Imitators of Severe Pre-eclampsia

Baha M. Sibai, MD

There are many obstetric, medial, and surgical disorders that share many of the clinical and
laboratory findings of patients with severe pre-eclampsia– eclampsia. Imitators of severe
pre-eclampsia– eclampsia are life-threatening emergencies that can develop during preg-
nancy or in the postpartum period. These conditions are associated with high maternal and
perinatal mortalities and morbidities, and survivors may face long-term sequelae. The
pathophysiologic abnormalities in many of these disorders include vasospasm, platelet
activation or destruction, microvascular thrombosis, endothelial cell dysfunction, and
reduced tissue perfusion. Some of these disorders include acute fatty liver of pregnancy,
thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, acute exacerbation of
systemic lupus erythematosus, and disseminated herpes simplex and sepsis syndromes.
Differential diagnosis may be difficult due to the overlap of several clinical and laboratory
findings of these syndrome. It is important that the clinician make the accurate diagnosis
when possible because the management and complications from these syndromes may be
different. Because of the rarity of these conditions during pregnancy and postpartum, the
available literature includes only case reports and case series describing these syndromes.
This review focuses on diagnosis, management, and counseling of women who develop
these syndromes based on results of recent studies and my own clinical experience.
Semin Perinatol 33:196-205 © 2009 Elsevier Inc. All rights reserved.

KEYWORDS severe pre-eclampsia, acute fatty liver, TTP, HUS

S everal microangiopathic disorders that are encountered

during pregnancy provide physicians with a formidable,
if not impossible, diagnostic challenge. Severe pre-eclampsia
with hemolysis, elevated liver enzymes, and low platelets
(HELLP) syndrome and many other obstetric and medical or
surgical conditions produce similar clinical presentations
and laboratory study results to pre-eclampsia.1 In addition,
pre-eclampsia is not infrequently superimposed upon one of
these disorders, further confounding an already difficult dif-
ferential diagnosis. Because of the remarkably similar clinical
and laboratory findings of these disease processes, even the
most experienced physician will face a difficult diagnostic
challenge.1 Therefore, an effort should be made to attempt to
identify an accurate diagnosis given the fact that management
strategies and outcome may differ among these conditions. In
this review, I will describe the pathogenesis, differential di-
agnosis, and management of the medical conditions de-
scribed in the box below.
Department of Obstetrics and Gynecology, University of Cincinnati, College
of Medicine, Cincinnati, OH.
Address reprint requests to Baha M. Sibai, MD, Department of Obstetrics and
Gynecology, University of Cincinnati, 231 Albert Sabin Way, Cincinnati,
OH 45267. E-mail: baha.sibai@uc.edu
Acute Fatty Liver of Pregnancy
Acute fatty liver of pregnancy (AFLP) is a rare but potentially
fatal complication of the third trimester. The incidence of this
disorder ranges from 1 in 10,000 to 1 in 15,000 deliveries.
The incidence is probably lower than that because the re-
ported rates are usually from large referral centers, which
tend to overestimate the true incidence.1-11 It has been sug-
gested that AFLP is more common in nulliparous women as
well as in those with multifetal gestation.1-7,9 The clinical onset
of symptoms ranges from 27 to 40 weeks, with an average of 36
weeks’ gestation6; however, cases have been reported in the sec-
ond trimester.11,2 In some cases, the first onset of signs/symp-
toms may be in the postpartum period.2,9 The patient typically
presents with a 1- to 2-week history of malaise, anorexia, nau-
sea, vomiting, midepigastric or right upper quadrant pain, head-
ache, or jaundice. The urine will have a bright yellow appear-
ance (Fig. 1). Rarely, the patient may present with hepatic
encephalopathy.13 Symptoms of preterm labor or lack of fetal
movement may be the presenting complaint in some of these
patients.2,3 In about 15-20%, the patient might not present with
any of the above symptoms.2-5
Physical examination reveals an ill-appearing patient with
jaundice. Some patients will have a low-grade fever. Other
findings may include hypertension and even proteinuria and

