The acronym HELLP was coined by Louis Weinstein in 1982 to describe a syndrome consisting of hemolysis (H), elevated liver enzymes (EL) and low platelets (LP). Some experts consider it a severe form of preeclampsia, while others believe that HELLP syndrome and preeclampsia are separate disorders with overlapping features. As many as 15- 20% of the patients with HELLP syndrome do not have antecedent hypertension or proteinuria.
This syndrome usually develops suddenly between 28-36 weeks gestation. Its etiology and pathogenesis are not well understood. Generally, the disorder is considered a placenta-instigated, liver-targeted acute inflammatory condition, with elements of disordered immunological processes. Like severe preeclampsia, it results from the aberrant development, function, and ischemia of the placenta. This ischemia in turn triggers the release of factors that injure the endothelium via the loss of normal pregnancy vascular relaxation, release of vasoconstrictors, and activation of platelets. Thus begins a cascade that is terminated only by delivery. The hemolysis which characterizes the syndrome is of microangiopathic origin. Red cells become fragmented as they pass through small vessels with pathological fibrin deposits and damaged endothelium. Obstruction of hepatic blood flow by the same fibrin deposits in hepatic sinusoids results in elevated liver enzymes, and periportal necrosis. In severe cases, intrahepatic hemorrhage, subcapsular hematoma, or even hepatic rupture may occur. Thrombocytopenia, the third aspect of the triad, results from increased consumption and destruction of platelets.
HELLP syndrome develops in 1 of 1000 pregnancies overall1,2, and in 4-12% of the patients already affected by severe preeclampsia or eclampsia. Unfortunately, when preeclampsia is not present, the problem is disguised, and diagnosis of the syndrome is often delayed by as much as 7 days. Onset is antepartum in 70% of the cases, usually in the third trimester, and within 48 hours of delivery in the other 30%. Of the patients affected postpartum, only roughly 20% have any signs or symptoms suggesting preeclampsia prior to delivery. In contrast to preeclampsia, HELLP syndrome is more often associated with Caucasian multiparous women above the age of 25 years.
The vague and varied nature of the
presenting complaints can make the diagnosis of HELLP syndrome, and its
distinction from preeclampsia, frustrating to physicians. Patients with
this syndrome may present with various signs and symptoms, none of which
are purely diagnostic. In fact, the majority of symptoms may also be
seen in patients with severe preeclampsia-eclampsia without HELLP
syndrome (table-1).
Presentation largely depends on the stage of
the disease. Approximately 90% of the patients present with generalized
malaise suggestive of a viral illness3. Because early diagnosis of HELLP
is critical, pregnant women who present with symptoms such as malaise
in the second half of their pregnancy should be immediately evaluated
with complete blood count and liver function tests to exclude it. Other
common symptoms include epigastric or right upper quadrant abdominal
pain, nausea, vomiting, headache and visual symptoms. At times, referred
pain from the liver can produce atypical neck and shoulder pain. Any
pregnant patient with epigastric or right upper quadrant abdominal pain
in the second half of pregnancy, particularly if in association with
nausea and or vomiting, has HELLP syndrome until proven otherwise4. When
the upper abdominal pain is writhing in nature and of sudden onset,
hepatic bleeding or rupture is the likely cause, constituting an
obstetric emergency. A small subset of patients may present with
symptoms related to their thrombocytopenia, such as mucosal bleeding,
petechial hemorrhages, ecchymosis or hematuria.
The
physical examination may be deceivingly normal. However, in the
majority, blood pressure will be elevated along with proteinuria and
right upper quadrant tenderness. Leg swelling, though common in
HELLP, may not be a useful marker as it is seen in 30% of healthy
pregnant women.
