg q12h for 48 hours55). More- option. Because the incidence of hematoma over, corticosteroid administration in these formation after cesarean delivery in women studies was by the intravenous rather than with HELLP syndrome may be as high as the intramuscular route, as recommended 20%,49 it may be prudent to place one or by the National Institutes of Health54 and more subfascial and/or subcutaneous drains 55 at the time of surgery, especially if there ACOG. The effect of large doses of intra- is evidence of significant intraoperative venous corticosteroids on fetal adrenal func- oozing or severe thrombocytopenia tion and fetal development is not known. As (<50,000/mm3). The drains can be removed such, expectant management and antepar- electively in 24 to 48 hours. If the gestational tum “treatment” of HELLP syndrome with age is more than 34 weeks, induction of la- large doses of corticosteroids is not univer- bor can be initiated with or without cervical sally accepted. ripening, if indicated. It is our usual practice In addition to antepartum corticosteroids, to check coagulation test results as well as Magann et al56 have also reported on the use hepatic and renal function test results every of postpartum intravenous corticosteroids 6 hours until delivery, and then daily until (10 mg q12h for two doses followed by 5 mg stable. q12h for two doses) to accelerate the rever- Several specific therapeutic maneuvers sal of HELLP syndrome. Although the fetal have been proposed in an effort to cure effect of high-dose corticosteroids is no or alleviate HELLP syndrome. These in- longer a concern postpartum, larger ran- clude, among others, plasma volume domized clinical trials are needed to verify expansion (using crystalloid or albumin), the efficacy of postpartum corticosteroid thrombolytic agents (low-dose aspirin, di- therapy for HELLP syndrome. With or with- pyridamole, heparin, antithrombin III, out corticosteroids, the vast majority of prostacyclin/thromboxane synthetase in- women with HELLP syndrome will recover hibitors), immunosuppressive agents (corti- within 96 hours of delivery. costeroids), exchange plasmapheresis, and dialysis. Magann et al52 reported that antepartum dexamethasone administration to women with HELLP syndrome significantly FUTURE PREGNANCIES increased maternal platelet count, decreased The reported risk of recurrent HELLP syndrome in a subsequent pregnancy ranges serum alanine aminotransferase and LDH, 57 58 increased maternal urine output, and re- from 3% to 27%. Future pregnancies are sulted in a longer entry-to-delivery interval also at increased risk of other adverse compared with women who did not receive events, including other manifestations of corticosteroids. A subsequent study by the preeclampsia, preterm delivery, fetal growth same group from the University of Missis- restriction, placental abruption, and cesar- sippi Medical Center reported that dexa- ean delivery. The overall risk of such com- methasone was more effective than beta- plications is 19–43%.57,58 316 NORWITZ ET AL Liver Rupture rupture, an immediate exploratory laparoto- Liver rupture is one of the most severe con- my and cesarean delivery should be per- sequences of severe preeclampsia/HELLP formed. Unnecessary manipulation of the syndrome, with a reported maternal death liver should be avoided because this may rate of more than 30%.59 It occurs most precipitate rupture. For the nonexpanding commonly in multiparas of advanced age. liver hematoma, surgical repair or evacua- Fortunately, it is rare. The precise cause of tion is usually not necessary. Expectant liver rupture remains unknown. The prevail- management with serial CT or abdominal ing theory is that endothelial dysfunction ultrasound examinations may be all that is with intravascular fibrin deposits and he- needed. patic sinusoidal obstruction leads to intrahe- If there is evidence of liver rupture, patic vascular congestion, increased intrahe- prompt surgical intervention under general patic pressure, and distention of Glisson’s endotracheal anesthesia is mandated. Atten- capsule, and finally to the development of a tion should be focused on the need for inva- subcapsular hepatic hematoma and liver sive hemodynamic monitoring and on blood rupture. product replacement and correction of coagulopathy, if indicated. After delivery of CLINICAL MANIFESTATIONS AND the fetus through a vertical skin incision, the DIAGNOSIS upper abdomen should be explored. There A high index of clinical suspicion is the key are several approaches to the management to prompt and accurate diagnosis. Pain in the of liver