196 0146-0005/09/$-see front matter © 2009 Elsevier Inc. All rights reserved.
doi:10.1053/j.semperi.2009.02.004
Imitators of severe pre-eclampsia
ascites and bleeding from severe coagulopathy. Because of
these findings, the diagnosis may be initially confused with
pre-eclampsia.1,2,6 Neurologic findings may range from nor-
mal to lethargy, agitation, confusion, and even coma.8,9,13,14
Laboratory Findings
The complete blood count usually reveals hemoconcentra-
tion, elevated white blood count, and platelet count that is
initially normal but may be low.1-6 Coagulation findings re-
veal low fibrinogen, prolonged prothrombin time (PT), and
low levels of antithrombin.1-10 These abnormalities are re-
lated to reduced production of these factors by the liver and
are consistent with disseminated intravascular coagulopathy
(DIC). In contrast, the DIC seen in severe pre-eclampsia and
abruptio placentae is due to abnormal consumption.15 Serum
electrolytes will reveal evidence of metabolic acidosis with
elevated creatinine and uric acid values. Blood sugar may be
normal but is usually low in the postpartum period.1-6,8,9,13
Blood sugars may also be elevated in association with second-
ary pancreatitis.1,8 Liver enzymes, such as AST, ALT, alkaline
phosphatase, and bilirubin, will be elevated. The increase in
bilirubin is mainly of the conjugated form, with levels usually
exceeding 5 mg/dL. Ammonia levels are also increased, par-
ticularly in late stage of the disease. Amylase and lipase values
may be elevated in the presence of concomitant pancreati-
tis.1,8 Hepatitis profile for A, B, and C will be negative.
Ultrasonography of the liver may reveal the presence of
increased echogenicity in severe cases; however, it is less
sensitive than computed tomography (CT) and magnetic res-
onance imaging (MRI).16-20 In addition, quantitation of liver
density by ultrasound is subjective and operator-dependent.
CT scan of the liver may show decrease or diffuse attenuation
in the liver. However, none of these techniques are suffi-
ciently sensitive to exclude a diagnosis of AFLP.2,20
Liver biopsy is the gold standard for confirming the diag-
nosis of AFLP. Histopathologic findings in AFLP reveal swol-
len, pale hepatocytes with central nuclei.21 The diagnosis can
be made only on a frozen section liver biopsy with special
stains for fat, such as oiled red (O).1,4 Plans to perform this
stain should be made before the biopsy procedure because it
Figure 1 Liver biopsy findings in herpes hepatitis. (Color version of
figure is available online.)
197
Table 1 Imitators of Severe Pre-eclampsia/HELLP Syndrome
● AFLP
● TTP
● HUS
● Exacerbation of lupus erythematosus
● Catastrophic antiphospholipid syndrome
● Systemic viral sepsis (disseminated herpes)
● Systemic inflammatory response syndrome/septic shock
● Other conditions (cholestasis of pregnancy, necrotizing
pancreatitis, etc.)
is not possible to be performed once the tissue has been
submitted to routine paraffin blocks. Liver biopsy should be
performed only after correction of coagulopathy. However,
this is rarely used in clinical practice, and the diagnosis is
usually made based on clinical and laboratory findings.1-9
In addition to the other conditions listed in Box I, the
differential diagnosis of AFLP should include idiopathic cho-
lestasis of pregnancy, Budd-Chiari syndrome, adult-onset
Reye’s syndrome, and drug-induced hepatic toxicity (acet-
aminophen overdose, tetracycline-induced toxicity, anticon-
vulsant drugs hypersensitivity, and methyldopa hepati-
tis).1,4,21
Maternal and Perinatal Complications
AFLP is associated with an increased risk of maternal mortal-
ity and morbidities. In the past, the rate of maternal death was
close to 70%; however, recent data indicate a mortality rate of
⬍10%, but maternal complications remain high. Table 1 descri-
bes maternal complications in recent series of AFLP.1-11,14,22,23
Recently, Davidson and coworkers reported on three women
with triplet gestation who had AFLP proven by liver biopsy
who survived. They suggested that women with triplets are at
increased risk for AFLP because of potential for increased
production of fatty acid metabolites by three fetuses. It has
been suggested that the improved maternal survival in recent
years was related to the supportive care and aggressive man-
agement of serious maternal complications by a multidisci-
plinary group of physicians from various specialties.2-9
Recently, Knight, and coworkers11 reported a prospective
national study of AFLP in the UK. The participants included
57 women with AFLP diagnosed mostly by clinical criteria;
55 had abdominal ultrasound scan, but only 12 (27%) had
either ascites and/or abnormal liver findings. Forty-two
(74%) were diagnosed antepartum and 15 (26%) postpartum
(within 4 days of delivery). In general, most of these patients
had a biochemical diagnosis of AFLP (mild prolongation of
PT, PTT, normal platelets), only 8 (16%) had acute renal
failure, and 4 (7%) required ventilatory support. There was
only 1 maternal death (1.8%) in a patient who received a liver
transplant.14
Both perinatal mortality and morbidities are increased in
patients of AFLP.2-9,20 The perinatal mortality among 160
births (142 pregnancies) in recent case series was 13.1%.9,22
In addition, neonatal morbidity remains high because of the
high rate of preterm delivery (74%) among reported cases.
198
The average gestational age at delivery was 34 weeks (range,
25-42 weeks).2-9,22
In the study by Knight and coworkers,11 the perinatal mor-
tality was 10.4% among 67 infants (6 stillbirths and 1 neo-
natal death).
Management of AFLP
The clinical course of women with AFLP is usually character-
ized by progressive and sometimes sudden deterioration in
