The Journal of Maternal-Fetal Medicine 66-15 (1997)

Recent Advances in the Management of Preeclampsia

Rani Lewis, MD,* and Baha Sibai, MD

Division of Maternal- Fetal Medicine, Department of Obstetrics and Gynecology, University of Tennessee, Memphis, Tennessee

Abstract The past decade has been characterized by few advances regarding the pathophysiology and prevention but many changes in the clinical treatment of patients with preeclampsia. Specifically, recommendations have been made for home or day-care management of a select group of patients with mild gestational hypertension or preeclampsia. Moreover, three randomized clinical trials revealed that expectant management with close monitoring of maternal and fetal conditions is possible in a select group of patients with severe preeclampsia at less than 34 weeks’ gestation. In addition, the efficacy of magnesium sulfate in the prevention and control of eclamptic convulsion has been validated in randomized controlled trials performed worldwide. In contrast, recent randomized trials failed to demonstrate any major henefit from the routine use of low-dose aspirin in pregnancy, whereas a recent meta-analysis found calcium supplementation during pregnancy to be effective in reducing the risk of hypertension. J. Matern.-Fetal Med. 6:6-15, 1997. 0 1997 WiIey-Liss, Inc.

Key Words: expectant management; outpatient management; seizure prophylaxis

I NTRODU CTl ON Preeclampsia, a disorder of later gestation, has been

known and studied for over a century. Historically, however, there have been a multitude of medical com- plications loosely associated with this disorder. To counter this, the Committee on Terminology of the American College of Obstetricians and Gynecologists (ACOG) proposed a standard classification for the dis- order in 197 1 [ 11. The classification included all hyper- tensive disorders occurring during pregnancy, catego- rized as (1) pregnancy-induced hypertension (also known as gestational hypertension or preeclampsia) , (2) chronic hypertension preceding pregnancy, and (3) chronic hypertension with superimposed gestational hypertensive states. In 1986, ACOG revised the recom- mendations on clinical management [2] . Their recom- mendations for therapy included (1) ambulatory, con- servative management for patients who were compliant and demonstrating improvement; (2) hospitalization with conservative management for noncompliant or not improving patients; and (3) definitive management of patients with severe preeclampsia. Using this new terminology, the incidence of preeclampsia has been

estimated to be between 2% and 35% [3]. The diagnosis and management of this disorder is therefore a subject that should be well within the purview of a generalist in obstetrics and gynecology.

The past decade has revealed many evolving changes in the clinical management of preeclampsia. Several of these modifications, such as plasmapheresis and inva- sive hemodynamic monitoring of preeclamptic patients, have been found less compelling, but others are cur- rently under clinical investigation. Much of the re- search over the past two decades has concerned the role of outpatient management in patients with mild gestational hypertension or preeclampsia, expectant management of patients with severe preeclampsia re- mote from term, and attempts at preventing preeclamp- sia with either low-dose aspirin or supplemental calcium therapy. In addition, earlier doubts regarding the pro-

*Correspondence to: Rani Lewis, M.D., Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Tennessee, Memphis, Memphis, TN 38103.

Received 3 December 1995; revised 1 January 1996; accepted 29 May 1996.

0 1997 Wiley-Liss. Inc.

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RECENT CHANGES IN MANAGEMENT OF PREECLAMPSIA 7

phylactic and therapeutic use of magnesium sulfate therapy in the prevention of eclamptic convulsions have been the subject of randomized trials. We there- fore elected to review some of the relevant studies performed during the past decade.

OUTPATIENT MANAGEMENT OF WOMEN WITH MILD GESTATIONAL

HYPERTENSION OR PREECLAMPSIA In tH&United States, the recommended therapy for

the management of patients with any form of gesta- tional hypertension has traditionally involved hospital- ization, either for evaluation or for the duration of the pregnancy [3,4]. Subsequent therapy is then based on several factors, including gestational age and the re- sponse of the patient to this therapy. Women with a gestational age that places the fetus at low risk for adverse outcome (generally, at least 37 weeks’ gesta- tion) are considered for delivery. Women with severe preeclampsia or evidence of maternal or fetal compro- mise are also delivered. Women with more mild forms of the disease and who are stable are managed expec- tantly as an inpatient [4]. Inpatient management has been assumed to provide the optimal care by allowing the patient to remain at relative bed rest and the physi- cian to maintain close follow-up of the patient, with close nursing assessment of both maternal and fetal well-being. This approach had been championed by Gilstrap et al. [4] and Sibai [3].