HELLP syndrome can
be a great masquerader, and the presenting symptoms, clinical findings
and laboratory results of this syndrome may suggest an array of
differential diagnoses as shown in Tables 2 and 3. Diagnosis is
notoriously difficult in the 15- 20% of the patients who have neither
hypertension nor proteinuria 5-7. However, its presence may erringly
lead toward preeclampsia. A delay in its diagnosis may be life
threatening. As numerous misdiagnoses are possible, and treatment delay
could be life-threatening, a pregnant woman with epigastric or right
upper quadrant pain, thrombocytopenia and abnormal liver functions in
the second half of pregnancy or early postpartum should be considered as
having HELLP syndrome until proven otherwise via immediate work up.
Lack of response to aggressive steroid treatment, especially with
persistence of the disease following delivery or first presentation of
the disease more than 7 days postpartum, should instigate testing for
other diagnostic possibilities.
Acute
fatty liver of pregnancy (AFLP) and HELLP syndrome share several
clinical features and can occur concurrently, so these are very
difficult to distinguish clinically. Prolongation of prothrombin time,
activated partial thromboplastin time, hypoglycemia and elevated serum
creatinine concentrations are more common with AFLP. Though liver biopsy
is the gold standard for diagnosing AFLP, because the procedure may be
hazardous during pregnancy, and treatment is often unaltered by results,
it is not commonly used in clinical practice.
Thrombotic
thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) may
also cloud the diagnosis of HELLP syndrome. Thrombocytopenia,
microangiopathic hemolytic anemia and renal failure are seen with both
TTP-HUS and HELLP syndrome. The severity of these three symptoms is
typically more serious with TTP-HUS. For therapeutic and prognostic
point of view it is important to distinguish TTP-HUS from severe
preeclampsia and HELLP syndrome. The time of onset and the association
with preceding proteinuria and hypertension help distinguish between
these two. TTP-HUS is usually variable in onset, whereas HELLP syndrome
typically develops in the third trimester, and is usually associated
with hypertension and proteinuria. Coagulation abnormalities are not
typically associated with either diagnosis except in severe HELLP
syndrome when associated with disseminated intravascular coagulation.
Work up
The
diagnosis of HELLP syndrome is most certain in the presence of signs
and symptoms of preeclampsia-eclampsia in a pregnant patient along with a
triad of laboratory abnormalities indicating microangiopathic
hemolysis, liver dysfunction and thrombocytopenia (Table 4). Though
considered to be the gold standard, liver biopsy is rarely needed to
establish the diagnosis and may be hazardous to perform secondary to the
possible underlying coagulopathy. Common histological findings in such
biopsies include periportal hemorrhage and fibrin deposits in hepatic
sinusoids.
Looking at its natural
progression, it appears that thrombocytopenia occurs first, followed by
elevated liver enzymes, and finally hemolysis. The rate of drop of
platelets is usually 35-50% per 24 hours (mean daily reduction of
40,000). Requiring a count of less than 100,000 to define
thrombocytopenia is ill advised as maternal morbidity doubles when
patients with severe preeclampsia have mild thrombocytopenia (platelets =
100,000-150,000) in association with abnormal liver function and
increasing lactate dehydrogenase (LDH). In addition, significant
pathology such as hepatic rupture or subcapsular hematoma can occur in
the patient with HELLP syndrome prior to a drop in platelets to below
100,000 8.
Depending on the laboratory abnormalities present,
HELLP syndrome is grouped into different subtypes per the Mississippi
and Tennessee classifications (Table 5). The degree of laboratory
abnormality present is difficult to determine with on the history or
physical examination. Therefore, laboratory tests should be ordered with
minimal clinical indications, and to rule in or out a diagnosis of
preeclampsia. Typical laboratory workup includes complete blood count,
coagulation studies, serum creatinine, urine protein, blood glucose,
peripheral blood smear and liver function tests.
Although some
degree of hemolysis is often noted and is the hallmark of the triad for
diagnosis, resultant anemia is uncommon or mild. Many physicians use
elevated LDH as a better indicator of hemolysis than hemoglobin. There
are five different isomers of LDH, and only LDH1 and LDH2 are
released
from ruptured red cells. However, liver ischemia also causes elevation
in total LDH in the majority of patients with severe preeclampsia or
HELLP syndrome. Therefore, elevated indirect bilirubin, low haptoglobin
and abnormal peripheral smear with schistocytes and or burr cells are
used in addition to LDH for diagnosis of hemolysis.
