Download Is there a role for expectant management?

Severe Preeclampsia at the Limit of Viability: Is there
a Role for Expectant Management?
Errol R. Norwitz, M.D., Ph.D.
Associate Professor, Yale University School of Medicine
Associate Director, Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and
Reproductive Sciences, Yale-New Haven Hospital, New Haven, Connecticut, U.S.A.
__________________________________________________________________________________________________
Preeclampsia (gestational proteinuric hypertension) complicates 6 to 8% of all pregnancies, and is the
second most common cause of maternal mortality in the United States (after thromboembolic disease) (14). Between 1979 and 1992, there were 1.5 maternal deaths due to preeclampsia/eclampsia per 100,000
live births, with a case-fatality rate of 6.4 deaths per 10,000 cases (5). Worldwide, preeclampsia/eclampsia
accounts for an estimated 50,000 maternal deaths per year (2-4,6). It is also associated with a high perinatal
mortality and morbidity, due primarily to iatrogenic prematurity (7).
Etiology
Preeclampsia is an idiopathic multisystem disorder specific to human pregnancy and the puerperium (1).
More precisely, it is a disease of the placenta since it has also been described in pregnancies where there is
trophoblast but no fetal tissue (complete molar pregnancies) (8). Similarly, in the rare situation of an
advanced abdominal (extrauterine) pregnancy complicated by preeclampsia, removal of the placenta is not
possible at the time of delivery of the fetus and, as such, preeclampsia persists postpartum instead of
resolving (9).
Despite aggressive research efforts, the pathogenesis of preeclampsia remains poorly understood.
Pathologic and physiologic observations as well as examination of epidemiologic studies and biochemical
aberrations have led to a number of theories to explain preeclampsia. At present, five hypotheses are the
subject of intense investigation: (a) genetic imprinting; (b) immune maladaption; (c) placental ischemia;
(d) generalized endothelial dysfunction; and (e) defective free fatty acid, lipoprotein, and/or lipid
peroxidase metabolism (10,11). However, there is as yet no single unifying theory that can account for all
of the findings in preeclampsia. Although the pathophysiology of preeclampsia is poorly understood, it is
clear that the blueprint for its development is laid down early in pregnancy. It has been suggested that the
pathologic hallmark is a complete or partial failure of the second wave of trophoblast invasion from 16 to 20
weeks' gestation, which is responsible in normal pregnancies for destruction of the muscularis layer of the
spiral arterioles (12-14). As pregnancy progresses, the metabolic demands of the fetoplacental unit increase.
Because of the abnormally shallow invasion of the placenta, however, the spiral arterioles are unable dilate to
accommodate the required increase in blood flow resulting in “placental dysfunction" that manifests clinically
as preeclampsia. Recently, investigators have suggested that excessive production of soluble fms-like
tyrosine kinase 1 (sFlt1) by the placenta may explain many of the maternal manifestations of preeclampsia
(15,16). Circulating sFlt1 serves as a “decoy” receptor that binds to and inactivates both vascular
endothelial growth factor (VEGF) and placental growth factor (PlGF), thereby leading to endothelial
dysfunction, hypertension, and proteinuria. These studies suggest that sFlt1 may be the elusive “toxemia”
factor. Although attractive, this hypothesis remains to be validated.
Diagnosis
It is likely that preeclampsia is not a single disease entity, but rather a clinical syndrome encompassing
three distinct elements: (a) new-onset hypertension (defined as a sustained sitting blood pressure 140/90
in a previously normotensive woman); (b) new-onset proteinuria (defined as >300 mg/24 h or 2+ on a
clean-catch urinalysis in the absence of urinary infection); and (c) new-onset significant non-dependent
edema (1). More recent consensus reports have suggested eliminating edema as a criterion for the
diagnosis (17). The diagnosis of preeclampsia can only reliably be made after 20 weeks of gestation.
Evidence of proteinuric hypertension prior to 20 weeks’ gestation should raise the possibility of an
underlying molar pregnancy, drug withdrawal, antiphospholipid antibody syndrome, multiple pregnancy,
or, rarely, a chromosomal abnormality (trisomy) in the fetus (18).
Classification
Preeclampsia is classified as either “mild” or “severe.” There is no “moderate” preeclampsia. A diagnosis
of severe preeclampsia should be entertained in women with new-onset proteinuric hypertension along
with one or more of a series of complications (Table 1). Only one of the listed clinical features is necessary
for the diagnosis of severe preeclampsia. Mild preeclampsia includes all women with preeclampsia, but
without any feature of severe disease.