This protocol had become the commonly accepted practice for the treatment of patients with preeclamp- sia. Limited information, however, was available to demonstrate the validity of this approach. T o further evaluate this issue, several randomized trials were per- formed. Matthews [5] randomized 135 women with gestational hypertension to inpatient bed rest vs. outpa- tient ad lib activity. Although the study lacked power to determine the optimum therapy, secondary to the sample size, he noted no difference in either maternal or perinatal mortality and morbidity. The therapeutic value of hospitalization in women with mild gestational hypertension was addressed by Feeney [6] in a nonran- domized, prospective study. Four hundred sixty-five women with nonproteinuric gestational hypertension were managed at home by midwives. Their outcome was compared to the outcome of 438 similar patients who were treated with the standard inpatient therapy. This study demonstrated that outpatient management with or without bed rest was safe as well as cost-effective

in this population. Hospitalization with bed rest was not shown to be essential to the management of such women.

The next issue raised was the assumption that hospi- talization was required to assure close follow-up. Tuff- nell et al. [7] performed a randomized controlled trial of daily antenatal assessment in “day-care units” vs. established clinical practice (frequently but not invari- ably utilizing hospital admission). They demonstrated a significant reduction in mean days in the hospital (1.1 vs. 5.1 days in hospital, odds ratio [OR] 4.0, 95% confidence internal [CI] 2.1-5.9), as well as mean num- ber of antenatal admissions (10 [30%] vs. 21 [88%], P < 0.0001) with outpatient daily antepartum assess- ment. While they failed to report information on mater- nal or fetal mortality and morbidity, they related no difference in mean birth weight (3,340 +- 476 vs. 3.321 -+ 463 g), 5 min Apgar score (9.3 ? 0.5 vs. 9.3 ? 0.6), or number of cesarean sections (3 vs. 2) between the two groups. They concluded that inpatient care neither improves outcome nor prevents the devel- opment of proteinuria in patients with gestational hy- pertension.

Crowther et al. [8] addressed this issue with a ran- domized, controlled study of modified bed rest in hospi- tal vs. ad lib activity at home in 218 women with nonproteinuric hypertension. The patients managed in the hospital were encouraged to remain at bed rest, although they were allowed to ambulate around the ward. All patients checked their urine daily for protein and were examined weekly. Primary outcome measure- ments were the development of severe hypertension (defined as a blood pressure 1160/110 mm Hg), pro- teinuria, and the incidence of preterm delivery. The neonatal assessment included the incidence of low birth weight and small-for-gestational-age infants, as well as the length of stay in the neonatal intensive care unit (NICU). The authors found a decrease in the risk of developing severe hypertension in the group allocated to hospitalization (OR = 0.47, 95% CI 0.26-0.83). However, no improvement in fetal growth or limitation in neonatal morbidity was noted with this regimen. They concluded that outpatient antenatal monitoring was a safe alternative to hospital admission. However, none of the above studies had an adequate sample size to evaluate major maternal and perinatal morbidity

Barton et al. [9] reported on 592 women with mild gestational hypertension who were managed at home

[7,81.

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8 LEWIS AND SlBAl

with automated blood pressure measurement and daily assessment of weight, proteinuria, and fetal well-being. They compared their findings to previously collected data on patients who were managed expectantly in the hospital and found that their therapy reduced the number of days of maternal hospitalization, without significantly ch%ging either maternal or perinatal outcome.

