Postgraduate Training Course in Reproductive Health/Chronic Disease

The management of preeclampsia complicated by HELLP syndrome

Review prepared for the 12th Postgraduate Course in Reproductive Medicine and Biology, Geneva, Switzerland

Didi Danukusumo, M.D.
Division of Maternal Fetal Medicine
Department of Obstetrics and Gynaecology
Fatmawati Hospital, Jakarta
Indonesia
Tutor: Dr. Rita Kabra
Department of Reproductive Health and Research
World Health Organization, Geneva
Switzerland

See also presentation

Abstract

OBJECTIVE: To review the management of preeclampsia complicated by HELLP syndrome.

METHODOLOGY: Systematic review of the literature.

RESULTS: Management of preeclampsia complicated by HELLP syndrome is still controversial. The only known definitive cure remains delivery. Until recently, all patients with a diagnosis of severe preeclampsia/HELLP syndrome were thought to need immediate delivery. Within the last years, expectant management of such patients has been reported with good success. The goal for managing preeclampsia with HELLP syndrome is ultimately to protect the mother and foetus and to prevent disease progression to eclampsia.
Some authors recommend that pregnancies older than 32-34 weeks should be delivered. Before 32-34 weeks, expectant management, if possible in a tertiary referral hospital, should be considered with the aim of improving the condition of the mother and the foetus with conservative treatment.
Vaginal delivery is generally preferable to cesarean section. Performance of cesarean section was associated with increased maternal morbidity. HELLP syndrome, by itself, is not an indication for cesarean section. Induction of labour is a reasonable option in the preeclamptic patient requiring delivery but clinical circumstances ultimately must dictate the delivery route.

CONCLUSION: Although it is still controversial, whether termination immediately or expectant management is better, it is universally agreed that 32 – 34 weeks gestation is the time for termination of pregnancy. Conservative management including the use of magnesium sulphate, antihypertensive agent, corticosteroid, plasma volume expansion give better result compared to immediate termination.

Introduction

Fatmawati Hospital in Jakarta, Indonesia is a tertiary referral hospital, with a Maternal Mortality Ratio 502.2/ 100,000 live birth in 2002 (9 maternal deaths among 1792 live birth). It is the only state hospital in the Southern part of Jakarta and serves people coming from 11 sub-district area at South Jakarta Municipalities, Tangerang District and the City of Depok. The two leading causes of maternal mortality were post partum haemorrhage (66.7%) and preeclampsia complicated by Haemolysis, Elevated Liver enzyme and Low Platelets count (HELLP) syndrome (22.2%) (1). The referral network from the public health centre and maternity clinics to the hospital had been created in an attempt to reduce maternal mortality.
When we examined the cause among maternal deaths caused by post partum haemorrhage, we found that the patients come too late to the hospital and very often in critical condition. But for preeclampsia complicated by HELLP syndrome, the most common cause of death was because of the difficulties in management at the hospital. The Case Fatality Rate (CFR ) for post partum haemorrhage was 0.4% in 2001 and 2.4% in 2002 . While for preeclampsia/eclampsia the CFR was 3.7 % in 2001 and 1.3% in 2002 (1).
HELLP syndrome is a special type of severe preeclampsia that constitutes a management dilemma for obstetricians. The high maternal and perinatal morbidity associated with it mandates continuing efforts to find an effective treatment. Iatrogenic preterm delivery increases the risk of adverse neonatal outcome. Prolongation of pregnancy, in theory, may be favourable for the foetus whereas it remains controversial whether maternal condition is further jeopardized by expectant management (2,3,4).
This systematic review aims at the management of preeclampsia complicated by HELLP syndrome, with special interest on the implementation of the results in Indonesia generally or more specific at the Fatmawati Hospital as the only referral hospital in South Jakarta.

Objective

To systematically review the literature on the management of preeclampsia complicated by HELLP syndrome.

