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Expectant management of severe preeclampsia remote

from term: hope for the best, but expect the worstErrol R. Norwitz, MD, PhD; Edmund F. Funai, MD

Preeclampsia (gestational proteinuric hypertension) com-plicates 5-6% of all pregnancies.1 It is the second mostcommon cause of maternal death in the United States (afterthromboembolic disease) and accounts for 12-18% of all preg-nancy-related maternal deaths (approximately 70 maternaldeaths per year in the United States and an estimated 50,000maternal deaths per year worldwide).1,2 It is associated alsowith a high perinatal mortality and morbidity rate, which is

primarily due to iatrogenic prematurity. The development ofpreeclampsia cannot be accurately predicted nor effectivelyprevented. Delivery of the fetus and placenta remains the onlydefinitive treatment. For all these reasons, the timing of deliv-

ery is critical to optimize maternal and perinatal outcome inthe setting of preeclampsia.

Preeclampsia is classified as mild and severe (there is no

moderate preeclampsia). Mild preeclampsia refers to diseasethat meets criteria for the diagnosis of preeclampsia but is notsevere disease. A diagnosis of severe preeclampsia requires ev-idence of new-onset proteinuric hypertension along with 1of a series of complications (summarized in Table 1). It shouldbe emphasized that only 1 of the listed criteria is required forthe diagnosis of severe disease. The distinction between mild

and severe preeclampsia is important because it dictatesmanagement.

The initial management of preeclampsia includes stabiliza-tion of the mothers condition, assessment of fetal well-being,and confirmation of gestational age. Evidence of nonreassur-ing fetal testing, maternal hemodynamic instability, or rapidlyworsening maternal status (including decreasing platelet

count, coagulopathy, or oliguria unresponsive to hydration)shouldprompt immediatedelivery. In the absence of such con-ditions, every effort should be made to optimize perinatal out-come, including transfer of the patient to a tertiary care centerand/or administration of antenatal corticosteroids, if indi-cated. Under most circumstances, delivery can be delayed for24-48 hours to achieve these goals. Delivery is the only defini-

tive treatment and is recommended for women with mild pre-eclampsia once a favorable gestational age has been reached.1,2

In contrast, delivery generally is recommended for all womenwith severe preeclampsia, regardless of gestational age, to pre-

vent impending maternal and fetal complications. The ques-tion as to whether it is reasonable to offer expectant treatment

to a woman with severe preeclampsiaremote from term is con-

troversial and hinges, at least in part, on the specific criteria by

which the patient is deemed to have severe disease (Table 2).

There are 2 circumstances in which expectant management

of severe preeclampsia remote from term is clearly acceptable.

The first is severe preeclampsia by proteinuria. Neither the

amount of protein spilled in the urine nor the rate of increase

correlates with maternal or perinatal outcome.3,4 As such, pro-

teinuria 5 g per 24 hours is not, of itself, an indication for

delivery. The second is severe preeclampsia on the basis of in-

trauterine growth restriction (IUGR) alone remote from term(32 weeks of gestation) with good fetal testing. Although not

candidates for immediate delivery, such parturients should be

treated as inpatients with at least daily fetal testing. The admis-

sion-to-delivery interval in such pregnancies averages 3 days,

and 85% of such women will require delivery within 1 week of

presentation.5

A number of investigators have challenged the traditional

teaching that all women with severe preeclampsia should be

delivered, regardless of gestational age, andhave arguedthat,in

addition to the 2 exceptions listed earlier, there are other cir-

cumstances in which such women can be treated expectantly.