This issue was further addressed by a prospective study of 1,330 women with mild preeclampsia between 27 and 40 weeks’ gestation [ 101. In this large Canadian trial, 32 1 women were followed with a regimen of modi- fied bed rest at home and daily biochemical and bio- physical follow-up. The authors demonstrated a reduc- tion in the length of absolute hospital stay of 2 days and a cost-saving of $700,000 over the 4.75 years of the study. While this study could have been better performed in a randomized fashion, it is interesting to note that the rates of perinatal and/or maternal morbidity were not increased with this supervised home management program. Indeed, one of the patients de- veloped eclampsia, disseminated intravascular coagulo- pathy, abruptio placentae, or fetal loss while receiving home management.

Supervised home or day-care management for women with mild gestational hypertension or pre- eclampsia is gaining significant notoriety, especially in the face of limited funds for medical costs and managed care. It is important to note that these studies were performed in a well-educated and closely monitored population. Our current recommendation for the man- agement of women with mild preeclampsia is for initial hospitalization for maternal and fetal evaluation. Women who demonstrate an understanding of the non- reassuring symptoms of the disease and who are reliable may be followed as outpatients with regular assessment of maternal and fetal well-being. The latter manage- ment can be accomplished at home, with either home nursing visits for maternal and fetal evaluation or an automated monitoring through a perinatal health ser- vice. This management is summarized in Figure 1.

EXPECTANT MANAGEMENT OF WOMEN WITH SEVERE PREECLAMPSIA

Traditionally, the recommendation for treatment of women diagnosed with severe preeclampsia has been expeditious delivery. In assessing the severity of the disease, most investigators use the ACOG criteria, which includes (1) systolic blood pressure 2160 mm

Hg or diastolic blood pressure 2100 mm Hg on two occasions, 6 h apart; (2) proteinuria 2 5 g/day; (3) a platelet count below 100,000 cells/pl, with no pre- viously identified etiology; (4) oliguria of 5400 ml in 24 h; (5) persistent cerebral or visual disturbances, and (6) persistent epigastric or right upper quadrant pain. While delivery has long been felt to be the best thera- peutic regimen for the mother, in certain cases remote from term it may not be the best for the fetus. As methods for monitoring both maternal and fetal well- being have improved, expectant management in an attempt to prolong gestation became an alternative option. The initial recommendations were made at a time when delaying the delivery of a very preterm infant for less than 3-4 weeks effected minimal improvement in the neonatal outcome, while potentially contributing to significant maternal morbidity. Preliminary studies on the postponement of delivery for 48 h, for the admin- istration and action of glucocorticoids, demonstrated minimal deterioration and some improvement in mater- nal and fetal condition. Subsequently, the length of time that delivery can be postponed has been in- creased [ 111.

Subsequently, a number of studies have made an effort to clarify the risks and benefits involved with conservative management of patients with severe pre- eclampsia [ 12-18]. These investigators suggested sig- nificant benefit with varying risk in the management of patients with severe preeclampsia in the second and third trimesters. Subsequently, Sibai et al. [ 191 devel- oped a protocol for the management of severe pre- eclampsia in the second trimester. Using this protocol, as well as a frequent use of steroids, the authors deter- mined that expectant management significantly im- proved the perinatal survival rate, decreased the inci- dence of neonatal complications, and did not increase the occurrence of maternal morbidity in such women. The authors were able to significantly prolong gestation (13.2 vs. 2.0 days), increase birth weight (880 vs. 709 g), and decrease the incidence of neonatal death (23.6 vs. 64.5%, P < 0.0005). At the same time, there was no significant increase in the incidence of severe maternal complications, including abruptio placentae; eclamp- sia; and/or the syndrome of hemolysis, elevated liver function tests, and low platelets (HELLP syndrome). Similar data were obtained with the extension of this therapy to patients with severe preeclampsia between 28 and 34 weeks gestation [20].