rupture, and the decision of which right upper quadrant and/or epigastric area approach to take depends on the hemody- and focal tenderness are the most important namic status of the patient, the extent of the clinical features, especially if they occur in rupture, the magnitude and rate of ongoing the setting of preeclampsia/HELLP syn- hemorrhage, and the experience of the sur- drome. Bilateral shoulder-tip pain is sugges- geons. Unlike repair of a traumatic liver lac- tive of intraabdominal hemorrhage. Rarely, an abdominal mass may be palpated. If an eration, simple suturing is rarely effective abdominal mass is noted, further abdominal because the entire liver is edematous and fri- examinations should be avoided because able and the hepatic parenchyma does not have the tensile strength to retain the su- such manipulations may cause the hema- 60 toma to rupture. Imaging techniques such as tures. Other surgical options include pack- ultrasound, computed tomography (CT), or ing with gauze, topical coagulant agents or magnetic resonance imaging (MRI) may en- collagen fleeces coated with fibrin glue, in- able early and accurate diagnosis of liver he- corporation of omental pedicles or surgical matoma or rupture. mesh into the liver, ligation of the hepatic artery, radiologic embolization of the hepatic artery, or hepatic lobectomy. Hepatic MANAGEMENT The management of liver hematoma and artery embolization was recently reported to have the highest maternal survival rate of rupture requires a multidisciplinary ap- 61 proach in a tertiary care facility, if possible. around 90% and should be attempted if The first priority is to stabilize the maternal hemorrhage can be controlled and if the pa- hemodynamic status. Aggressive blood tient is hemodynamically stable. transfusion may be necessary. Immediate The recurrence rate of liver rupture is un- consultation with a staff anesthesiologist determined, because only a few cases of and a general or vascular surgeon is indi- pregnancies in such women have been de- cated. If a liver hematoma is diagnosed in scribed. However, in all but one reported in- the antepartum period without evidence of stance,62 there was no recurrence. Acute Complications of Preeclampsia 317 Pulmonary Edema the effect of intravenous magnesium sulfate Pulmonary edema refers to an excessive ac- administered for preterm labor or seizure cumulation of fluid in the pulmonary inter- prophylaxis on colloid osmotic pressure and stitial and alveolar spaces. It complicates the risk for pulmonary edema in 294 preg- around 0.05% of low-risk pregnancies but nant women. Only 4 of the 294 women de- may develop in up to 2.9% of pregnancies veloped pulmonary edema, and all of them complicated by preeclampsia.63 had low colloid osmotic pressure in the setting of severe preeclampsia. The authors ETIOLOGY AND PATHOPHYSIOLOGY concluded that magnesium sulfate does not The causes of pulmonary edema are often significantly change colloid osmotic pres- multifactorial. According to the Starling sure and, as such, does not pose a signifi- equation, any factor that results in a reduc- cantly increased risk of pulmonary edema.66 tion in colloid osmotic pressure (or in the Only 30% of cases of pulmonary edema colloid osmotic pressure/pulmonary capil- in the setting of preeclampsia occur before lary wedge pressure gradient), an increase in delivery.63 The vast majority (90%) of such capillary permeability, or an increase in in- patients have underlying chronic hyperten- travascular hydrostatic pressure will lead to sion, and they are more likely to be multipa- extravasation of fluid from the vasculature rous and of advanced maternal age.63 In the and predispose to the development of pul- setting of chronic hypertension with super- monary edema.64 imposed preeclampsia, systemic vascular The underlying physiologic changes in resistance and left heart filling pressures are the maternal cardiovascular system that ac- increased. This leads, in turn, to a decrease company pregnancy predispose to the devel- in cardiac output and an increase in pulmo- opment of pulmonary edema. Such changes nary vascular hydrostatic pressure, which include an increase in plasma blood volume, culminates in the development of pulmo- cardiac output, heart rate, and capillary per- nary edema. An additional feature that may meability and a decrease in plasma colloid predispose to the development of pulmonary osmotic pressure. These changes are often edema in the setting of preeclampsia is an exaggerated in the setting of preeclampsia, increase in capillary leak and capillary fluid leading to a further