Diagnosis of preeclampsia complicated by HELLP syndrome

The occurrence of haemolysis (H), elevated liver enzymes (EL) and low platelets (LP) has long been recognized as complications of preeclampsia. In 1982 Weinstein introduced the acronym HELLP for these laboratory abnormalities, however, cut-off levels for abnormality were not stated. Why some women with preeclampsia develop HELLP syndrome and others not is poorly understood. Haemolysis, defined as the presence of microangiopathic haemolytic anaemia, is the main clinical symptom of the HELLP syndrome. It is thought to result from the passage of red blood cells through small blood vessels with intima damage and fibrin deposition. The signs of intravascular haemolysis in the HELLP syndrome are: schistocytes, burr cells and polychromasia in peripheral blood smears, haptoglobin consumption, increase in bilirubin and lactic dehydrogenase levels. Hepatic involvement in the HELLP syndrome is associated with periportal and/or focal parenchymal lesions with large hyaline deposits of fibrin-like material. These deposits of fibrin-like material, seen in the sinusoids, may obstruct blood flow and cause cellular damage and distension of the liver capsule resulting in right upper-quadrant or epigastric pain and elevated liver enzymes. Another defining sign of HELLP syndrome is a decrease in circulating platelets. Some unknown factor leads to undue intravascular platelet activation resulting in the release of thromboxane A₂ and serotonin. Thromboxane A₂ and serotonin cause vasospasm, platelet aggregation, and further enhance endothelial damage already present in preeclampsia. The fact that thrombocytopenia occurs secondary to increased platelet consumption or destruction is in concurrence with the finding of increased megakaryocytes in bone marrow studies (2).
The reported incidence of HELLP syndrome among patients with preeclampsia ranges from 4 to 12% depending on the criteria that are used to define the syndrome (2,3,4). The incidence is highest among older, white and multiparous patients. HELLP syndrome occurs in 30% of cases postpartum, with the majority developing within 48 h after delivery (2,3). Standardized laboratory values to diagnose the syndrome were suggested by Witlin and Sibai (3). The following criteria to diagnose the HELLP syndrome were proposed: (1) haemolysis, defined by abnormal peripheral blood smear, increased bilirubin (≥1.2 mg/dl [ ≥17 µmol/l]), increased lactic dehydrogenase (LDH>600 U/l); (2) elevated liver enzymes, defined as increased aspartate aminotransferase (ASAT ≥70 U/l or 3 standard deviations above the mean pertinent to the hospital laboratory) and increased LDH; (3) low platelets, defined as platelet count <100×10⁹ cells/l. Using these strict criteria the incidence of HELLP syndrome among patients with severe preeclampsia-eclampsia in a tertiary care centre was 20–25% (2,3). Another definition uses a triple classification system in which HELLP syndrome is defined by the presence of low platelets (<150×10⁹ cells/l), evidence of haemolysis, and increased levels of LDH and ASAT or alanine aminotransferase (ALAT), with thresholds for LDH and transaminase level abnormalities at the upper limits of normal pregnancy values pertinent to the hospital laboratory. Classification is than based on platelet count: class 1, ≤50×10⁹ cells/l; class 2, between >50×10⁹ and ≤100×10⁹ cells/l; class 3, between >100×10⁹ and ≤150×10⁹ cells/l. With this classification system the incidence of HELLP syndrome (class 1 and 2) was 24.4% among patients with severe preeclampsia. Among patients with class 1 and 2 HELLP syndrome the incidence of eclampsia and coagulation abnormalities was 12.0% and 12.2%, respectively. Identifying patients with class 3 HELLP syndrome has little clinical significance (2,3,4).
It should be emphasized that these classifications or strict cut-off values are quite arbitrary. Basically, HELLP syndrome means preeclampsia with signs of organ involvement, and as such severe preeclampsia. Maternal and perinatal prognosis is primarily determined by the gestational age at onset, and the moment of clinical diagnosis, and not by the presence or absence of signs and symptoms suggestive of HELLP syndrome (2,3,4) (Tables 1 and 2).