Several randomized prospective trials have been

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RECENT CHANGES IN MANAGEMENT OF PREECLAMPSIA 9

Diagnosis of Mild f Pre-eclampsia

Maternal and Fetal Evaluation

Stable Q I

riL < 37 weeks’ gestation

I

Favorable cervix Worsening symptoms

Non-reassuring fetal testing

Unfavorable

6 Unstable

I Ambulatory Management

Fig. 1. Management of patients with mild preeclampsia

performed to better evaluate this issue. Odendaal et al. [20] evaluated women with severe preeclampsia between 28 and 34 weeks’ gestation. They randomized the patients to “aggressive” therapy (delivery after 48 h for corticosteroid benefit) vs. “expectant” therapy (attempt to delay delivery until 34 weeks’ gestation). Patients in the expectant management group received prazosin for management of hypertension. Sibai et al. [21] studied women between 28 and 32 weeks’ gestation. Patients were randomized to aggressive vs. expectant management, with patients managed expectedly until 34 weeks’ gestation and treated with hydralazine, nifedipine, or labetalol for control of hypertension. In addition, Fenakel et al. [22] random- ized women with severe hypertension to nifedipine or hydralazine and managed all expectantly. In all three trials, delivery was expedited in the presence of oliguria (<400 m1/24 h) , thrombocytopenia (< 100,000 plateletddl), eclampsia, pulmonary edema, or recalcitrant hypertension. The results of these trials are listed in Table 1.

Our recommendation for the treatment of severe preeclampsia remote from term is hospitalization for the evaluation of maternal and fetal well-being. During this time, patients are begun on intravenous (IV) mag- nesium sulfate therapy for seizure prophylaxis. Antihy- pertensive agents are given for control of hypertension

(1 160/110). Laboratory evaluations include complete blood count (CBC) and platelet count, serum creati- nine, uric acid, lactic dehydrogenase, and aminotrans- ferases. Fetal well-being is evaluated with a daily bio- physical profile. Women remain hospitalized until delivery (Table 2).

We believe that this management is best performed at a tertiary care center. This will optimize maternal and neonatal monitoring, as well as provide intensive care for (potentially) very preterm neonates.

ANTICONVULSANT MEDICATIONS FOR SElZU RE PROPHY LAXlS

Considerable conflict exists regarding the need for seizure prophylaxis, the optimal anticonvulsant for this purpose, and the type of gestational hypertension that increases the patients’ risk to the point that this is appropriate therapy. While the use of medications for prophylaxis of seizures is by no means a recent change, many modifications have been made in the selection of patients to receive this therapy. The recommendations from ACOG state that “essential management (of pre- eclampsia) include (s) preventing convulsions,” which “involves the use of parenteral magnesium sulfate (MgS04) . . . given either intramuscularly or intrave- nously [2,23]. However, while MgSO, is the drug of choice in the United States, it is less frequently used

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10 LEWIS AND SIBAI

TABLE 1. Randomized Trials of Aggressive vs. Expectant Management in Women with Severe Preeclampsia

Gestational Gestational Gest-al age at age at Pregnancy Neonatal

age entry delivery prolongation morbidity/ References (weeks) (weeks) (weeks) (days) P mortality P Odendaal et al. [20] 28-34

Aggressive (n = 20) 30.14 5 2 1.3 <0.05 15 <0.05 Expectant (n = 18) 31.86 5 2 7.1 6

Aggressive (n = 46) 30.4 5 1.6 30.8 -+ 1.7 2.6 Expectant (n = 49) 30.7 ? 1.5 32.9 -+ 1.5 15.4

Nifedipine (n = 24) 34.6 5 2.3 15.5 <0.07

Sibai et al. [21] 28-32

Fenakel et al. [22] 26-36

Hydralazine (n = 25) 33.6 ? 2.4 9.5

Data are presented as mean ? SD, where available.