Significant
elevation of alkaline phosphatase is often seen in normal pregnancy;
however, the elevation of transaminases, lactate dehydrogenase and
bilirubin, indicates hepatic pathology. The value of transaminases in
early to moderate disease rarely exceeds 1000. Levels in excess of this
suggest hepatitis or hepatic rupture from HELLP syndrome.
Unfortunately
there is no consensus with regard to laboratory parameters for
diagnosis of HELLP syndrome. Laboratory abnormalities often return to
normal within a short time of delivery with occasional transient
worsening within the first 24-48 hour postpartum 9-14. There should be
an upward trend in platelet count and downward trend in lactate
dehydrogenase and transaminases by the fourth postpartum day when there
are no associated complications from HELLP syndrome 9-11,15. Liver tests
typically normalize earlier than the platelet count. The latter may
take as long as 6-11 days depending on the severity of thrombocytopenia.
Further
tests such as urine analysis, chest X-ray, liver imaging, etc. are
ordered when associated complications such as disseminated intravascular
coagulation (DIC), pulmonary edema, subcapsular liver hematoma or liver
rupture are suspected. Additional testing may be needed at times to
rule out other possible conditions (Table 2) that closely resemble HELLP
syndrome.
Treatment
Although management of HELLP syndrome
is highly controversial (Table 6), once diagnosed, a decision should be
made regarding delivery. Due to the progressive nature of the disease,
these patients should always be hospitalized with strict bed rest and
care in labor and delivery due to the potential for sudden deterioration
of maternal or fetal condition. Patients diagnosed with HELLP prior
to 35 weeks should be transferred to a tertiary care center. After
assessment and stabilization of maternal status, the fetus is evaluated
by fetal heart rate tracing, biophysical profile and or doppler studies.
The assessment of maternal and fetal status helps determine when
delivery is required or imminent, as delivery is the only true cure for
this syndrome. 
When the mother and fetus are both stable
and the gestational age is less than 34 weeks, there is considerable
disagreement regarding management. For most, delivery is preferably
delayed for 24-48 hours for steroid administration. Prompt delivery is
indicated when the gestational age is beyond 34 weeks, or earlier in
presence of nonreassuring fetal status or if there are associated
complications of HELLP syndrome such as multiorgan dysfunction, DIC,
abruptio placentae, renal failure, pulmonary edema, liver infarction or
hemorrhage etc.6,17.
Some authors recommend expectant management
beyond 48 hours in a select group of stable patients with HELLP syndrome
if the fetus is extremely premature (<26 weeks of gestation). This
conservative group recommends prolonging pregnancy in the hospital until
the development of maternal or fetal
indications for delivery, achievement of fetal lung maturity or 34 weeks
of gestation. However, it should be noted that there is no improved
perinatal outcome associated with this pregnancy prolongation18. Some of
the measures used in these patients include one or more of the
following: bed rest, adequate blood pressure control, chronic
intravenous magnesium administration, antithrombotics such as aspirin or
dipyridamole, steroids and plasma volume expanders (fresh frozen
plasma, crystalloid, colloids, etc).
As HELLP syndrome is
considered a systemic inflammatory response syndrome, similar to the
inflammatory condition of severe preeclampsia, anti- inflammatory or
immunosuppressive agents like corticosteroids are given as consideration
for its treatment. There is no consensus regarding the use of high dose
steroids such as dexamethasone (10mg every 12 hours IV) in class 1 and 2
HELLP syndrome or complicated class 3 HELLP syndrome, other than for
the indication of aiding fetal lung maturity. The preferred steroid and
dosing duration are still not established. Though improvements in
laboratory parameters are often seen in HELLP syndrome patients
receiving this high dose steroids, maternal morbidity and mortality
along with duration of hospital stay and rate of blood product
transfusion remain the same. Therefore, the timing of delivery should
not be changed in patients showing transient improvement in laboratory
values from high dose steroids. Continuation of HELLP syndrome pregnancy
beyond 26 weeks and the time necessary for steroid enhancement of fetal
lung maturation increases the risk of still birth substantially 19,20.