increase in the incidence extravasation secondary to vascular endo- of pulmonary edema. Moreover, in normal thelial damage.67 pregnancy, plasma colloid osmotic pressure DIAGNOSIS decreases from around 22 mm Hg at term to Pulmonary edema is a clinical diagnosis 16 mm Hg after delivery (and from 18 mm characterized by worsening dyspnea and or- Hg at term to 14 mm Hg postpartum in preg- thopnea along with signs of respiratory com- nancies complicated by preeclampsia65). promise (tachypnea, auditory crackles and The reduction in colloid osmotic pressure rales, hypoxemia). Arterial blood gas and after delivery may result from excessive chest x-ray may assist in the diagnosis. In blood loss, fluid shifts secondary to in- select patients, electrocardiography, creased capillary permeability (especially in echocardiography, spiral CT imaging, preeclamptic pregnancies), or excessive ventilation/perfusion scan, or pulmonary ar- crystalloid infusion. Such changes help to teriography may be necessary to exclude explain at least in part why 70–80% of cases other causes of cardiopulmonary compro- of pulmonary edema in the setting of pre- mise, such as pulmonary embolism, pneu- eclampsia develop after delivery.63,65 An- monia, and cardiomyopathy. other confounding factor is magnesium sulfate, which is often administered to pre- MANAGEMENT eclamptic women for seizure prophylaxis. Prompt diagnosis and intervention are man- To address this issue, Yeast et al66 measured datory. The goal of management is to stabi- 318 NORWITZ ET AL lize the mother, expedite resolution of the of a pulmonary artery catheter and transfer pulmonary edema, and then make a decision to an intensive care unit should be consid- about delivery. Appropriate management of ered. In patients with severe pulmonary acute pulmonary edema can be summarized edema, mechanical ventilatory support may by the letters LMNOP: be necessary. In the setting of congestive heart failure, ● Lasix (furosemide) administered intrave- administration of a ␤-adrenergic antagonist nously as a single dose of 20 to 40 mg over 2 may be indicated. In the past, ␤-blockade minutes to promote diuresis. If an adequate was considered contraindicated in patients response is not seen within 30 to 50 minutes, with congestive heart failure. However, the dose should be increased to 40 to 60 mg more recent studies have shown that such administered by slow intravenous injection to a maximum of 120 mg in 1 hour. Electrolytes agents can antagonize the deleterious effects of the sympathetic nervous system activa- (especially potassium) should be supple- 69 mented as needed. tion that occurs in congestive heart failure. ● Morphine sulfate should be administered in- As such, ␤-blockade is now considered a travenously at a dose of 2 to 5 mg as needed in key component of the management of acute an attempt to reduce the adrenergic vasocon- congestive heart failure. However, the use of strictor stimuli to the pulmonary arteriolar such agents in pregnancy and especially in and venous beds. preeclampsia complicated by congestive + ● Na (sodium) and water restriction, and strict heart failure remains to be established. input/output monitoring. ● Oxygen supplementation using a non- rebreather face mask at 8 to 10 L/min, along with continuous monitoring of oxygen satura- Renal Failure tion using a pulse oximeter. Acute renal failure is characterized by an ● Positioning (elevation) of the maternal head abrupt reduction in the maternal glomerular and chest to improve ventilation by reducing filtration rate, leading to excessive retention pulmonary capillary wedge pressure. of urea and water as well as numerous electrolyte and acid-base abnormalities. Acute In addition to these standard measures, it renal failure is a rare complication of pre- is appropriate to follow the patient’s blood eclampsia, but the actual incidence remains pressure, electrocardiogram, and fetal heart undetermined. According to one center’s rate tracing. Afterload reduction using a va- experience, 18% of all cases of acute renal sodilator (eg, hydralazine, a calcium chan- failure were of obstetric origin.70 Among nel blocker, or an angiotesin-1 converting those patients, 20.9% of cases occurred in enzyme inhibitor [which should be used the setting of preeclampsia. Other condi- only after delivery]) may be necessary, es- tions that should be considered include he- pecially in parturients with chronic hyper- molytic uremic syndrome, primary renovas- tension and superimposed preeclampsia. cular disease, and placental abruption. Because most obstetric patients have normal left ventricular