TABLE 2. Guidelines for Selection of Patients for Conservative Management of Severe Preeclampsia Remote From Term

Expedited delivery

Maternal Uncontrolled severe hypertension’ Eclampsia Thrombocytopenia (platelet count < 1 OO,OOO/pl)

AST, ALTh > 2 X upper limit of normal

Pulmonary edema Renal compromise‘ Persistent neurologic symptomsJ

Fetal distress, diagnosed with N S T or BPI“ Amniotic fluid index 5 2 Ultrasonographically estimated fetal

weight <5th percentile

with epigastric or right upper quadrant pain

Fetal

Conservative management

Controlled hypertension Urinary protein < 5 g/day Oliguria <0.5 ml/kg/h that resolves

with fluid intake or bed rest Elevated AST or ALTh, without

abdominal tenderness

BPI” 2 6 Amniotic fluid index > 2 Ultrasonographically estimated fetal

weight >5th percentile Reverse umbilical artery end-diastolic flow

,‘Systolic blood pressure > 160 mni Hg o r diaatolic blood pressure > 110 mm Hg despite maximum recommended doses of two antihypertensive medications.

‘Persistent oliguria (<5 ml/kg/h) or elevation in serum creatinine 2 1 mg/dl over baseline. AST, aspartate aminotransferase; ALT, alanine aminotransferase.

’ Persistent headache or visual changes. “NST. nonstress test. ‘BPP, biophysical profile.

outside of North America [24]. Instead, standard anti- convulsants, such as phenytoin, diazepam, and pheno- barbitol, are used more frequently for the treatment of seizures [24].

The necessity of medical seizure prophylaxis in women with gestational hypertension was addressed by Moodley and Moodley in 1994 [ 251. They randomized 228 women with severe proteinuric hypertension to receive MgS04 with antihypertensive therapy vs. anti-

hypertensive therapy alone. They admitted that the study was flawed in that (1) there was not a significant number of patients to achieve power and (2) several women received a preadmission administration of phe- nobarbitone. However, there was no significant differ- ence in number of convulsions, birth weight, Apgar score, or maternal complications between the two groups.

Controversy also surrounds the most appropriate

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RECENT CHANGES IN MANAGEMENT OF PREECLAMPSIA 11

TABLE 3. Randomized Trials of Anticonvulsants for the Prevention of Preeclampsia

Rate of cervical Cesarean

Gestational dilation section References age (weeks) (cmih) (%) Seizures P

Friedman et al. I301 NS MgSO, (n = 60) 36.0 ? 4.1 1.5 ? 1.0 25 (42) 0 Phenytoin (n = 45) 35.4 ? 4.3 3.3 ? 3.1 19 (43) 0

MgS04 (n = 1,049) 283 (27) 0 Phenytoin (n = 1,089) 241 (22) 10

Lucas et al. [24] 0.004

Data are presented as mean 2 SD, where available. NS, not significant.

medication to be used for the prophylaxis of seizures. In 1992, Sibai [26] declared MgS04 “the ideal anticon- vulsant in preeclampsia-eclampsia” based partially on the lack of comprehensive data demonstrating a supe- rior agent for this purpose. Since that time, data both agreeing [27,28] and disagreeing [29] with this state- ment have been published.

In 1993, Friedman et al. [30] performed a random- ized clinical trial of the use of phenytoin vs. MgS04 in 105 patients with severe preeclampsia or eclampsia. MgS04 was administered via a 6 g bolus over 20 min, followed by a continuous intravenous infusion of 2 g/ h. The phenytoin dose was based on the patient’s body weight. They found that patients receiving phenytoin had more rapid cervical dilatation and a decreased incidence of postpartum anemia. There were no sei- zures in either group after initiation of therapy. They recognized that they did not have a sufficient sample size to demonstrate a two-fold difference in seizures between the two groups but were able to demonstrate a degree of efficacy with phenytoin therapy, pending a larger study.

More recently, Lucas et al. [24] randomized 1,089 women with gestational hypertension or preeclampsia to receive MgS04 vs. phenytoin. In this trial, MgSO, was administered as a 10 g intramuscular (IM) loading dose, followed by maintenance doses of 5 g IM every 4 h. Phenytoin was given as a 1 g loading dose IV, over 1 h, followed by a 500 mg oral dose 10 h later. The results of these two trials are listed in Table 3.