Two examples deserve further attention. First, there is prece-dent in the literature to support the expectant treatment of

women with severe preeclampsia by blood pressure criteria

alone before 32 weeks of gestation. This approach, although

potentially dangerous for the mother, has been substantiated

in a number of clinical trials.6,7 Second, there has been a recent

trend towards expectant management of severe preeclampsia

with HELLP (hemolysis, elevated liver enzymes, low platelets)

syndrome to treat the patient with steroids. Although high-

dose intravenous dexamethasone has been shown to increase

significantly maternal platelet count and urine output and to

decrease circulating aspartate aminotransferase and lactate de-

hydrogenase levels, thereby leading to a longer diagnosis-to-

delivery interval, it has not been shown to improve maternal or

perinatal outcome.8,9 As such, expectant management and ste-

roid treatment forHELLPsyndromehas notreceiveduniversal

acceptance. Indeed, in their latest Practice Bulletin in 2002, the

American College of Obstetricians and Gynecologists clearly

states that: Considering the serious nature of this complica-

tion, it seems reasonable to conclude that women with HELLP

syndrome should be delivered regardless of their gestational

age.1

The latest article to challenge the principal of immediate de-

livery for all women with severe preeclampsia, regardless ofgestational age, appears in this issue of this Journal. In this

From Department of Obstetrics, Gynecology & Reproductive

Sciences, Yale University Schoolof Medicine, New Haven, CT.

0002-9378/free

2008 Mosby, Inc. All rights reserved.

doi: 10.1016/j.ajog.2008.06.084

See related article, page 247

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observational study, Bombrys et al10 report on the maternaland perinatal outcome in a case series of 46 parturients (51

fetuses) with severe preeclampsia at

27 weeks of gestationwho were treated expectantly. Maternal and perinatal outcomeare analyzed by week of gestation. Although a number of sim-ilar case series have been published in the past,6,11-21 such re-ports are valuable because many institutions are unwilling tooffer expectant treatment in this setting, given the risks to themother. This report adds to the existing literature in severalrespects. First, it reinforcesthe fact that expectant managementof severe preeclampsia remote from term is fraught with ma-ternal risk, with nearly one-half of all mothers experiencingsignificant morbidity. Further, when combined with data fromearlier publications,11-15,19-21 this report provides compelling

evidence that expectant management of severe preeclampsia at24 weeks of gestation is a largely futile endeavor. Finally,

these data suggest that the presence of IUGR in women withsevere preeclampsia remote from term is associated with a very

high perinatal mortality rate and, as such, probably should beregarded as a relative contraindication to expectant manage-ment. As the authors themselves point out, this report is retro-spective and includes a small sample size. Indeed, their recom-mendation that patients with evidence of severe (fetal growthrestriction) at time of onset of disease be delivered after com-pletion of a course of corticosteroids10 isbasedonatotalof14perinatal deaths (7 stillbirths and 7 neonatal deaths) among 34fetuses who were delivered at 26 weeks of gestation and di-rectly contradicts the recommendations of at least 1 previouspublication that was based on the outcome of 155 singletonpregnancies with IUGRand severe preeclampsia that was man-

aged expectantly at

34 weeks of gestation.

18

As such, theseconclusions should be interpreted with caution.

TABLE 1

Criteria for the diagnosis of severe preeclampsia

Criteria Definition

Symptoms.......................................................................................................................................................................................................................................................................................................................................................................

Symptoms of central nervous

system dysfunction

Subjective complaints of blurred vision, scotomata, altered mental status, and/or severe headache

.......................................................................................................................................................................................................................................................................................................................................................................

Symptoms of liver capsuledistention or rupture

Subjective complaints of persistent right upper-quadrant and/or epigastric pain

................................................................................................................................................................................................................................................................................................................................................................................

Signs.......................................................................................................................................................................................................................................................................................................................................................................

Blood pressure criteria Sitt ing blood pressure 160 mm Hg systolic and/or 110 mm Hg diastolic on 2 separateoccasions at rest at least 6 hours apart

.......................................................................................................................................................................................................................................................................................................................................................................

Eclampsia Generalized seizures and/or unexplained coma in the setting of preeclampsia and in the absenceof other neurologic conditions

.......................................................................................................................................................................................................................................................................................................................................................................