maternal and fetal conditions.9 Therefore, patients in whom
AFLP is considered require hospitalization in a labor and
delivery unit. Fetal heart rate monitoring and/or performing
of a biophysical profile should be performed concurrently
with maternal evaluation. Evidence of fetal compromise may
be present even in those with stable maternal conditions.
Nonreassuring fetal testing may be secondary to maternal
acidosis and/or reduced uteroplacental blood flow.1-6 The
presence of maternal acidosis may be reflected in reduced-
to-absent fetal movement, absent fetal breathing, or tone dur-
ing biophysical profile testing.1
The next step in management is to confirm or exclude the
diagnosis of AFLP according to the clinical findings and re-
sults of blood tests.1,23 The presence of bleeding and/or severe
coagulopathy requires transfusion with fresh frozen plasma
and other blood products as needed. The ultimate treatment
for this condition is maternal stabilization and delivery be-
cause there are no reports of women recovering from AFLP
spontaneously. The presence of AFLP is not an indication for
delivery by cesarean section because of the risks of bleeding
complications in the presence of coagulopathy.2-6,10 The de-
cision to perform cesarean delivery should be based on fetal
gestational age, fetal condition, and presence of labor. Induc-
tion of labor with an attempt for vaginal delivery within 24
hours is a reasonable approach. Because of the associated
coagulopathy, most anesthesiologists will avoid epidural an-
algesia. Maternal analgesia during labor can be provided by
intermittent use of small doses of systemic opioids. The use of
pudendal block should be avoided because of the risk of
bleeding and hematoma formation into this area. Caution
should be exercised to avoid vaginal trauma and lacerations
during vaginal delivery.1
In case of cesarean delivery, the patient should receive
general anesthesia. It is advisable to avoid incisions that re-
quire extensive dissection, such as the Pfannenstiel incision,
and meticulous attention should be given to secure hemosta-
sis. It is advisable to perform a midline incision, to use a
subfascial drain, and to keep the skin incision open for at
least 48 hours to avoid hematoma formation.1,23
In the postpartum period, the patient should be monitored
very closely with careful evaluation of vital signs, intake–
output, and bleeding. Some of these patients may develop
acute refractory hypotensive shock in the immediate postpar-
tum period. Serial measurements of hematologic, hepatic,
and renal function should be performed and recorded in an
organized fashion. Blood sugars should be monitored every
few hours with a bedside glucometer because of the risk of
hypoglycemia in the postpartum period. Glucose infusions
B.M. Sibai
can be used to maintain blood sugars above 60 mg/dL. Ane-
mia and DIC should be treated as needed by a packed red
blood cells, platelets, and fresh frozen plasma. It is important
to aggressively treat maternal hypotension to avoid further
injury to the liver, kidneys, and other organs. Invasive hemo-
dynamic monitoring may be necessary in some patients to
assess fully the intravascular volumes and maintain cardiac
output, and in patients who develop acute respiratory dis-
tress syndrome (ARDS).
Pancreatitis is a potentially lethal complication of AFLP,
and thus all patients with AFLP should undergo serial screen-
ing of serum lipase and amylase for several days after the
onset of hepatic dysfunction.1,8 Abnormalities in these en-
zymes typically appear after hepatic and renal dysfunction.
The development of pseudocysts with secondary infections
or hemorrhagic pancreatitis with resultant retroperitoneal
bleeding increases the risk for maternal death.8
In general, most patients with AFLP will start to improve
2-3 days after delivery. In some cases, however, deterioration
in liver function tests, renal function, mental status, and co-
agulopathy may continue for about 1 week. In such cases,
some authors suggest using plasmapheresis to improve ma-
ternal outcome. This method of treatment was recently re-
ported in six such cases with no maternal death. However,
the value of such therapy remains unclear. In rare cases, a
patient will progress into fulminant hepatic failure, requiring
liver transplantation.21
Counseling of Women with AFLP
Several case reports and case series22-26 have noted an asso-
ciation between the development of AFLP and/or HELLP
syndrome and a deficiency of long-chain 3-hydroxyacyl-co-
enzyme A dehydrogenase (LCHAD) in infants born to
women with the above complications. This disorder of mito-
chondrial fatty acid oxidation might lead to significant in-
crease in maternal fatty acid levels that are highly toxic to the
liver. Based on these findings, some authors suggest that
women with AFLP as well as their partners and children
should undergo molecular testing for Glu 474 Gln mutation
in the LCHAD.22,24 Screening for this mutation would allow
early diagnosis and treatment in newborns of affected moth-
ers and would allow counseling about subsequent pregnan-
cies.22,25 The risk of recurrence is increased in women who
are carriers for this mutation, particularly if the fetus is also
affected during a subsequent pregnancy. There are few case
reports describing recurrent AFLP in women without the
above mutation2,4; however, the risk of this recurrence re-
mains unknown because of the limited number of pregnan-
cies reported following AFLP in these women.
Thrombotic Microangiopathies
Thrombotic thrombocytopenic purpura (TTP) and hemo-
lytic uremic syndrome (HUS) are two microangiopathic dis-
orders that are extremely rare during pregnancy/postpartum.