To further address this issue of the use of anticonvul- sant medications in obstetrics, the Eclampsia Trial Col- laborative Group recently published data on the best anticonvulsant medication for the treatment of eclamp- tic women [3 11. They compared the efficacy of MgS04, phenytoin, and diazepam administration in the reduc-

tion of seizures in women with eclampsia. MgS04 was administered in either of the two regimens described earlier. Diazepam was given as a loading dose of 10 mg IV over 2 min. This was followed by a continuous infusion of an additional 20 mg over the next 24 h. Phenytoin was not used for the control of a woman actively seizing. Instead, 10 mg of diazepam was given IV, followed by a loading dose of phenytoin, 1 g slow IV infusion over 20 min, then 100 mg every 6 h for 24 h. The primary outcome measures were recurrent convulsions and maternal morbidity.

With this trial, they demonstrated that MgSO, was significantly more effective in the prevention of further seizures than either diazepam (13.2 vs 27.9%, relative risk [RR] = 0.48,95% CI 0.36-0.63) or phenytoin (5.7 vs. 17.1%, RR = 0.33,95% CI 0.21-0.53). In addition, MgSO, was associated with a lower maternal mortality than either diazepam (3.8 vs. 5.1%, RR = 0.74, 95% CI 0.40-1.36) or phenytoin (2.6 vs. 5.2%, RR = 0.5, 95% CI 0.24-1.95), although this difference failed to achieve statistical significance. They concluded that MgS04 is more effective than either of the other two medications in the prevention of further seizures, as well as being equally safe. When it is realized that 10% of all direct maternal deaths [32] account for 50,000 maternal deaths per year [33], the importance of pre- vention of eclamptic seizures becomes understood.

The use of MgS04 for the prevention of eclamptic seizures is not entirely without risk. Magnesium toxicity can culminate in cardiorespiratory arrest if it is not prevented or immediately treated. The group of women with renal insult secondary to preeclampsia are at par- ticularly high risk for the occurrence of this complica- tion. In addition, some studies have reported low Apgar scores, respiratory depression, and hyporeflexia in pre- term neonates of mothers receiving MgSO, [34]. Fi-

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12 LEWIS AND SlBAl

nally, there is suspicion that patients given prophylactic MgSO, for the prevention of seizures may have an increased incidence of cesarean section, secondary to the tocolytic activity of magnesium. We feel, however, that the decrease in maternal morbidity with this ther- apy far outweighs the theoretic risk of neonatal mor- bidity.

The final issue raised with the use of anticonvulsants for women with gestational hypertension is the determi- nation of the group at risk. This issue was addressed by Burrows and Burrows [35], with an 8 year cross- sectional study of hypertensive patients. Patients were classified as having nonproteinuric gestational hyper- tension, preeclampsia, chronic hypertension, or chronic hypertension with superimposed preeclampsia. They found that 96% of the 1,618 patients studied did not receive seizure prophylaxis and that only 1.4% of the total population experienced any seizure activity. Non- proteinuric patients had a seizure rate of 0.3%, whereas proteinuric patients had a seizure rate of 3.9%. Patients diagnosed with either preeclampsia or superimposed preeclampsia had a lower incidence of seizure activity when they were also treated with antihypertensive agents (3.7% vs. 5.8%). The authors felt that the reduc- tion in seizure prophylaxis has not changed the preva- lence of seizures nor increased maternal or fetal morbid- ity. In the group identified as being at the highest risk (patients with preeclampsias or proteinuric hyperten- sion), 40 patients would need to be given seizure pro- phylaxis to prevent one seizure. They called for a ran- domized control trial to determine the justification of seizure prophylaxis in hypertensive obstetrical patients. As mentioned previously, the current recommendation in the United States is for universal prophylaxis in all women with gestational hypertension or preeclampsia [2,30]. The above trials now provide some information that demonstrates a benefit in the use of MgS04 in women with either severe preeclampsia and eclampsia.

Our current recommendation, based on a review of the above literature, is for the liberal use of MgSO,, both for prophylaxis and for treatment of eclamptic seizures. Currently, a placebo controlled randomized clinical trial is under way to evaluate the safety and efficacy of MgSO, in patients with gestational hyperten- sion or preeclampsia.