Table 1. Clinical Symptoms and Signs of Preeclampsia complicated by HELLP syndrome

• Blood Pressure
  • > 160 mmHg systolic
  • > 110 mmHg diastolic
• Pulmonary oedema
  • Dyspnoea
  • Chest discomfort
  • Tachyon
  • Tachycardia
  • Pulmonary rate
  • CXR
• Oliguria < 500 ml per 24h
• Symptoms of end organ involvement
  • Headache or visual disturbance
  • Clonus or deep tendon hyperreflexia
  • Epigastric or Right upper quadrant pain
• Fetal involvement
  • Fetal growth restriction
  • Oligohydramnios
  • Absent fetal movements
  • Absent or reversed umbilical end-diastolic Doppler flow velocity waveforms

Modified from (2).

Table 2. Laboratory Diagnostic Criteria for HELLP syndrome*

• Haemolysis
  • Abnormal peripheral smear : schistocytes, burr cells and polychromasia
  • Total bilirubin level > 12 mg/dL
  • Lactate dehydrogenase level > 600U/L
• Elevated liver function test result
  • Serum aspartate amino transferase level > 70U/L
  • Lactate dehydrogenase level >600 U/L
• Low platelet count
  • Platelet count < 100 000/mm³

*) The Laboratory diagnostic criteria used at the University of Tennessee Division of Maternal Fetal Medicine (Memphis TN) (3).

Management of preeclampsia complicated by HELLP syndrome (Table 3)

Should preeclampsia complicated by HELLP syndrome be managed conservatively or by termination of pregnancy is still controversial. The only known cure remains delivery. Until recently, all patients with a diagnosis of severe pre-eclampsia/HELLP syndrome were thought to need immediate delivery. Within the last several years, expectant management of such patients has been reported with good success (2,3,4). The goal for managing pre-eclampsia including HELLP syndrome is ultimately to protect the mother and foetus and to prevent disease progression to eclampsia (4).
Durig from the Universitäts-Frauenklinik, Inselspital Bern mentions that conservative management of HELLP-syndrome is not recommended because it has not been validated in prospective controlled studies (5).
Curtin et al., at the Department of Obstetrics and Gynaecology, Medical College of Ohio, Toledo, USA, reported the lowest perinatal mortality rates6 with aggressive management (expeditious delivery).
Gardeil et al., at the Department of Obstetrics & Gynaecology, University College Hospital Galway, mention that conservative management is not an option when HELLP syndrome occurs long before fetal viability has been reached (7). Peeva, Chang and Zeng mention that in their experience prompt delivery is the treatment (8,9,10).
The necessity to terminate pregnancy immediately when HELLP syndrome is diagnosed has been challenged by some authors (11,12,13,14). Haddad et al. compared 32 cases of HELLP syndrome between 28 and 32 weeks' gestation with 32 matched cases of severe preeclampsia without HELLP syndrome, all managed expectantly with plasma volume expansion and vasodilatation and found no significant differences in maternal or neonatal outcome (11). Van Pampus et al. found that severe maternal complications occurred at the onset of HELLP syndrome and were not preventable by immediate termination of pregnancy (13,14).
The most important factors for successful management of such patients is meticulous medical management in a tertiary centre by a skilled team of perinatologists and anaesthesiologists familiar with the clinical manifestations of HELLP syndrome (4,15).
Some authors suggest that pregnancies, complicated by HELLP syndrome should be delivered at 32-34 weeks. Before 32-34 weeks, expectant management is generally possible in a tertiary referral hospital, aiming to improve the condition of the mother and the foetus with conservative treatment (19,29).

The Conservative treatment (Table 4)

1. Magnesium Sulphate

Magnesium sulfate remains the drug of choice for the treatment of pre-eclampsia for the purpose of preventing progression to eclampsia. In the past, some controversy existed as to whether more standard anti-convulsant medication should be utilized to manage this condition (4). The result of the Magpie Trial showed that magnesium sulfate reduces the risk of eclampsia, and it is likely that it also reduces the risk of maternal death. At the dosage used in the trial it does not have any substantive harmful effects on the mother or child, although a quarter of women will have some side-effects (20).
Two recent reviews published in the Cochrane library, concluded that magnesium sulfate seems to be a superior agent for the prevention of seizures and for the prevention of current seizures when compared to phenytoin and diazepam (30,31). In most institutions, magnesium sulfate is initially administered in a 4–6-g i.v. bolus over 20 min, followed by a continuous infusion ranging from 1 to 3 g/h. The continuous rate is largely determined by the renal function of the recipient (4).