Pulmonary edema orcyanosis

Excessive fluid accumulation in the lungs

.......................................................................................................................................................................................................................................................................................................................................................................

Cerebrovascular accident(stroke)

Acute loss of brain function (as evidenced by focal neurologic signs, altered mental status, and/orcoma) because of a disturbance in the vasculature that supplies blood to the brain

.......................................................................................................................................................................................................................................................................................................................................................................

Cortical blindness Partial or total loss of vision in a normal-appearing eye that is caused by damage to the visualregion of the occipital cortex

.......................................................................................................................................................................................................................................................................................................................................................................

IUGRa Estimated fetal weight 5th percentile for gestational age or 10th percentile for gestational agewith evidence of fetal compromise (oligohydramnios, abnormal umbilical artery Dopplervelocimetry)

................................................................................................................................................................................................................................................................................................................................................................................

Laboratory findings.......................................................................................................................................................................................................................................................................................................................................................................

Proteinuria 5 G per 24 hours or 3 on 2 random urine samples that are collected at least 4 hours apart.......................................................................................................................................................................................................................................................................................................................................................................

Oliguria and/or renal fai lure Urine output 500 mL per 24 hours and/or serum creatinine 1.2 mg/dL.......................................................................................................................................................................................................................................................................................................................................................................

HELLP syndrome Evidence of hemolysis (abnormal peripheral smear, total bilirubin 1.2 mg/dL, lactatedehydrogenase600 U/L), elevated liver enzymes (alanine aminotransferase70 U/L, lactatedehydrogenase600 U/L), and low platelets (100,000 platelets/mm3)

.......................................................................................................................................................................................................................................................................................................................................................................

Hepatocellular injury Serum transaminase levels 2 normal.......................................................................................................................................................................................................................................................................................................................................................................

Thrombocytopenia 100,000 platelets/mm3.......................................................................................................................................................................................................................................................................................................................................................................

Coagulopathy Prolonged prothrombin time (1.4 seconds), low platelet count (100,000 platelets/mm3), andlow fibrinogen (300 mg/dL)

......................................................................................................................................................................................................................................................................................................... .......................................................................a In 2000, IUGR was excluded from the criteria for the diagnosis of severe preeclampsia by the National High Blood Pressure in Pregnancy Working Group,2 but it remains as a criterion for

the diagnosis of severe preeclampsia as defined by the American College of Obstetricians and Gynecologists. 1

Norwitz. Expectant management of severe preeclampsia remote from term. Am J Obstet Gynecol 2008.


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TABLE 2

Expectant management of severe preeclampsia

Criteria

Is it reasonable tooffer expectanttreatment in thissetting? Supportive literature

Symptoms No Sibai BM, Barton JR. Expectant management of severe preeclampsia remote from term: patient selection,management and delivery indications. Am J Obstet Gynecol 2007;196:514.e1-9

................................................................................................................................................................................................................................................................................................................................................................................

Blood pressurecriteria

Yes Reference6

................................................................................................................................................................................................................................................................................................................................................................................

Reference 7................................................................................................................................................................................................................................................................................................................................................................................

Schiff E, Friedman SA, Sibai BM. Conservative managment of severe preeclampsia remote from term.Obstet Gynecol 1994;84:626-30

................................................................................................................................................................................................................................................................................................................................................................................

Eclampsia No Reference1................................................................................................................................................................................................................................................................................................................................................................................

Sibai BM, Barton JR. Expectant management of severe preeclampsia remote from term: patient selection,management and delivery indications. Am J Obstet Gynecol 2007;196:514.e1-9

................................................................................................................................................................................................................................................................................................................................................................................

Pulmonary edema No Sibai BM, Barton JR. Expectant management of severe preeclampsia remote from term: patient selection,

management and delivery indications. Am J Obstet Gynecol 2007;196:514.e1-9................................................................................................................................................................................................................................................................................................................................................................................Cerebrovascularaccident

No Reference1

................................................................................................................................................................................................................................................................................................................................................................................