PREVENTION OF PREECLAMPSIA A greater understanding of the pathophysiology of

preeclampsia has led to the concept that the third

trimester signs and symptoms, previously felt to be pa- thognomonic of preeclampsia, are indeed late manifes- tations of effects that began early in the first trimester. Many investigators, therefore, have attempted a num- ber of therapeutic regimens, early in gestation, to affect the likelihood of the development of preeclampsia closer to term. Many hypotheses have been proposed to effect the subsequent development of preeclampsia; two of those that have gained the greatest acceptance are the use of low-dose aspirin and the use of calcium supplementation of the diet.

Low-Dose Aspirin Therapy

There have been several pharmacologic agents con- sidered for prophylactic use in the therapy of patients at risk for the development of preeclampsia. One agent that has been extensively studied and the focus of a multicenter, randomized trial, is acetylsalicylic acid (aspirin). Pregnancies complicated by preeclampsia have been found to be associated with enhanced plate- let activation. The platelet-derived prostaglandin thromboxane A2 is a noted vasoconstrictor and platelet aggregator and is known to be elevated in these pa- tients. Aspirin, a prostaglandin synthesis inhibitor, works by irreversible acetylation of cyclooxygenase, which causes a decreased production of both thrombox- ane A] (causing vasoconstriction and platelet aggrega- tion) and prostacyclin (a vasodilator and platelet anti- aggregant), as well as other prostaglandins. However, at a dose I 100 mg, aspirin has been found to preferen- tially inhibit fetoplacental thromboxane A2 synthesis [36]. The prophylactic use of aspirin in women at risk for the development of preeclampsia could potentially cause an equilibrium in the thromboxane-prostacyclin level [37], more consistent with that seen in women without preeclampsia. As a result, several trials with limited sample sizes were conducted in women with varying risk factors for an increased incidence of pre- eclampsia [38-411. These trials revealed significant re- duction in preeclampsia and fetal growth restriction with the use of low-dose aspirin therapy [42].

Several large multicenter, randomized, placebo-con- trolled trials have recently been undertaken to more fully investigate the usefulness of this therapy. The first included women at low risk for the development of preeclampsia. With this study of 3,100 nulliparas, Sibai and colleagues [43] from the Maternal-Fetal Medicine Network demonstrated a decreased incidence of pre- eclampsia among the group randomized to receive aspi-

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RECENT CHANGES IN MANAGEMENT OF PREECLAMPSIA 13

rin therapy (4.6% vs. 6.3%, RR = 0.7,95% CI 0.6-1.0). There was no difference seen in the incidence of non- proteinuric gestational hypertension. However, the in- cidence of abruptio placentae was significantly greater among women receiving aspirin therapy (11 vs. 2, P = 0.01), although there was no significant improve- ment in neonatal outcome.

The Collaborative Low-Dose Aspirin Study in Preg- nancy (CLASP) was a second multicenter, randomized, placebo-controlled trial in which 9,364 women requir- ing prophylaxis or treatment of preeclampsia were ran- domly assigned to 60 mg of aspirin versus matching placebo and followed for the development of pre- eclampsia or intrauterine growth retardation (IUGR) [44]. The results of the trial revealed no significant reduction in the incidence of preeclampsia, IUGR, still- birth, or fetal death in women receiving low-dose aspi- rin. However, there was a significant reduction in the likelihood of preterm delivery and a trend toward re- duction of preeclampsia among women with previous preeclampsia resulting in preterm birth. In addition, they did not report an increase in placental bleeding or abruptio placentae.

The Italian study of aspirin in pregnancy investigated its use in the prevention of IUGR and pregnancy- induced hypertension. This study was performed in a prospective manner, using 50 mg per day; women included were felt to be at “moderate” risk for the development of IUGR [45]. They found no difference in the rate of abortions, stillbirths, mean birth weight, perinatal mortality, or incidence of preterm delivery. In addition, there was no difference in the occurrence of either gestational hypertension or preeclampsia. They concluded that low-dose aspirin is not beneficial in preventing IUGR in women at moderate risk.