Management
Despite intensive research efforts, it is not possible at this time to prevent preeclampsia (19,20). Stabilization
of the mother’s conditions and assessment of fetal wellbeing are the first responsibilities of management
for parturients with severe preeclampsia. Thereafter, every effort should be made to distinguish women
with preeclampsia from those with other disorders, including gestational non-proteinuric hypertension,
chronic hypertension, chronic renal disease, and systemic lupus erythematosis. Laboratory evaluations
should include hematocrit (hemoconcentration supports the diagnosis of preeclampsia), examination of
blood smear (looking for evidence of microangiopathic hemolysis), platelet count, quantification of protein
excretion, and serum concentrations of creatinine, uric acid, alanine aminotransferase (ALT), aspartate
aminotransferase (AST), and lactic acid dehydrogenase (LDH) (17).
Delivery of the fetus and placenta is generally accepted to be the only effective treatment for preeclampsia,
and is recommended for women with mild preeclampsia once a favorable gestational age has been reached.
In contrast, immediate delivery is recommended for all women with severe preeclampsia, regardless of
gestational age, to prevent potential maternal and fetal complications. Immediate delivery does not
necessarily mean cesarean delivery (21). The decision of whether to proceed with cesarean or induction of
labor and attempted vaginal delivery should be individualized based on such factors as parity, gestational
age, cervical examination (Bishop score), maternal desire for vaginal delivery, and fetal status and
presentation. In general, less than one-third of women with severe preeclampsia remote from term (<32
weeks’ gestation) with an unfavorable cervix will have a successful vaginal delivery (22,23). Cervical
ripening agents can be used to improve the Bishop score, but prolonged inductions should be avoided.
Expectant management of severe preeclampsia
Delivery is generally recommended for all women with severe preeclampsia, regardless of gestational age.
This raises the question: Is there a role for expectant management of severe preeclampsia at the limit of
fetal viability? Phrased in this way, several specific issues need to be addressed:
(1) What constitutes the limit of fetal viability?
In the U.S., there is no national definition of fetal viability. The federal government and judiciary have
chosen to defer to the individual states in this matter. As such, fetal viability is variably defined. In
Minnesota, for example, fetal viability is defined as ‘the earliest well-documented surviving pregnancy
delivered in the state’ and is currently regarded as 22 weeks. In Massachusetts, any fetal demise 350 g
and/or 20 weeks must be reported to the Massachusetts Department of Public Health. However, the
State’s opinion on viability has only been addressed indirectly. Massachusetts General Law c. 112, sec. 12
L-Q states that ‘elective pregnancy termination be performed at 24 weeks of greater only if necessary to
save the life of the mother.’ Moreover, in such instances, it is necessary that ‘the physician take all
reasonable steps, both during and after the abortion, in keeping with good medical practice, consistent with
the procedure being used, to preserve the life and health of the aborted child.’ As such, the state shifts the
responsibility for decision making to the physician, and expects the physician to rely on his/her education,
training, experience, and understanding of recent advances in the field to make an appropriate decision. In
a recent survey of members of the Society of Maternal-Fetal Medicine, the majority of respondents placed
viability somewhere within the 23rd week (23-0/7 and 23-6/7 weeks) of gestation (24).
In light of the confusion surrounding the definition of the limit of fetal viability, it may be more useful to
consider the issues of the management of severe preeclampsia in “periviable” pregnancies. In this regard,
periviability can be regarded as ‘the range of gestational ages in well-dated pregnancies where the
incidence of adverse perinatal outcome is sufficiently high and the individual variation in organ system
development is sufficiently great that significant morbidity and mortality can be anticipated.’ This
definition likely includes a gestational age range of 22 to 26 weeks.
(2) Can delivery be delayed for 48 hours to complete a full course of antenatal corticosteroids?
There is evidence to suggest that fetuses born of preeclamptic pregnancies have a reduced incidence of
respiratory distress syndrome (25) and intraventricular hemorrhage (26). However, this is not a reason to
withhold antenatal corticosteroid therapy. If the pregnancy is less than 34-0/7 weeks’ gestation and no
prior courses have been administered, antenatal corticosteroids should be administered to enhance fetal
lung maturation and, possibly, decrease further the incidence of intraventricular hemorrhage and
necrotizing enterocolitis (27,28). If an initial course of corticosteroids was administered early in pregnancy
(i.e., prior to 28 weeks), there may be additional benefit to the fetus of a single “rescue dose” or a repeat
course prior to 34 weeks’ gestation (29). However, routine repeat courses of antenatal corticosteroids
should be avoided.