2. Antihypertensive agents

Evidence exists that the use of antihypertensive drugs in pregnancy-induced hypertensive disorders associated with severe hypertension is beneficial (2). The objective of treatment is to avoid vascular damage due to blood pressure elevation without causing excessive reduction in blood pressure that would critically affect uteroplacental perfusion (2). The most commonly used threshold for treatment is a sustained diastolic blood pressure of 110 mmHg or higher (2,3,4). There are several antihypertensive drugs that are appropriate during pregnancy. Suitable oral therapeutic agents in the less acute setting include methyldopa, beta blockers (labetalol or oxprenolol) and calcium channel blockers (nifedipine). In the more acute setting, intravenous agents may be required and reasonable selections include intravenous beta blockers (labetalol), hydralazine, nitroglycerin or sodium nitroprusside (4).
A Cochrane systematic review on drugs for the treatment of very high blood pressure during pregnancy concludes that the choice of antihypertensive should depend on the experience and familiarity of an individual clinician with a particular drug, and on what is known about adverse maternal and fetal side effects. Exceptions are diazoxide and ketanserin, which are possible not first choices (32).

3. Volume expansion

Women with established severe preeclampsia/HELLP syndrome prior to delivery often have a contracted circulating intravascular volume and it can be reasoned that plasma volume expansion should be given in an attempt to improve the maternal systemic and uteroplacental circulation. It should be remembered that intravascular volume expansion carries the risk of volume overload, which may lead to pulmonary or cerebral oedema in women with established preeclampsia in whom colloid osmotic pressure tends to be low. Plasma volume expansion may be particularly hazardous after delivery, when venous volume usually rises. Repeated doses of volume loading should only be applied with careful monitoring of maternal and fetal condition (2,4,9).

4. Corticosteroids

The use of corticosteroids was recommended after the observation that its administration for inducing fetal lung maturation exerted a temporary beneficial effect on the laboratory parameters of HELLP syndrome in the mother. Studies were undertaken to evaluate the effect on antepartum and postpartum HELLP syndrome and to establish the most effective corticosteroid regimen. Recovery was accelerated by corticosteroid administration in the puerperium. Hematologic abnormalities recur after completion of the therapy. Thus far, high-dose corticosteroids have shown particular promise in stabilizing the condition of patients long enough to temporarily postpone delivery (e.g., in order to facilitate the transfer to a tertiary care centre) and in expediting patient recovery following delivery (11,12,21,22,23,24).
Some negative fetal and maternal sequelae have been reported with multiple courses of antenatal corticosteroid administration. Further studies are necessary to evaluate the effects of extended use of corticosteroids for the indication of maintaining stabilization to allow for temporizing management (2).

5. Prostacycline

Intravenous prostacyclin is a powerful vasodilator and the most potent inhibitor of platelet aggregation known. In a canine model both prostacyclin and ketanserin were effective as platelet aggregation inhibitors in 97 and >90% of animals exposed to the respective drugs. Prostacyclin was used with success in the treatment of some patients with trombocytopenia and HELLP syndrome (2,16).