An additional study, due in the literature from the Maternal-Fetal Medicine Network, will deal with the effect of low-dose aspirin on the prevention of pre- eclampsia among high-risk pregnancies (i.e., women with chronic hypertension, previous preeclampsia, multifetal gestations, or class B-F diabetes mellitus.

Calcium Therapy

In 1980, Belizan and Villar [46] reported an inverse association between dietary calcium intake and fre- quency of preeclampsia. This was followed by a number of epidemiologic analyses and case reports linking ele- vated dietary calcium to low blood pressure in nonpreg- nant, normotensive pregnant, and preeclamptic women.

In a review of the literature to date, Belizan et al. [47] hypothesized a mechanism of action for this effect. They described a situation where there is an elevation in parathyroid hormone level which is known to be associated with an increase in intracellular free calcium levels. The intra- to extracellular movement of calcium acts as a trigger for vascular smooth muscle contraction and thus may cause an elevation in blood pressure. Women with an elevation in serum calcium secondary to an increase in dietary calcium would be expected to have a lower parathyroid hormone concentration and, thus, lower blood pressure.

This theory of a calcium effect agrees with theories behind the use of the more common therapeutic regi- mens for the control of hypertension and preeclampsia (MgS04, calcium channel blockers). Another theory concerns the inverse relationship seen between calcium concentration and renin release.

Belizan et al. [48] performed a prospective, random- ized, placebo-controlled trial of calcium (2 g/day ele- mental calcium) vs. placebo. They demonstrated that the rates of hypertensive disorders of pregnancy were lower in the group receiving calcium (9.8 vs. 14.8, OR 0.63, 95% CI 0.44-0.9). In addition, they noted that a low ratio of urinary calcium to urinary creatinine, when measured at 20 weeks’ gestation, was a good predictor of a decrease in gestational hypertension. Fi- nally, they noted no increase in side effects secondary to the calcium supplementation of the diet.

However, a recent metaanalysis has demonstrated a reduction in the risk of gestational hypertension with the use of 1.5-2.0 g/day of calcium [49]. Calcium sup- plementation was associated with halving the risk of pregnancy-induced hypertension (OR 0.44, 95% CI 0.33-0.59) and significantly lowering the risk of pre- eclampsia (OR 0.34, 95% CI 0.22-0.54). Additional benefits from the use of calcium supplementation were also seen.

A multicenter, randomized, placebo-controlled trial of calcium therapy is currently being performed in the United States. We are awaiting more complete data on this issue, prior to making a recommendation for this therapy.

SUMMARY During the past decade, numerous investigations

have dealt with the pathophysiology, prevention, and management of preeclampsia. Several reports have de- scribed the role of endothelial cell dysfunction in the

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14 LEWIS AND SIBAI

pathophysiology of preeclampsia and have attempted to explain the signs and symptoms of the disease based on this mechanism. The roles of nitrous oxide (endo- thelin-derived relaxing factor) or new etiologic agents, such as fibronectin, are currently being explored. Bar- ring a better understanding of the underlying patho- physiology, improvement in the management of these patients shows the greatest promise in decreasing both maternal and fetal mortality and morbidity. Closely monitored outpatient management of women with mild gestational hypertension or preeclampsia can be used to gain time for the development of fetal maturity without increasing maternal morbidity. Hospitalized management of women with severe preeclampsia re- mote from term can be performed to maximize both maternal and fetal well-being. MgS04 can be used for both the prophylaxis and treatment of eclamptic sei- zures while awaiting further data comparing this medi- cation to other anticonvulsants. Low-dose aspirin ther- apy, while not being shown to be useful in the prevention of preeclampsia in the general population, may become an important part of prevention of pre- eclampsia in women at higher risk. Calcium supplemen- tation can be used to decrease the risk of preeclampsia, pending further trials of aspirin therapy. These prophy- lactic and therapeutic regimens can be used while greater understanding of the pathophysiologic mecha- nism is being gained.

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