HELLP
syndrome is not an indication for cesarean delivery (Table 7). Vaginal
delivery is attempted in patients in gestations beyond 32 weeks, or in
the presence of active labor or membrane rupture. Induction or
augmentation of labor with pitocin or prostaglandins is acceptable in
this group of patients. Alternately, in patients of gestation less than
30 weeks with an unfavorable cervix (Bishop score <5) and in the
absence of active labor, cesarean section is the preferred mode of
delivery6. Elective cesarean section is also recommended for patients
with fetal growth retardation or oligohydramnios. When cesarean delivery
without a trial of labor is planned, it is recommended that the surgery
be scheduled for six hours from the beginning of high dose of steroid
administration to stabilize the disease process, improve laboratory
parameters, enable institution of regional anesthesia21,22, and reduce
the need for blood product transfusion.
Magnesium sulfate
should be administered intrapartum and early postpartum for seizure
prophylaxis regardless of blood pressure. It is started at the beginning
of the observation period, continued through the intrapartum period,
and then for 24-48 hours postpartum. The standard regimen includes a 6gm
loading dose of magnesium over 20 minutes followed by a maintenance
dose of two grams per hour continuous intravenous administration. Serial
monitoring of its blood level is indicated in the presence of
compromised renal function with serum creatinine more than 1 mg/dl. As
in patients with severe preeclampsia, antihypertensives are used for
systolic blood pressures above 160, and or diastolic pressures of more
than 105 to avoid intracerebral bleeding6. The preferred
antihypertensives include hydralazine, labetalol and nifedipine (Table
8) 23. Nitroglycerine and sodium nitroprusside are useful in cases of
refractory hypertension if delivery is imminent. The prolonged use of
nitroprusside can lead to cyanide poisoning of the fetus, and therefore
is used as a last resort. Blood pressure should be recorded every 15
minutes during the implementation of antihypertensive therapy, and once
stabilized, recorded every hour.
For pain
control in labor small intermittent doses of narcotics can be given
intravenously. When the platelet count is below 75,000, regional
anesthesia and pudendal blocks are both contraindicated to avoid the
risk of bleeding and hematoma formation. Some physicians use a more
conservative 100,000 platelet count to contraindicate regional and
pudendal block. If indicated, patients considered to be at bleeding risk
can be delivered by cesarean section under general anesthesia. Some
authors noticed greater successful use of epidural anesthesia in
patients who had received steroids secondary to the transient
improvement in platelet count 22,24. Once in place, the epidural
catheter should not be removed until the count improves. It should be
noted that low platelet count is not a contraindication for local
infiltration of anesthetics for episiotomy or perineal laceration
repair.
Both maternal and fetal conditions are assessed
continuously during the intrapartum period. Platelet count should be
maintained at more than 20,000 and 40,000 for vaginal and cesarean
delivery respectively. In patients with platelet count at less than
40,000, 4- 10 units of platelets are transfused at the time of
intubation25. Platelet transfusion is also indicated in patients with
significant bleeding or platelet count less than 20,000 irrespective of
the intended mode of delivery. Because of the short half-life of
platelets, repeated transfusion is usually not advised. Prophylactic
platelet transfusion has been shown to neither reduce the incidence of
postpartum hemorrhage nor hasten the normalization of platelet count. In
the case of cesarean delivery, intraperitoneal and or subcutaneous
closed suction drains through a separate stab incision may reduce wound
hematoma formation, which may be seen in up to 20% of the patients with
HELLP syndrome. Some even leave the skin incision open for the first 48
hours postoperative, however this delayed skin closure or type of skin
incision has been shown to have no effect on wound hematoma incidence
26.