Cortical blindness No Cunningham FG, et al. Blindness associated with preeclampsia and eclampsia. Am J Obstet Gynecol1995;172:1291-8

................................................................................................................................................................................................................................................................................................................................................................................

IUGR Yes Chari RS, et al. Daily antenatal testing in women with severe preeclampsia. Am J Obstet Gynecol1995;173:1207-10

................................................................................................................................................................................................................................................................................................................................................................................

Reference5................................................................................................................................................................................................................................................................................................................................................................................

Reference 18................................................................................................................................................................................................................................................................................................................................................................................

Proteinuria Yes Schiff E, et al. The importance of urinary protein excretion during conservative management of severepreeclampsia. Am J Obstet Gynecol 1996;175:1313-16

................................................................................................................................................................................................................................................................................................................................................................................

Reference 4................................................................................................................................................................................................................................................................................................................................................................................Airoldi J, et al. Clinical significance of proteinuria in pregnancy. Obstet Gynecol Surv 2007;62:117-24

................................................................................................................................................................................................................................................................................................................................................................................

Oliguria and/orrenal failure

No Reference1

................................................................................................................................................................................................................................................................................................................................................................................

HELLP syndrome No van Pampus M, et al. Maternal outcome following temporizing management of the (H)ELLP syndrome.Hypertens Pregnancy 2000;19:211-20

................................................................................................................................................................................................................................................................................................................................................................................

Reference1................................................................................................................................................................................................................................................................................................................................................................................

Matchaba P, et al. Corticosteroids for HELLP syndrome in pregnancy. Cochrane Database Syst Rev 2004;CD002076

................................................................................................................................................................................................................................................................................................................................................................................

Vidaeff AC, et al. Corticosteroids for the syndrome of hemolysis, elevated liver enzymes, and low platelets(HELLP): what evidence? Minerva Ginecol 2007;59:183-90

................................................................................................................................................................................................................................................................................................................................................................................


................................................................................................................................................................................................................................................................................................................................................................................

Hepatocellularinjury

No Reference 1

................................................................................................................................................................................................................................................................................................................................................................................


................................................................................................................................................................................................................................................................................................................................................................................

Thrombocytopenia N o Reference1................................................................................................................................................................................................................................................................................................................................................................................


................................................................................................................................................................................................................................................................................................................................................................................

Coagulopathy No Reference1................................................................................................................................................................................................................................................................................................................................................................................

Sibai BM, Barton JR. Expectant management of severe preeclampsia remote from term: patient selection,

management and delivery indications. Am J Obstet Gynecol 2007;196:514.e1-9Norwitz. Expectant management of severe preeclampsia remote from term. Am J Obstet Gynecol 2008.

www.AJOG.org Editorials

SEPTEMBER 2008 American Journal of Obstetrics &Gynecology 211

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In summary, preeclampsia remains a major cause of mater-

nal and neonatal morbidity and death. Appropriate timing ofdelivery is critical to the reduction of preeclampsia-related

morbidity and death and to the optimization of outcome forboth the mother and fetus. There is absolutely no medical ben-

efit to the mother remaining pregnant once she has been diag-

nosed with severe preeclampsia. By agreeing to continued ex-pectant treatment, she is taking on a small, but significant, riskto her own health in an attempt to delay delivery until a more

favorable gestational age is reached. In our view, expectantmanagement of severe preeclampsia remote from term shouldbe undertaken only under specific circumstances (Table 2): if

the woman has a viable pregnancy (24 weeks of gestation)without evidence of IUGR, if she is hospitalized in a tertiary

care center, and if she agrees to takeon the potential risks to herhealth of continuing the pregnancy after extensive counsel-ing by subspecialists in both maternal-fetal medicine and

neonatology. f

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