They are usually reported as case reports or small case se-
ries.1,26-35 Thus, their expected development during preg-
Imitators of severe pre-eclampsia
nancy or postpartum is probably ⬍1 case in 100,000 preg-
nancies. Because of that, they are even infrequent in referral
tertiary perinatal centers.26-35 The underlying pathological
disturbance involves systemic or intrarenal aggregation of
platelets within the arterioles and capillaries in association
with endothelial cell injury. In patients with TTP, high levels
of endothelial membrane protein thrombomodulin as well as
large multimers of von Willebrand factor (VWF) are found in
maternal serum.36,37 These abnormal molecules cause micro-
vascular platelet aggregates in various organs with resultant
thrombocytopenia and mechanical injury to erythrocytes.
This latter process results in microangiopathic hemolytic
anemia.36-38
Most multimers of VWF in the plasma originate from the
endothelial cells, but they also can be produced by plate-
lets.36 A VWF-cleaving metalloprotease (ADAMTS13) in
plasma normally prevents the entrance into the circulation
(or persistence) of unusually large multimers.36 This enzyme
is produced mainly by hepatocytes, and it degrades these
multimers by cleavage to peptide bonds directly on the sur-
face of endothelial cells.36 In most patients with acquired
TTP, plasma ADAMTS13 activity is markedly reduced (⬍5%
of normal).39 This reduction of activity of ADAMTS13 pre-
vents timely cleavage of large multimers of VWF as they are
secreted by endothelial cells. Consequently, the uncleaved
multimers induce adhesion and aggregation of platelets in
the microcirculation.36-39
Unlike the findings in TTP, the levels of ultralarge VWF
multimers are generally not elevated in patients with HELLP
syndrome.40,41 However, one study found that the amount of
active VWF was significantly increased in patients with
HELLP syndrome compared with the amount measured in
healthy pregnant women and in those with pre-eclampsia
without HELLP syndrome.42 In the same study, the authors
found that ADAMTS 13 activity was lower in patients with
HELLP syndrome (74 ⫾ 21%) as compared with the values
in patients with normal pregnancies (10.5 ⫾ 15%), but the
values in HELLP syndrome were within the normal range
(61-142%).42 In addition, two other studies found that the
activity of ADAMTS 13 was reduced, but within normal
range, and inactivating autoantibodies against ADAMTS 13
were absent in patients with HELLP syndrome.41,43 These
findings suggest that measurements of ADAMTS 13 activity
and/or of inactivity autoantibodies can distinguish between
HELLP syndrome and TTP.40-43
The classic clinical pentad of TTP consists of thrombocy-
topenia, microangiopathic hemolytic anemia, neurologic ab-
normalities, fever, and renal dysfunction. The complete pen-
tad is rarely seen in patients with documented cases of TTP39,
but 50-75% will have the first three clinical findings.27-39
Anemia and thrombocytopenia are frequently severe.36-39
The presenting symptoms may include abdominal pain,
nausea, vomiting, gastrointestinal bleeding, epistaxis, pete-
chiae, or purpura.37-39 Neurologic abnormalities are often
difficult to diagnose and may include transient and recurrent
symptoms, such as headache, visual changes, confusion,
aphasia, transient paresis, weakness, and seizures.28-39 Fever
is present in about 30-40% of cases, and when present, it is
199
Figure 2 Urine of a patient with AFLP. (Color version of figure is
available online.)
usually ⬍101°F. Renal involvement manifests as hematuria,
proteinuria, and renal insufficiency. The urine is usually tea-
colored, similar to that in patients with HELLP syndrome. In
contrast, the urine color in AFLP patients is usually bright
yellow (Fig. 2). Hypertension may be present or absent. In
severe cases, the pathological lesion of TTP may involve other
organs, such as liver, pancreas, heart, and lungs.37,38 The
extent of involvement of different systems will lead to differ-
ent and specific clinical manifestations.
Laboratory findings will reveal thrombocytopenia (platelet
count ⬍100,000/mm3, usually ⬍20,000), severe anemia
(hematocrit ⬍25%), marked elevation in serum levels of lac-
tate dehydrogenase (LDH), and the presence of fragmented
erythrocytes (schistocytes, helmet cells).36-39 It has been sug-
gested that elevated LDH levels are largely derived from isch-
emic or necrotic tissue cells as well as ruptured red blood
cells.36 Liver enzymes may be normal or elevated, and coag-
ulation studies are frequently normal.29-39
HUS is mostly seen in children in association with enteric
infections with Escherichia coli that produce Shiga toxin.36,37
It is extremely rare during pregnancy, and almost all cases
have been described in the postpartum period (within 48
hours to 10 weeks).1,29,44-48 The microvascular injury mainly
affects the kidneys and results from glomerular and arteriolar
fibrin thrombi. Patients with HUS present with edema, hy-
pertension, bleeding manifestations, or severe renal fail-
ure.1,26,29,30,44-48 Renal involvement is more severe than in
other thrombotic microangiopathies.36-38 Microscopic hema-
turia and proteinuria are always present. Acute renal failure is
an important feature in the clinical course of the disease, and
most patients with HUS in pregnancy or postpartum will be
left with some form of residual renal deficit. Laboratory find-
ings are similar to those found in TTP, but they are of less
magnitude. However, renal function is always markedly ab-
normal.1,29,30,44-48
Maternal Outcomes in TTP-HUS
Maternal mortality and morbidity are usually high in preg-
nancies complicated by TTP or HUS. Maternal mortality rates
200 B.M. Sibai