Although hypoglycemia is more commonly seen with AFLP, it can
also be seen in patients with HELLP syndrome. As hypoglycemia is a
major marker of imminent death in patients with HELLP syndrome, it
should be checked frequently during labor. Every attempt should be made
to keep blood sugar above 60 mg/dl. The patient might need 10% or 50%
dextrose to keep blood sugars in the safe range.
HELLP syndrome
may develop de novo most commonly in the first 48 hours postpartum,
though it may take up to 7 days to manifest. However, regardless of
antepartum or postpartum incidence, management is no different. With
good supportive care, a majority of patients recover completely. It is
important to continue monitoring fluid balance, laboratory
abnormalities, and pulse oximetry closely into the immediate postpartum
period. Patients who have developed the severe complications of help
warrant monitoring for several days. Seizure prophylaxis with magnesium
is continued for 24-48 hours postpartum, and some also continue the high
dose intravenous steroids for the first 24-48 hours after delivery.
Dexamethasone is the most preferred steroid, and is commonly
administered as two 10 milligram doses 12 hours apart, followed by two
additional doses of 5 milligrams each at 12-hour interval. Alternatively
some physicians continue high dose steroids until liver function
improves and platelet count exceeds 100,000. Clinical and laboratory
improvements are commonly seen within a few days of the delivery except
in patients with severe disease, renal dysfunction, ascites, and DIC.
Maternal serum LDH and platelets are the best markers of disease status.
If interventions are not successful, and patient condition continues to
deteriorate after delivery, it is important to exclude other diagnosis
such as TTP, HUS, and AFLP. Plasma exchange and plasma infusion has been
used sparingly for recalcitrant and or complicated HELLP syndrome that
is unresponsive to standard therapy.
Significant renal injury is
infrequently seen in patients with HELLP syndrome in the absence of
abruptio placentae or major hemorrhage. Aggressive steroid use has no
convincing renal benefits. Most of these patients respond to short
repeated cycles of dialysis if needed, and some require only a brief
initial dialysis course, to avoid permanent kidney impairment.
Short-term dialysis is needed in only a third of the patients with
impaired kidney function from HELLP syndrome. However, 40% of the
patients with prior chronic hypertension who are affected by HELLP
syndrome require chronic dialysis.
The incidence of subcapsular
hematoma is less than 2% in HELLP syndrome. It can lead to catastrophic
hemorrhage, and rupture may be spontaneous or secondary to labor or
convulsions. Typically the right lobe of the liver is involved, and any
sudden increase in intraabdominal pressure can result in rupture of a
subcapsular hematoma. Therefore, to avoid this most feared complication,
exogenous trauma to the liver such as frequent abdominal palpation or
emesis should be avoided, and utmost care should taken when transporting
patients with subcapsular hematoma. As the associated maternal and
fetal mortality is greater than 50% when rupture occurs, early
recognition is the key. Besides pain in the upper abdomen, these
patients present with acute abdominal swelling and signs of peritoneal
irritation along with hemorrhagic shock and modest elevation of liver
enzymes. Profound hypovolemic shock in a previously hypertensive
pregnant patient is the hallmark of ruptured liver hematoma. Sudden drop
in blood pressure may also be associated with sepsis, severe hemolysis,
or excessive vasodilatation from antihypertensives in pregnant women
with severe hemoconcentration. Abdominal imaging confirms the diagnosis
of rupture, and paracentesis is rarely needed, but can diagnose
hemoperitoneum. There are several options for management, including
fluid replacement, blood transfusion, correction of coagulopathy, the
use of cell saver at the time of laparotomy, surgical packing/drainage,
loosely suturing omentum or surgical mesh to the liver’s surface, argon
beam coagulation, and hepatic artery embolization. In the absence of
rupture, subcapsular hematoma patients need surgical intervention only
in the presence of hemodynamic instability, persistent bleeding,
increasing pain or continued expansion of the hematoma. When they
survive, they typically have no hepatic sequelae. Hemodynamically stable
patients with subcapsular hematoma can be managed conservatively via
close hemodynamic monitoring, coagulation studies and serial
surveillance of the hematoma via CT or ultrasound. It should also be
kept in mind that there is a risk of recurrence of the syndrome in
subsequent pregnancy.