systolic function, inotropic ETIOLOGY AND PATHOGENESIS support is rarely necessary. According to The characteristic histologic renal lesion in ACOG, severe preeclampsia with pulmo- preeclampsia is glomerular endotheliosis, in nary edema is one of the indications for in- which the glomeruli are large and swollen vasive pulmonary artery catheterization,68 with vacuolated endothelial cells. This his- although most patients can be managed ini- tologic feature, coupled with the generalized tially without invasive hemodynamic moni- vasoconstriction that characterizes pre- toring. However, if the pulmonary edema is eclampsia, leads to a 25–30% decrease in re- refractory to initial management or if it is ac- nal plasma flow and glomerular filtration companied by persistent oliguria, insertion compared with normal pregnancy.71 How- Acute Complications of Preeclampsia 319 ever, functional impairment of renal func- 13 patients with chronic hypertension and tion in women with preeclampsia is gener- superimposed preeclampsia had bilateral ally mild and reverses completely after de- cortical necrosis; 9 of 11 (81.8%) surviving livery. As such, clinically significant acute patients required long-term dialysis, and 4 renal failure in preeclampsia is rare. had subsequently died of end-stage renal The causes of acute renal failure can be disease before publication. The authors con- divided into three broad categories: prerenal cluded that early identification and appro- (which refers to renal hypoperfusion with- priate management of acute renal failure in out parenchymal involvement), intrarenal previously healthy parturients with pre- (which suggests intrinsic renal parenchymal eclampsia did not result in residual long- damage), and postrenal (which implies ob- term renal damage. structive uropathy). Prerenal and intrarenal The same investigators from Memphis, pathology (acute tubular necrosis) accounts Tennessee, subsequently reported their ex- for 83–90% of all cases of acute renal failure perience with HELLP syndrome and acute in preeclampsia.72,73 Renal damage second- renal failure.75 The overall incidence of ary to these pathologic changes is seen most acute renal failure in the setting of HELLP commonly in preeclampsia and usually re- syndrome was 7.3% in their cohort, with a solves completely after delivery. In contrast, maternal death rate of 13% and a perinatal bilateral renal cortical necrosis, which ac- death rate of 34%. The majority of the 32 counts for 10–29% of cases of acute renal patients with HELLP syndrome and acute failure in pregnancy,72–74 is a far more seri- renal failure were postpartum. Further ous condition and is associated with signifi- analysis suggested that the presence of un- cant rates of maternal and perinatal death derlying chronic hypertension was associ- and complications. It is seen most com- ated with a less favorable pregnancy out- monly in women with underlying chronic come and a more guarded long-term progno- hypertension and superimposed preeclamp- sis. sia, known parenchymal renal disease, pla- 74 cental abruption, or DIC. MANAGEMENT The management of acute renal failure in the PROGNOSIS 72 setting of preeclampsia should focus on ex- In 1990, Sibai et al reported on their expe- cluding other diagnoses, especially condi- rience of the short-term pregnancy outcome, tions that may be reversible (eg, dehydra- subsequent pregnancy outcome, and remote tion or obstructive uropathy). Supportive prognosis in 31 patients with preeclampsia therapy includes blood pressure control, po- complicated by acute renal failure collected sitioning patients so as to improve renal over a period of 11 years. The actual inci- blood flow, correcting fluid and electrolyte dence of acute renal failure could not be de- imbalance, and maintaining adequate nutri- termined because most of their patients were tion. If dialysis is required in pregnancy, he- referred from outside institutions. The ma- modialysis is preferred over peritoneal di- ternal death rate was 10% (3/31). Overall, 14 alysis. of their 31 patients (46.6%) required dialysis, and there was no difference in the per- centage of women requiring dialysis for preeclampsia (50%) and chronic hypertension Disseminated Intravascular with superimposed preeclampsia (42%). All Coagulopathy 18 patients with acute renal failure in the set- DIC is a hematologic disorder characterized ting of preeclampsia had acute tubular ne- by a generalized increase in both fibrin for- crosis, with complete resolution of renal mation and fibrinolysis, leading to excessive function after delivery. In contrast, 3 of the