Table 2 Maternal Complications in Recent Series of 150 Perinatal Outcome in TTP-HUS

Pregnancies with AFLP
Complication % ever, recent case series reported a fetal loss rate of 20%. Most
Death 0-20
DIC 50-100
Hypoglycemia 50-100
ATN 50-100
Encephalopathy 20-67
Ascites 30-50
Sepsis 30-50
Pulmonary edema/ARDS 15-30
Pancreatitis 0-40
Diabetes insipidus ? Patients with TTP/HUS should be managed in consultation
were as high as 60% before the use of plasma infusions and
plasma exchange. In the cases reviewed by Weiner for the
years 1966-1987, the maternal mortality for TTP was 44%,
and for HUS it was 55%.48 However, recent case series report
a maternal mortality rate of 0-10%.31-34 This improved sur-
vival in recent studies is attributable to early detection (prior
history of TTP or HUS), inclusion of minor forms of TTP,
inclusion of women with probable HELLP syndrome or
eclampsia, and to improved therapeutic measures, such as
plasma infusion, plasma exchange, or immune suppressive
therapy.26,33,34 However, maternal morbidities continue to be
high (Table 2).27-35
In general, maternal outcome is usually favorable with very
low maternal mortality and morbidities in those known to
have TTP/HUS before pregnancy, because these patients re-
ceive close observation with serial plasmapheresis or ex-
change as needed.1,26-29,33,34 In contrast, maternal mortality
and morbidities are usually high in those who develop the
manifestations for the first time during pregnancy and/or
postpartum.1,26,29,35 In such cases, there is a delay in confirm-
ing the diagnosis because of confusion with HELLP syn-
drome and other medical conditions. As a result, plasma-
pheresis is usually initiated late in the disease process.26,35
In the review by Weiner,48 the fetal loss rate was 80%. How-
cases of TTP develop antepartum with average gestational age
at diagnosis of 26 weeks. Therefore, preterm delivery is com-
mon. These pregnancies are also associated with reduced
uteroplacental blood flow secondary to maternal hypoxia or
vascular lesions in the placenta.43,49 Perinatal outcome re-
ported in recent series is summarized in Table 3.27-35
Management of TTP/HUS
with a hematologist and/or a nephrologist. Plasma transfu-
sions and exchanges have revolutionized the treatment of
these syndromes. Fresh frozen plasma (platelet-poor), cryo-
precipitate-poor plasma (cryosupernatant), and plasma tre-
ated with a mixture of solvent and detergent all contain the
needed deficient metalloprotease.41-43 Plasma exchange will
help remove unusually large multimers of VWF and autoan-
tibodies against the metalloprotease (ADAMTS13).41-43 This
therapy is usually effective in approximately 90% of cases.
Plasma infusion alone has a response rate of 64%. Treatment
should be initiated soon after the diagnosis is made. A re-
sponse manifested by an increase in platelet count and reduc-
tion in LDH levels is expected within a few days of initiating
therapy. Plasma exchanges should be performed daily until
the platelet count becomes normal and hemolysis resolves, as
evident by decrease in LDH levels.42,43
Some patients with TTP and high antibody titers against
ADAMTS may not respond to plasma exchange alone. These
patients require immunosuppressive therapy and/or splenec-
tomy.37,41,42 Platelet transfusions should be avoided if possi-
ble, given the potential for increased microvascular throm-
bosis. Because severe hemorrhage can occur with TTP, it is
reasonable to transfuse platelets when there is the potential
for life-threatening bleeding.37 Red cell transfusion should be
used according to clinical need.38,39 Furthermore, immuno-
suppressive agents with steroids, cyclophosphamide, vin-
cristine, or rituximab may be needed in patients who