Obstetricians, with the supervision of
perinatologists, are able to care for these patients in a majority of
cases. Depending on the status of the patient, and the complications
associated, additional specialized care may be needed. Other helpful
consultants may include hematologists, transfusion medicine specialists,
critical care specialists, nephrologists, and surgeons.
Mortality, Morbidity, Complications, Prognosis
Not
surprisingly, the presence of HELLP syndrome increases maternal
mortality 16 and morbidity. This is particularly high for patients with
complete or true HELLP syndrome over those with incomplete HELLP
syndrome27. Neurologic abnormality due mostly to cerebral
hemorrhage/stroke is the most common system involved in autopsy 28.
Understandably, class 1 or class 2 HELLP syndrome patients are more
likely to have complications over patients with class 3 HELLP syndrome.
However, the outcome of most of the pregnant patients with HELLP
syndrome is generally good and they recover completely.
Associated
complications may include pulmonary edema, acute renal failure, DIC,
abruptio placentae, liver hemorrhage/rupture/failure, adult respiratory
distress syndrome, stroke, sepsis, death, wound hematoma, blood product
transfusion with its associated risks, and ascites (Table 9). Though not
always, the risk of serious morbidity correlates with increasing
severity of maternal symptoms and laboratory abnormalities. Marked
ascites of a volume of greater than one liter, is associated with a
higher incidence of cardiorespiratory complications29. While the
postpartum onset of HELLP syndrome increases the risk of renal
complications and pulmonary edema30, the presence of abruption increases
the incidence of DIC17,30. Other comorbid conditions such as lupus,
diabetes, fetal demise, eclampsia and peripartum hemorrhage increase the
complications associated with HELLP syndrome.
Liver
infarction is another possible complication, which may be manifest by
fever, right upper quadrant pain and marked elevation of transaminases.
This diagnosis can be confirmed by liver ultrasound, and typically the
outcome of these patients is favorable following delivery.
Perinatal
mortality ranges from 10-20% in HELLP syndrome8,19. This high mortality
is associated with early gestational age (<28 weeks) and its
complications including growth retardation and abruption of
placenta18,19,31. Incidence of preterm delivery is up to 70%, with 15%
prior to 28 weeks gestation16,19. Infants of mothers with HELLP syndrome
have high rates of respiratory distress syndrome, bronchopulmonary
dysplasia, intracerebral hemorrhage, necrotizing enterocolitis and
neonatal thrombocytopenia. Although neonatal thrombocytopenia occurs in a
substantial percentage (38%) of newborns, a higher incidence of
intraventricular hemorrhage has not resulted when compared with controls
matched for same gestational age with no association of HELLP syndrome
32-34.
Patients with HELLP syndrome have a higher incidence of
preeclampsia (20%) in subsequent pregnancy, especially those patients
who develop HELLP during the second trimester. The overall incidence of
recurring HELLP syndrome in subsequent pregnancy is less than 5%.
Although aspirin and calcium have been tried, there is no current
preventive therapy for recurrent HELLP syndrome. However, because of
relatively low incidence of recurrence, subsequent pregnancy is
generally not discouraged. Interestingly, the incidence of preterm
delivery, fetal growth restriction, abruptio placentae and fetal death
is higher in subsequent pregnancies for these mothers, even in the
absence of preeclampsia or recurrent HELLP syndrome. Therefore, close
follow up is crucial in subsequent pregnancies.
The use of oral
contraceptives is not typically contraindicated in these patients
outside of pregnancy unless an associated thrombophilia exists. Some
recommend a thrombophilia work up, including that for antiphospholipid
antibody syndrome, in patients with atypical early presentations of
HELLP syndrome.
Despite voluminous literature on this disease
entity, its diagnosis and management remains unfortunately
controversial. More work needs to be done on this topic.
References