consumption of clotting factors, which 320 NORWITZ ET AL presents clinically as a bleeding diathesis. eclampsia is a combination of platelet count The most common causes of DIC in preg- and activated partial thromboplastin time. nancy are excessive blood loss with inad- equate blood component replacement, pla- MANAGEMENT cental abruption, amniotic fluid embolism, Evidence of DIC in the setting of severe and severe preeclampsia/HELLP syndrome. preeclampsia/HELLP syndrome should prompt immediate delivery. The decision of whether to proceed with induction of labor DIAGNOSIS or cesarean delivery depends on such factors Diagnosis requires a high index of suspicion as gestational age, parity, cervical Bishop coupled with appropriate blood tests. score, motivation of the patient, and the se- Thrombocytopenia, which can be docu- verity of DIC (eg, a rapidly falling platelet mented in about 10% of parturients with se- count may make cesarean delivery a more vere preeclampsia,76 is often the first indica- appropriate choice). Moderate to severe tor of DIC. Moreover, a normal platelet thrombocytopenia (especially a platelet count effectively excludes the diagnosis. count <70,000/mm3) may be a contraindica- Other hematologic aberrations that can be tion to regional anesthesia because of the used to confirm the diagnosis include an in- risk of spinal hematoma.80 crease in circulating fibrin degradation Because DIC is a consumptive coagu- products, D-dimer, platelet factor 4, lopathy and therefore a progressive condi- ␤-thromboglobulin, thrombomodulin, fibri- tion, early diagnosis and prompt and ap- nopeptide A, thrombin-antithrombin com- propriate management are critical to reduc- plexes, and a decrease in circulating anti- ing maternal and perinatal death and com- thrombin III, fibrinogen, and protein C ac- plication rates. Heparin administration is tivity. However, many of these tests are not generally recommended for the treat- expensive, time-consuming, and not clini- ment of DIC in parturients with severe cally useful. Sibai et al77 defined DIC as preeclampsia/HELLP syndrome.81 The cor- evidence of excessive bleeding with throm- nerstones of management include mainte- bocytopenia (<100,000/mm3), plasma fi- nance of intravascular volume and replace- brinogen level less than 300/mg/dL, and fi- ment of blood components and/or coagula- brin-split products more than 40 µg/mL. Us- tion factors, as indicated by laboratory ing this strict definition, they reported a 38% parameters. Each unit of packed red blood incidence of DIC in the setting of HELLP cells has a volume of 250 mL and contains syndrome.77 However, many pregnancies citrate-phosphate-dextrose as a preserva- complicated by severe preeclamp- tive. Packed red blood cells have a hemato- sia/HELLP syndrome have evidence of crit of about 70%, and in the absence of con- “subclinical” consumptive coagulopathy tinued hemorrhage, each unit should in- without evidence of bleeding, suggesting crease the hematocrit by 2–3% and the that DIC is a consequence, not a cause, of hemoglobin by about 1 g/dL in a healthy 70- preeclampsia. Roberts and May,78 on the kg (154-lb) woman.82 Fresh-frozen plasma other hand, have argued that abnormal labo- contains significant amounts of factors II (fi- ratory DIC parameters are rarely seen in se- brinogen), V, and VIII as well as providing vere preeclampsia/HELLP syndrome unless additional colloid support. Fresh-frozen there is a concurrent placental abruption. plasma should be administered when the Exactly which laboratory parameters to prothrombin time is at least 1.5-fold normal check is controversial. Metz et al79 have (ie, when the international normalized ratio suggested that the most practical and cost- [INR] is Ն1.5). The initial dose is usually 2 effective approach to screening for con- units. Each unit has a volume of 200 to 250 sumptive coagulation in the setting of pre- mL and raises circulating clotting factors by Acute Complications of Preeclampsia 321 about 2–3%.82 Cryoprecipitate refers to a accident as a result of acute hypertension is concentrated extract of fresh-frozen plasma the leading cause of maternal death in pre- that is enriched with factors II (fibrinogen) eclampsia.84 and VIII. Each unit has a volume of only 10 to 15 mL. Transfusion of cryoprecipitate DIFFERENTIAL DIAGNOSIS should be considered when circulating fi- Acute hypertension may be the result of any brinogen levels drop below 100 mg/dL in one of a number of disorders. Although the the setting of DIC. When to recommend etiology is usually apparent, consideration platelet transfusion, however, is