Table 3 Maternal/Perinatal Outcome in TTP/HUS

Maternal Outcomes
No. of No. of CNS* Renal Perinatal Outcomes
Authors Women Pregnancies Death Injury Injury Death Preterm
Hayward, et al.27 9 9 1 2 2 1 4/9
Ezra, et al.28† 5 8 1 0 0 4 4/8
Egerman, et al.29 11 11 2 1 4 2 5/11
Dashe, et al.30 11 13 3 0 5 1 3/13
Castella, et al.31* 9 9 1 0 0 2 4/9
Vesely, et al.32† 5 7 0 0 1 3 4/7
Dulcoy-Bouthars34 5 6 0 0 0 1 2/5
Shamseddine33 4 4 1 0 0 3/5 4/5
Stella, et al.35 12 14 3 0 1 4/16 —
Total 71 81 12/71 (17%) 3 (3%) 13 (18%) 21/73 (29%) 30/67 (45%)
*CNS, central nervous system.
†Only definite cases developing during pregnancy are included.
Imitators of severe pre-eclampsia
develop exacerbations or relapse after plasma exchange is
stopped.37,41,42
The treatment of HUS is similar to that of TTP. However,
the response to plasma infusions is not as favorable, and most
patients will require dialysis.
Delivery is the only cure for patients with HELLP syn-
drome or AFLP. In contrast, pregnancy should be continued
in patients with TTP or HUS who develop the condition
remote from term in the absence of fetal compromise and in
those who respond to plasma infusions and/or plasma ex-
change. In rare cases, plasmapheresis results in improve-
ments in fetal heart rate tracing.50 However, theses patients
require close observation of laboratory and clinical findings
because of the risk of relapse. Some of the managements used
in such patients have included corticosteroids, antiplatelet
agents, weekly plasma infusions, and serial plasma exchange
or dialysis.1,26,33-35
Counseling of Women with TTP
Women who develop TTP during pregnancy should be aware
of the potential of relapse after delivery as well as of risk of
relapse in subsequent pregnancies.28,30,32,34,35,38 Therefore,
these women should be instructed about the symptoms of
early relapse and to report these symptoms immediately.
There are few case reports describing recurrent TTP/HUS in
subsequent pregnancies28,32,34,35,38; however, the risk of this
recurrence remains unknown because of limited data.
Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is an autoimmune dis-
order that is characterized by deposits of antigen–antibody
complexes in capillaries and various visceral structures. Most
patients are female and of reproductive age (26-40 years
old).51 The clinical findings may be mild or severe amd may
affect multiple organ systems, including the kidneys (nephri-
tis), lungs (pleuritis or pneumonitis), liver (hepatitis), and
brain.51-59 In patients with lupus nephritis, the clinical and
laboratory findings are similar to those of severe pre-eclamp-
sia.51-57 Such patients will have hypertension, proteinuria,
and microscopic hematuria. In some of these women, partic-
ularly during an acute exacerbation, patients will have
thrombocytopenia. The thrombocytopenia is usually mild to
moderate (⬎50,000/mm3).51-59 Most patients with lupus
have skin lesions (typical discoid or malar rash), and joint
symptoms and fever are very common during an acute flare.
During the active phase of SLE exacerbation, laboratory
findings will show pancytopenia, thrombocytopenia, hemo-
lytic anemia, and an increase in anti-DNA antibodies. Serum
complement levels may be normal or depressed. Severe lupus
flares occur in 25-30%, and it may develop for the first time
during pregnancy or in the postpartum period.51,55 In pa-
tients with lupus nephritis who develop active flare during
pregnancy, the clinical and laboratory findings are similar to
those with severe pre-eclampsia and HELLP syndrome.53-56,58
The exact diagnosis may be difficult, particularly in those
with associated antiphospholipid antibodies (APAs).58-63
201
APAs (lupus anticoagulant and/or anticardiolipin antibod-
ies) are present in 30-40% of patients with systemic lu-
pus.59-61 These patients are at increased risk for thrombotic
events. Patients with lupus and APA are at risk for tissue
ischemia secondary to thromboembolic events and throm-
botic microangiopathy, resulting in a clinical picture similar
to that seen in HELLP syndrome, eclampsia, TTP, and
HUS.61-67 Thrombocytopenia is seen in about 40-50% of
these cases and hemolytic anemia in 14-23%.61 Cerebral le-
sions and symptoms will develop because of cerebral vascu-
litis and/or cerebral vaso-occlusive disease. In such patients,
the clinical and laboratory findings are similar to those with
eclampsia.61 In patients with renal involvement, hyperten-
sion and proteinuria are the rule with findings identical to
severe pre-eclampsia.
The catastrophic antiphospholipid syndrome occurs in
⬍1% of patients with APA syndrome.60 It is characterized by
acute thrombotic microangiopathy affecting small vessels of
multiple organs (at least three). The most common affected
organs are the kidneys and central nervous system.60,61 Liver
involvement will result in cellular necrosis and infarcts, lead-
ing to elevated liver enzymes.64-66 The clinical and laboratory
findings may also be similar to other microvascular angiopa-
thies.60-67
Maternal–Perinatal Outcome
Pregnancy outcome is usually favorable in patients with SLE
who were in remission before pregnancy and who do not
develop a flare during pregnancy.51,57 In addition, the out-
come is favorable in those without lupus nephritis and/or
absent antiphospholipid antibodies.52,55-57 However, mater-
nal morbidities and perinatal mortality and morbidity are
increased in those with lupus nephritis central nervous sys-
tem disease and in those with antiphospholipid antibod-
ies.51-55,59-62 These latter pregnancies are associated with high
rates of miscarriage, fetal death (4-19%), intrauterine growth
restriction, and preterm delivery (38-54%). This high rate of
fetal loss and perinatal complications is related to decidual
vascular thrombosis and placental infarctions and hemor-
rhage.59-62 Maternal complications include a high rate of early
onset pre-eclampsia and complications related to thrombo-
embolism and microangiopathy.57-61 Maternal morbidities
are substantially increased in those with APA syndrome.58-67
Maternal mortality is almost 50% in patients who develop the
catastrophic APA syndrome.61
Management
Management of SLE flare during pregnancy will depend on
the presence of the organ systems involved, laboratory find-
ings (thrombocytopenia, APAs), and the presence or absence
of nephritis. Treatment usually includes the use of cortico-
steroids, low-dose aspirin, hydroxychloroquine immuno-
suppressive drugs, and heparin.51-68 The usual dose of ste-
roids is 40-80 mg/day of prednisone, and for aspirin it is 81
mg/day. Prednisone therapy is usually used in patients with
lupus nephritis, whereas combined regimens of prednisone
and low-dose aspirin are recommended in patients with
202 B.M. Sibai

Table 4 Frequency of Various Signs and Symptoms Among Imitators of Pre-eclampsia–Eclampsia

HELLP
Signs and Symptoms Syndrome AFLP TTP HUS Exacerbation of SLE
Hypertension 85% 50% 20-75% 80-90% 80% w/APA/nephritis
Proteinuria 90-95% 30-50% with hematuria 80-90% 100% w/nephritis
Fever Absent 25-32% 20-50% ?* Common during flare
Jaundice 5-10% 40-90% Rare Rare Absent
Nausea/vomiting 40% 50-80% Common† Common Only w/APA‡
Abdominal pain 60-80% 35-50% Common Common Only w/APA
Central nervous system 40-60% 30-40% 60-70% ? 50% w/APA
*?, values not reported.
†Common, reported as the most common presentation.
‡APA, antiphospholipid antibodies ⴞ catastrophic antiphospholipid syndrome.