Antenatal corticosteroids appear to be protective against the development of respiratory distress syndrome
after just 4 hours. However, the maximal protective effect is evident 48 hours after the initial dose. The
decision of whether or not to delay delivery for 48 hours to complete a ‘full course’ of antenatal
corticosteroids should be individualized. Factors which may preclude such an approach include, but are not
limited to, gestational age >34 weeks, non-reassuring fetal testing, maternal hemodynamic instability, and
rapidly worsening maternal condition (including rapidly decreasing platelet counts, coagulopathy, and
oliguria unresponsive to hydration).
(3) Exceptions to the rule
The definitive treatment of preeclampsia is delivery to prevent potential maternal complications. Delivery
is recommended for all women with severe preeclampsia, irrespective of gestational age. Although
controversial, this recommendation is based on a series of retrospective clinical studies demonstrating an
increase in maternal and/or perinatal mortality and morbidity with expectant management (for example,
references 30-32). However, delivery is not always in the best interests of the fetus; therefore, exceptions
to this recommendation may be made (below). The rationale for delaying delivery in these pregnancies is
to reduce perinatal morbidity and mortality by delivery of a more mature fetus and, to a lesser degree, to
achieve a more favorable cervix for vaginal birth. The risk of prolonging pregnancy is continued poor
perfusion of major organs with the potential for severe end organ damage to the brain, liver, kidneys,
placenta/fetus, and hematologic and vascular systems of the mother. There are only three situations where
expectant management of severe preeclampsia should be recommended:
 Severe preeclampsia by proteinuria (>5 g/24 hour) alone is not an indication for delivery. It has been
demonstrated in many clinical studies that neither the rate of increase nor the amount of proteinuria affects
maternal or perinatal outcome in the setting of preeclampsia (33,34). In light of such data, it is somewhat
disappointing to note that the latest AGOC Practice Bulletin on this topic did not remove proteinuria >5
g/24 hour as a criterion for the diagnosis of severe preeclampsia (35).
 Pregnancies complicated by severe preeclampsia on the basis of intrauterine fetal growth restriction
(IUGR) alone remote from term (<32 weeks) with good fetal testing may be managed conservatively, with
a view to achieving a more favorable gestational age prior to delivery (36). Such parturients should be
managed as in-patients with daily fetal testing (37). However, the admission-to-delivery interval in such
pregnancies averages three days, and over 85% of such women will require delivery within one week of
presentation (36).
 The use of antihypertensive agents to control blood pressure in the setting of preeclampsia has been
shown to neither alter the course of the disease nor diminish perinatal morbidity or mortality (38-40).
These data serve to confirm that hypertension is a clinical feature - and not the underlying cause - of
preeclampsia. The cause of the blood pressure elevation in preeclampsia is not clear. It has been suggested
that it may represent an attempt of the body to maintain perfusion through an underperfused (ischemic)
placenta, and may be triggered by a “distress signal” from the feto-placental unit (41). Moreover, the use of
antihypertensive agents in preeclampsia may provide a false sense of security by masking an increase in
blood pressure as a sensitive measure of worsening disease, and is therefore not generally recommended.
This situation should not be confused with the use of antihypertensive agents to (a) treat parturients with
chronic hypertension or (b) prevent maternal cerebrovascular accident in the acute setting while effecting
delivery. Cerebrovascular accident accounts for 15-20% of deaths from preeclampsia/eclampsia. The risk
of hemorrhagic stroke correlates directly with the degree of elevation in systolic blood pressure (and is less
related to the diastolic pressure), but it is not clear whether there is a threshold systolic pressure above
which emergent therapy should be instituted (42). It is generally recommended that a systolic blood
pressure of 170 mm Hg be used as threshold to initiate antihypertensive treatment in previously
normotensive reproductive-aged women, although this cut-off has not been tested prospectively and the
cerebral vasculature of women with underlying chronic hypertension can probably tolerate higher systolic
pressures without injury. Other endpoints that have been suggested for instituting or reinstituting
antihypertensive therapy include a sustained systolic blood pressure >160 mmHg, diastolic blood pressure
>105 to 110 mm Hg (>100 mm Hg in adolescents), or the presence of end organ damage (such as left
ventricular hypertrophy or renal insufficiency) (17).