controver- should be given to diagnostic possibilities sial. Some authorities have suggested that other than preeclampsia if the clinical pre- platelets be administered routinely if the sentation is atypical. Such alternative diag- circulating platelet count is less than noses include pheochromocytoma, renal 20,000/mm3 or if the platelet count is less vein thrombosis, clonidine withdrawal, co- than 50,000/mm3 if a surgical procedure is caine ingestion, methamphetamine inges- planned, if there is active bleeding, or if tion, and acute flare of an underlying colla- massive transfusion is anticipated.82 Other gen vascular disease. In most instances, practitioners note that such threshold recom- however, the cause of acute hypertension is mendations are arbitrary and that platelet the result of either worsening of underlying transfusion can usually be avoided even essential hypertension or acute exacerbation when platelet counts are below these val- of preeclampsia. ues.83 However, in such circumstances, it is usually prudent to have platelets immedi- PATHOPHYSIOLOGY ately available in the event a platelet trans- Why hypertensive emergencies occur in fusion is needed. Platelets are prepared in a some patients and not others remains un- volume of 40 mL containing a total of 55 × clear. Some authorities have attempted to 109 platelets. One unit of platelet concen- define threshold parameters for hyperten- trate will usually increase the platelet count sive crisis and have suggested that a diastol- by 5,000 to 10,000/mm3. The usual dosage ic blood pressure of more than 115 mm Hg is 1 unit per 10 kg body weight.82 Small and/or a systolic blood pressure of more than amounts of erythrocytes are present in plate- 200 mm Hg should be used to define hyper- let concentrates. If ABO and Rh type- tensive crisis.85,86 However, clinical experi- specific platelets are not available, an Rh- ence has shown that cerebrovascular acci- negative woman can be sensitized by Rh- dent can occur in women whose blood pres- positive platelets. Anti-D immune globulin sure has remained consistently below these (RhoGAM) should be administered, if indi- threshold parameters. Others have proposed cated. that it is the rate of blood pressure change, rather than an absolute measurement, that is responsible for the cerebral injury.85 Hypertensive Emergencies Hypertensive crises can affect numerous Hypertensive emergencies may complicate organ systems. Retinal detachment and/or preeclampsia as well as chronic hyperten- hemorrhage, congestive heart failure, myo- sion. Although the pathophysiology may be cardial infarction, renal failure, liver failure, different, the approach to acute evaluation placental abruption, and hypertensive en- and management is the same, with the prin- cephalopathy may all result from acute and cipal goal being avoidance of hypertensive uncontrolled hypertension. Clinical evi- encephalopathy and cerebrovascular acci- dence of any of the above end-organ effects dent. Less clear is whether aggressive con- should prompt a rapid response, with efforts trol of blood pressure reduces the risk of directed at blood pressure control. Most pa- eclampsia. Although rare, cerebrovascular tients may be managed without using inva- 322 NORWITZ ET AL sive hemodynamic monitoring, but patients must occur in an intensive care facility. In- with severe or atypical cases are best man- travenous sodium nitroprusside is the anti- aged in a tertiary center with such monitor- hypertensive agent of choice in this setting. ing under the direction of clinicians skilled At doses exceeding 8 µg/kg per minute, con- in critical care medicine. cerns about cyanide and thiocyanate accu- mulation in the fetal compartment have been MANAGEMENT expressed. As such, close monitoring of cya- Hypertensive emergencies in pregnancy nide levels in patients receiving high doses present a significant clinical challenge. The of sodium nitroprusside for extended peri- most important first step in the management ods is recommended. Other medications that of hypertensive crisis is to lower blood pres- may be used in this setting to acutely lower sure. Dramatic and rapid lowering of blood blood pressure are summarized in Table 3. pressure should be avoided. Ideally, an ini- The definitive management of hyperten- tial reduction of blood pressure of about sive crisis in the setting of preeclampsia is 20%, with systolic and diastolic pressure delivery. Regional analgesia and anesthesia goals of 140 to 150 mm Hg and 90 to 100 are preferred in this setting, provided there is mm Hg, respectively, will provide the most no evidence of coagulopathy and no other favorable outcome.87 Hypertension refrac- contraindications to regional anesthesia. tory to medical therapy is an indication for Avoidance of hypotension is critical in these urgent termination of the pregnancy, and, in patients. If general anesthesia is needed, extreme circumstances, perimortem cesar- blood pressure control is essential, and pre- ean delivery may be necessary.85 medication may be necessary to avoid the In acute hypertension complicated by hy- increase in blood pressure that often accom- pertensive encephalopathy, management panies induction of general anesthesia.