APAs.59-61,68 Alternative regimens have included the use of
heparin plus low-dose aspirin. For patients with severe
thrombocytopenia that does not respond to the above regi-
mens, intravenous ␥ globulin may be beneficial.61 Recent
data also suggested that the use of other agents, such as aza-
thioprine, cyclosporin, and hydroxychloroquine, may be re-
quired in management of some of these patients.54,59,68 In
patients with catastrophic APA syndrome, treatment includes
full anticoagulation with heparin, steroids, plus plasma-
pheresis.60,61,66
In summary, the clinical presentations of AFLP, TTP, HUS,
and exacerbation of SLE can be easily confused with those
of severe pre-eclampsia– eclampsia HELLP syndrome. Al-
though these conditions share a range of signs and symptoms
(Table 4) and laboratory tests (Table 5) with HELLP syn-
drome, each has some distinguishing clinical findings or lab-
oratory results. Making the right diagnosis is extremely im-
portant regarding decisions about need for delivery as well as
treatment and complications.
Systemic Viral Sepsis
Disseminated herpes simplex is a rare complication during
pregnancy. It is usually seen in immunocompromised preg-
nant women. The onset is usually in the third trimester (av-
erage onset of 30 weeks) with clinical presentation of fever,
abdominal pain, and upper respiratory symptoms.69-72 Some
patients will have hepatitis without jaundice and encephali-
tis.69,71,72 Hepatitis is a common finding in fulminant sep-
sis.70,72 Hypertension and proteinuria are absent. Laboratory
findings will reveal leukopenia, thrombocytopenia, hemoly-
sis, DIC, markedly elevated levels of AST (⬎2000 IU/L), and
severe elevations in LDH levels. In fulminant cases, the am-
monia levels may be elevated; however, bilirubin values are
usually normal or slightly elevated, which is different from
the usual finding in patients with AFLP. The diagnosis is
usually made in the presence of vesicular lesions in the skin,
perineum, or the cervix. Liver biopsy will show the typical
intranuclear inclusions (Cowdry type A inclusions) with as-
sociation with cell necrosis and hemorrhage (Fig. 2). The CT
scan may show the typical mottled appearance in the liver
(multiple low-density areas that do not enhance with contrast
injection), which is different from the CT scan findings in
patients with HELLP syndrome, AFLP, or liver infarction.1
Disseminated herpes infection is associated with high ma-
ternal and perinatal mortality if not treated promptly.69-72 In
a review of 24 cases of herpes simplex hepatitis in pregnancy
up to the year 1998, Kanga and Graves70 found an overall

Table 5 Frequency and Severity of Laboratory Findings Among Imitators of Pre-eclampsia–Eclampsia