The only deviation from these guidelines is the recent trend towards expectant management of women with
severe preeclampsia by blood pressure criteria alone prior to 32 weeks' gestation. This approach, although
potentially dangerous for the mother, has been substantiated by a number of recent studies (43-45). It
should be made clear that there is no benefit to the mother of expectant management, and that she is taking
on a small but significant risk to her own health with a view to delaying delivery until a more favorable
gestational age is reached.
 HELLP (Hemolysis, Elevated Liver enzymes, Low Platelets) syndrome is a serious complication of
preeclampsia that was first described by Pritchard et al. in 1954 (46), although the term HELLP syndrome
was coined by Weinstein in 1982 (47). When preeclampsia is complicated by HELLP syndrome, the
maternal and perinatal mortality rates are significantly increased. Reported maternal mortality rates range
from 0% to 24%, and results most often from liver rupture, coagulopathy, acute renal failure, pulmonary
edema, carotid thrombosis, and cerebrovascular accident (48). Perinatal mortality is related most closely to
complications of prematurity, fetal growth restriction, and placental abruption. Reported perinatal
mortality rates range from 7.7% to 60% (48). Delayed diagnosis and delayed or inappropriate treatment are
commonly sited as reasons to explain the poor overall prognosis associated with HELLP syndrome.
Several specific therapeutic maneuvres have been proposed in an effort to cure or alleviate HELLP
syndrome. These include, among others, plasma volume expansion (using crystalloid or albumin),
thrombolytic agents (low dose aspirin, dipyridamole, heparin, antithrombin III, prostacyclin/thromboxane
synthetase inhibitors), immunosuppressive agents (corticosteroids), exchange plasmaphoresis, and dialysis
(for example, 49-51). Magann et al. (52) reported that antepartum dexamethazone administration to
women with HELLP syndrome significantly increased maternal platelet count, decreased serum ALT and
LDH, increased maternal urine output, and resulted in a longer entry-to-delivery interval as compared with
women who did not receive corticosteroids. A subsequent study by the same group from University of
Mississippi Medical Center reported that dexamethazone was more effective than bethamethazone in the
antepartum “treatment” of HELLP syndrome (53). Of note, the dose of dexamethazone recommended in
these studies for antepartum treatment of HELLP syndrome (12 mg q 12 hourly until delivery) are
significantly higher than those recommended by NIH (27) or ACOG for promotion of fetal lung maturity
(6 mg q 12 hourly for 48 hours [28]). Moreover, corticosteroid administration in these studies was by
intravenous rather than intramuscular route as recommended by NIH (27) and ACOG (28). The effect of
large doses of intravenous corticosteroids on fetal adrenal function and fetal development is not known. As
such, expectant management and antepartum “treatment” of HELLP syndrome with large doses of
corticosteroids is not universally accepted. Indeed, in their latest Practice Bulletin (35), ACOG states that
“considering the serious nature of this complication, it seems reasonable to conclude that women with
HELLP syndrome should be delivered regardless of their gestational age.”
Conclusion
Preeclampsia is a multisystem disorder specific to pregnancy with a high maternal and perinatal morbidity
and mortality. Although the etiology of preeclampsia is unknown, it is clear that the blueprint for the
development of this condition is laid down early in pregnancy. Preeclampsia likely represents the clinical
end-point of multiple contributory factors, and it is unlikely that any single cause will be found. Once the
diagnosis of preeclampsia has been made, treatment options are limited. Delivery of the fetus and placenta
remains the only effective treatment. A healthy respect for this condition coupled with aggressive and early
intervention in the event of preeclampsia complications may be able to minimize adverse maternal and
perinatal events in the setting of severe preeclampsia.
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Table 1: Features of severe preeclampsia
Symptoms
 Symptoms of central nervous system dysfunction (blurred vision, scotomata, and/or severe headache)
 Symptoms of liver capsule distention or rupture (right upper quadrant and/or epigastric pain)
Signs
 Severe elevations in BP (defined as BP 160/110 on two separate occasions at least 6 hours apart)
 Pulmonary edema
 Eclampsia (defined as generalized seizures and/or unexplained coma in the setting of preeclampsia
and
in
the absence of other neurologic conditions)
 Cerebrovascular accident
 Cortical blindness
 Fetal intrauterine growth restriction






Laboratory findings
Proteinuria (>5 grams per 24 hours)
Renal failure or oliguria (<500 ml per 24 hours)
Hepatocellular injury (serum transaminase levels 2 x normal)
Thrombocytopenia (<100,000 platelets/mm3)
Coagulopathy
HELLP (Hemolysis, Elevated Liver enzymes, Low Platelets) syndrome