TABLE 3. Pharmacologic Management of Acute Hypertensive Crisis Drug Dosing Comment Recommended First-Line Therapy Hydralazine 5 mg IV push q 10 min × 2 doses; then Be aware of hypotension and 10 mg IV push q 20 min as needed potential to adversely effect until blood pressure has stabilized at uteroplacental perfusion. 140–150/90–100 mm Hg Labetalol 10–20 mg IV push; repeat q 10–20 min Be aware of hypotension and with doubling doses (not to exceed potential to adversely effect 80 mg in any single dose) to a uteroplacental perfusion. maximum of 300 mg total Nifedipine 10 mg orally q 30 min × 2 doses; then Sublingual nifedipine is best 10–20 mg orally q 4–6 hourly avoided.* Recommended Therapy in Women Refractory to First-Line Agents Sodium nitroprusside 0.5–3.0 µg/kg/min IV infusion (not to Should be used only by someone exceed 800 µg/min) with critical care experience Nitroglycerin 5 µg/min IV infusion, increase as Relatively contraindicated in the required every 5 min to maximum setting of hypertensive dose of 100 µg/min encephalopathy as it may increase cerebral blood flow and intracranial pressure*

Adapted from Repke JT. Preeclampsia and hypertension. In: Repke JT, ed. Intrapartum Obstetrics. New York: Churchill Livingstone, 1996:271. * Grossman E, Messerli FH, Grodzicki T, Kowey P. Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies? JAMA. 1996; 276:1328–1331. Acute Complications of Preeclampsia 323 Hypertensive Encephalopathy white matter, and midbrain. Because petechial hemorrhages were associated with and Cortical Blindness capillary thrombi, the authors concluded Cortical blindness is a known complication that the lesions were caused by a vascular of severe preeclampsia. Other ophthalmo- disturbance that produced local ischemia. logic manifestations of preeclampsia in- Severe diffuse cerebral edema is occasion- clude retinal detachment, retinal arteriolar ally seen in eclampsia; however, the more vasospasm, and thrombosis of the central typical lesion is localized edema at the gray retinal arteries.88,89 The incidence of corti- matter/white matter junction in the occipital cal blindness as a manifestation of hyperten- lobe. The susceptibility of the posterior cir- sive encephalopathy in severe preeclampsia culation to the lesions of hypertensive en- is 1–15%.90,91 cephalopathy is a well-known but poorly understood phenomenon.98,99 One possible PATHOPHYSIOLOGY explanation involves the regional heteroge- The brain is normally protected from ex- neity of the sympathetic vascular innova- tremes of blood pressure by an autoregulation. In experimental studies, the sympa- tory system that ensures constant perfusion thetic innervation of the intracranial arteri- over a wide range of systemic pressures. In oles has been shown to protect the brain response to systemic hypotension, cerebral from marked increases in blood pressure.100 arterioles dilate to maintain adequate perfu- Moreover, ultrastructural studies have sion, whereas vessels constrict in response shown that the internal carotid system is to high systemic pressures. Above the upper much better supplied with sympathetic in- limit of autoregulation, hypertensive en- nervation than is the vertebrobasilar sys- cephalopathy may develop.92 Hypertensive tem.101 Acute hypertension would, accord- encephalopathy is a subacute neurologic ing to this hypothesis, stimulate the perivas- syndrome characterized by headache, sei- cular sympathetic nerves, which would zures, visual aberrations, and other neuro- protect the anterior but not the more poorly logic disturbances (altered mental status, fo- innervated posterior circulation. This would cal neurologic signs) in the setting of el- result in breakthrough of autoregulation evated blood pressure. Although the with edema mainly in the occipital lobes, syndrome is usually reversible if the hyper- and resultant ophthalmologic manifesta- tension is treated early, it may be fatal if it is tions. unrecognized or if treatment is delayed.93,94 Two