HELLP Exacerbation of
Laboratory Findings Syndrome AFLP TTP HUS SLE
Thrombocytopenia (<100,000/mm3) >20,000 >50,000 <20,000 >20,000 >20,000
Hemolysis 50-100% 15-20% 100% 100% 14-23% w/APA*
Anemia <50% Absent 100% 100% 14-23% w/APA
DIC <20% 73% Rare Rare Rare
Hypoglycemia Absent 61% Absent Absent Absent
VW factor multimers Absent Absent 80-90% 80% <10%
ADAMTS 13% < 5% Absent Absent 33-100% Rare Rare
Impaired renal function 50% 90-100% 30% 100% 40-80%
LDH (IU/L) >600 Variable >1000 >1000 with APA
Elevated ammonia Rare 50% Absent Absent Absent
Elevated bilirubin 50-60% 100% 100% <10%
Elevated transaminases 100% 100% Usually mild† Usually mild† with APA
*Abbreviations: APA, antiphospholipid antibodies; DIC, Disseminated intravascular coagulopathy; VW, von Willebrand; SLE, systemic lupus
erythematosus; LDH, lactic dehydrogenase.
†Levels < 100 IU/L.
Imitators of severe pre-eclampsia
maternal mortality of 39% and perinatal mortality of 39%.
Maternal mortality was 0% among 13 women treated with
acyclovir and 20% among 4 women treated with vidarabine,
whereas it was 67% among 15 women receiving no antiviral
therapy.70 In addition, the perinatal mortality was 18% in
those receiving acyclovir, 67% among those receiving vidara-
bine, and 44% among those receiving no therapy. Therefore,
accurate and urgent diagnosis is important because early
therapy with acyclovir improves survival. The usual dose of
intravenous acyclovir is 10-15 mg/kg of body weight every 8
hours to be continued for at least 10 days.69-72 These patients
should be managed in an intensive care facility. There is no
need for early delivery in the absence of fetal indications.70
Systemic
Inflammatory Response
Syndrome (SIRS)/Septic Shock
SIRS describes a systemic inflammatory process that can be
generated by infection or by noninfectious causes, such as
pancreatitis, burns, and major trauma.73-78 It is characterized
by a hyperdynamic state, endothelial cell injury, leukocyto-
sis, neutrophil activation, and tissue hypoperfusion with
multiorgan dysfunction.71,73-78 Sepsis is SIRS due to infection
that is associated with hypoperfusion or hypotension with
organ dysfunction. Septic shock is a subset of sepsis defined
as sepsis-induced hypotension despite adequate fluid resus-
citation along with the presence of perfusion abnormalities,
such as lactic acidosis, renal dysfunction (oliguria, acute tu-
bular necrosis), hepatic dysfunction, and acute changes in
mental status.73-78 Laboratory findings include leukocytosis
or leukopenia (white blood count ⬍4000), thrombocytope-
nia, hemolysis, DIC, elevated liver enzymes, and elevated
bilirubin.
Some authors suggested that the maternal syndrome of
pre-eclampsia share many of the clinical and laboratory find-
ings of patients with SIRS.79,80 Both syndromes are character-
ized by systemic inflammation, neutrophilia, and neutrophil
activation. Indeed, many of the clinical and laboratory find-
ings of women with HELLP syndrome, such as hemoly-
sis, hepatocellular necrosis, renal dysfunction, pulmonary
edema, ARDS, and thrombocytopenia, are similar to those
seen in patients with severe sepsis and septic shock.79,80 A
recent report by Afessa and coworkers74 found that 59% of
obstetric patients admitted to ICU developed SIRS.
In general, patients with severe sepsis or septic shock will
have fever, but hypertension and proteinuria are absent.
However, hypertension or proteinuria may be absent in 10-
15% of patients with HELLP syndrome. In addition, leuko-
cytosis and fever may be present in women with pre-eclamp-
sia because of endomyometritis, particularly after cesarean
delivery. Table 1 compares clinical and laboratory findings
between those with disseminated herpes and SIRS/sepsis in
pregnancy.
Septic shock is rare during pregnancy or postpartum.73-76
It should be considered in the differential diagnosis of pa-
tients with fever, microangiopathic hemolysis, thrombocyto-
203
penia, renal insufficiency, altered mental status, and pulmo-
nary insufficiency. The clinical picture can mimic HELLP
syndrome, AFLP, TTP and HUS, and an SLE flare. It can be
the primary cause or it can be a complication of any one of the
above syndromes. The clinical findings include a tempera-
ture ⬎38°C or ⬍36°C, tachycardia (pulse ⬎100 bpm),
tachypnea (respiratory rate ⬎24/min), and hypotension (sys-
tolic blood pressure ⬍90 mm Hg). Cardiac output is initially
elevated, systemic vascular resistance is low, and venous re-
turn is reduced. With reduced tissue perfusion, oxygen de-
livery is impaired, resulting in increased lactate levels sec-
ondary to anerobic cellular metabolism. Both hypotension
and poor tissue perfusion will ultimately lead to multiple
organ failure.73-78
Maternal and Perinatal
Outcome in Septic Shock
Mabie and coworkers73 reported the etiology, management,
and outcome in 18 patients with septic shock during preg-
nancy. The etiology of shock were pyelonephritis in 6
women, chorioamnionitis in 3, postpartum endometritis in
3, toxic shock syndrome in 2, and 1 each of septic abortion,
appendicitis, ovarian abscess, necrotizing fasciitis, and bac-
terial endocarditis. Five women (28%) died, and 15 (82%)
had multiorgan dysfunction. The perinatal survival was 50%
(10 of 20, one set of triplets). Five of the 10 losses were ⱕ20
weeks’ gestation, and 5 were stillbirths.73 Afessa and cowork-
ers74 reported on 44 obstetric patients who developed SIRS; 2
patients had septic shock and 18 had severe sepsis. Two
women (4.5%) died, and 36 (82%) had multiorgan failure.
Management of Septic Shock
Treatment of septic shock consists of resuscitation with flu-
ids, vasopressors, antibiotics, hemodynamic monitoring, re-
moval of source of infection (surgery or percutaneous drain-
age of abscesses), and modifying of inflammatory mediators.
Patients with SIRS or septic shock require admission to an
intensive care unit to monitor volume replacement with crys-
talloids or blood components, to monitor vital signs, urine
output, oxygenation, and mental status.73-78 Fluid resuscita-
tion will include 3-4 L of crystalloid over 60 minutes, to
correct hypotension and to achieve a central venous pressure
of 8-12 mm Hg. If hypotension persists, then vasoactive
agents are used. The first drug of choice is dopamine, titrated
up to 20 mg/kg/min to achieve a MAP of at least 65 mm Hg
(MAP needed to keep adequate tissue perfusion, particularly
cerebral perfusion).73-78 Other vasoactive drugs, such as do-
butamine or norepinephrine, can be used as needed. If the
patient does not show good response to broad spectrum an-
tibiotic therapy, attention should be given to identify a source
of infection (retained products of conception, microabscesses
in uterine wall, pelvic abscess, etc.) that require surgical in-
tervention.71,73-76 In general, delivery is required if there is
evidence of an infected fetus, amniotic fluid, or placental
tissues. On the other hand, delivery is not indicated in the
absence of infection in the uterine cavity. A detailed descrip-
204
tion of pathophysiology and management of sepsis has been
described.76-80
Conclusions
Several microangiopathic disorders can occur any time dur-
ing pregnancy or during the postpartum period. The inci-
dence of these disorders is extremely low; however, the ma-
ternal and perinatal complications are extremely high. The
clinical presentation and laboratory findings in these disor-
ders can mimic those seen in pre-eclampsia and eclampsia.
Consequently, there is the potential for delay in diagnosis
and treatment during management of these women. There-
fore, it is important that managing physicians be aware of the
etiology, diagnostic findings, and management of such dis-
orders. Finally, a rapid diagnosis and close consultation with
an interdisciplinary team of physicians, such as maternal–
fetal medicine, nephrologist, hematologist, critical care, etc.,
may result in optimal outcome for the mother and fetus.12
Box I Imitators of Severe
Pre-eclampsia/Hellp Syndrome
● AFLP
● TTP
● HUS
● Exacerbation of lupus erythematosus
● Catastrophic antiphospholipid syndrome
● Systemic viral sepsis (disseminated herpes)
● SIRS/septic shock
● Other conditions (cholestasis of pregnancy, necrotizing
pancreatitis, etc.)
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