6. Serotonin2-receptor blockers

Because preeclampsia has been recognized as an endothelial disease resulting in increased platelet aggregation the selective blockade of the vasoconstrictor and platelet aggregating effects of serotonin mediated by its serotonin (S₂)-receptor may provide an attractive pharmacotherapeutic option in the management of severe preeclampsia. Blockade of the S₂-receptor with ketanserin may counteract serotonin-dependent vasoconstriction and increased platelet aggregation that is characteristic of preeclampsia.
Beneficial effects of ketanserin administration on HELLP syndrome, a rise in platelet count and a marked relief of epigastric pain, have been reported by Bolte et al. They concluded that ketanserin could be especially useful in the management of HELLP syndrome. In a study comparing the use of ketanserin with dihydralazine the incidence of HELLP syndrome was significantly lower in patients receiving ketanserin. In a retrospective study, including 169 patients receiving ketanserin and 146 patients receiving dihydralazine, laboratory data pointed to a beneficial effect of ketanserin on platelet count and liver enzymes. Furthermore, a significant difference in the occurrence of postpartum HELLP syndrome in these severe preeclamptic patients was found in 11% with ketanserin versus 30% with dihydralazine (2,16).

7. Plasma exchange therapy

Some more specific therapies for the treatment of HELLP syndrome have been proposed. Analogous to the treatment of other microangiopathic haemolytic disorders such as haemolytic uremic syndrome and thrombotic trombocytopenic purpura the use of exchange plasmapheresis with fresh frozen plasma has been advocated as treatment in persistent cases of HELLP syndrome. Because exchange plasmapheresis is an invasive and expensive procedure of questionable value that carries a high risk of plasma-transmitted infections its use is not generally recommended (2,23,26,27,28).

Table 3. Review of management of preeclampsia/HELLP syndrome

Table 4. Conservative therapy for HELLP Syndrome

Termination of the pregnancy

Pregnancies at 32 - 34 weeks of gestation are universally agreed as the right time for termination of severe preeclampsia complicated by HELLP syndrome. Vaginal delivery is generally preferable to cesarean section, even in patients with manifestations of severe disease. Performance of cesarean section was associated with increased maternal morbidity in women with HELLP syndrome. HELLP syndrome, by itself, is not an indication for cesarean delivery. Induction of labour is a reasonable option in the preeclamptic patient requiring delivery but clinical circumstances ultimately must dictate the delivery route (2,3,4).
The choice of anaesthetic technique is another controversial issue relating to the intrapartum care of preeclampsia. Every method of analgesia and anaesthesia carries risks that can be minimized but not eliminated. Aggravation of severe hypertension by tracheal intubation can cause intracranial haemorrhage, left ventricular failure and pulmonary oedema. In contrast, excessive reductions in blood pressure in the mother resulting from the use of regional techniques can decrease uterine blood flow and threaten the foetus. The American College of Obstetricians and Gynaecologists suggests that epidural anaesthesia (or parenteral analgesia) is suitable for labour pain relief, and regional or general anaesthesia is acceptable for cesarean section, depending on the individual clinical circumstances (3,24).
Thus, individual patient concerns, clinical circumstances, resource availability, and operator experience should all play a part in the choice of anaesthetic technique. Significant thrombocytopenia and placental abruption are relative contraindications to conduction anaesthesia. On the other hand, airway pathologies might favour a regional approach. Complications are not avoidable, even with proper techniques. However, careful selection of the best technique for a particular given patient will minimize whatever risks are present (3,24).

Conclusion

Preeclampsia complicated by HELLP syndrome is one of the causes of maternal mortality. Until recently, all patients with a diagnosis of severe pre-eclampsia/HELLP syndrome were thought to need immediate delivery. Within the last several years, expectant management of such patients has been reported with good success. The goal for managing pre-eclampsia/HELLP syndrome is ultimately to protect the mother and foetus and to prevent disease progression to eclampsia.
It is universally agreed that a pregnancy from 32-34 weeks should be delivered. Before 32-34 weeks, expectant management is generally possible in a tertiary referral hospital, to improving the condition of the mother and the foetus with conservative treatment.
Vaginal delivery is generally preferable to cesarean section. Performance of cesarean section was significantly associated with increased maternal morbidity in women with HELLP syndrome. HELLP syndrome, by itself, is not an indication for cesarean delivery. Induction of labour is a reasonable option in the preeclamptic patient requiring delivery but clinical circumstances ultimately must dictate the delivery route.

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