theories have been proposed to ac- The clinical findings are nonspecific and the count for the clinical and radiologic abnor- diagnosis may be difficult to establish, par- malities associated with hypertensive en- ticularly in patients who have other ill- cephalopathy and cortical blindness. The nesses. Various neurologic conditions such first postulates that hypertensive encepha- as cerebrovascular accident, venous throm- lopathy results from spasm of the cerebral bosis, and encephalitis can mimic hyperten- vasculature in response to acute hypertensive encephalopathy.95 Radiologic imaging sion, resulting in ischemic injury, arteriolar studies may be useful in establishing the di- necrosis, and cytotoxic edema.102–105 A agnosis in the appropriate clinical setting.96 more recent alternative hypothesis suggests The classic autopsy studies of Sheehan that the syndrome results from breakthrough and Lynch97 in the 1960s refuted the pre- of autoregulation with passive overdisten- vailing opinion that preeclampsia/eclampsia tion of cerebral arterioles, leading to in- was frequently associated with widespread creased capillary permeability with leakage cerebral edema. The most common lesions of fluid and proteins into the surrounding tis- described were multiple petechial hemor- sues, resulting in vasogenic (hydrostatic) rhages in the cortex, subcortical region, edema.92,96,106 In both instances, the end re- 324 NORWITZ ET AL sult is focal cerebral edema. The presence of Conclusion cerebral edema on head CT or MRI is there- Preeclampsia remains a significant cause of fore not helpful in defining the mechanism maternal and perinatal death and complica- underlying hypertensive encephalopathy. tions. Once the diagnosis of preeclampsia The availability of improved neuroimaging, has been made, treatment options are lim- including single-photon emission computed ited. For this reason, much attention has re- tomography (SPECT), which can distin- cently been focused on preeclampsia pre- guish between areas of hyper- and hypoper- vention. Despite an extensive research ef- fusion, has enabled a more detailed investi- fort, no single strategy has yet been shown to gation of the response of the cerebral vascu- be beneficial in preventing the development lature to hypertension. of preeclampsia in either low- or high-risk 36 In 1992, Schwartz et al96 reported on the populations. Preeclampsia is a disorder of use of CT, MRI, and SPECT in 14 patients placental implantation and is therefore not with hypertensive encephalopathy, includ- entirely preventable. Delivery of the fetus ing 8 with preeclampsia. All patients had hy- and placenta remains the only curative treat- podense lesions in the occipital lobes on CT, ment. A healthy respect for this condition, which correlated with lesions of increased coupled with aggressive and early intervention in the event of preeclampsia complica- signal intensity on T2-weighted MRI. tions, may be able to minimize adverse ma- SPECT performed on two patients during ternal and perinatal events in the setting of hypertensive episodes revealed areas of in- severe preeclampsia. creased cerebral perfusion, which corre- sponded with lesions on CT and MRI. These data support the concept that hypertensive References encephalopathy results primarily from in- 1. American College of Obstetricians and creased capillary permeability leading to va- Gynecologists. Hypertension in preg- sogenic edema. If vasospasm and resultant nancy. ACOG Technical Bulletin No. 219. ischemia were important features, decreased Washington, DC: ACOG, 1996. cerebral perfusion on SPECT would have 2. Meekins JW, Pijnenborg R, Hanssens M, been observed with possible infarction. et al. A study of placental bed spiral arteries and trophoblast invasion in normal and However, infarction is a rare occurrence 93,96,98,103,104 severe pre-eclamptic pregnancies. Br J Ob- both clinically and experimen- stet Gynaecol. 1994;101:669–674. 107 tally. 3. Report of the National High Blood Pres- sure Education Program Working Group on high blood pressure in pregnancy. Am J MANAGEMENT Obstet Gynecol. 2000;183:S1-S22. Cortical blindness and other manifestations 4. Morriss MC, Twickler DM, Hatab MR, et of hypertensive encephalopathy are a con- al. Cerebral blood flow and cranial mag- traindication to expectant management of netic resonance imaging in eclampsia and preeclampsia in pregnancy. Delivery of the severe preeclampsia. Obstet Gynecol. 1997;89:561. fetus and placenta remains the only curative 5. Rochat RW, Koonin LM, Atrash HF, et al. treatment. 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