Severe Hepatic Dysfunction in Pregnancy

8/13/2019 Severe Hepatic Dysfunction in Pregnancy

1/15

Review

QJM

Severe hepatic dysfunction in pregnancy

T.M. RAHMAN and J. WENDON1

From the Department of Intensive Care Medicine, St Thomas Hospital, London, and1Institute of Liver Studies, Kings College Hospital, London, UK

Summary

Acute liver disease in pregnancy may have fatalconsequences. Pre-eclampsia, HELLP syndromeand acute fatty liver of pregnancy form a spectrumof disease that range from mild symptoms tosevere life-threatening multi-organ dysfunction.Early recognition of signs and prognostic indicators

may enable prompt referral to specialist centresproviding the multidisciplinary support requiredto reduce maternal and perinatal morbidity andmortality. We review the common causes of acutehepatic failure associated with pregnancy, andcurrent management practices.

IntroductionPregnancy induces physiological, hormonal andphysical changes. These changes may be respon-

sible for the incidence of acute hepatic failure (AHF)in pregnancy both pre- and post-partum. Acute fattyliver of pregnancy (AFLP), pre-eclampsia andHELLP (haemolysis, elevated liver enzymes, andlow blood platelet count) syndrome have beendemonstrated as being the main causes of severehepatic failure in pregnancy. They are thought torepresent a spectrum of the same pathologicalprocess. They are described as being specific tothe trimester in which they appear, but this is notalways the case. We will be concerned with thepathological processes taking place that specif-

ically affect the liver during pregnancy, increasingmorbidity and mortality in both mother and fetus.

Pre-eclampsia, HELLP syndrome and AFLP aresignificant causes of maternal and perinatal mor-bidity and mortality. Several retrospective studiesindicate an incidence of 1 in 13 000 pregnancies forAFLP compared to 16 per 1000 deliveries for theHELLP syndrome. Pre-eclampsia occurs in 5% of allpregnancies usually occurring in the second or third

trimester. These processes may be involved withrarer complications, including veno-occlusive dis-

ease, hepatic rupture, haematoma, and haemor-rhage, and are associated with significant mortality.In a recent case-control study, risk factors wereidentified as: age over 34 years, non-White ethnicgroup, past or current hypertension, previouspostpartum haemorrhage, delivery by emergencycaesarean section, antenatal admission to hospital,multiple pregnancies, social exclusion, and takingiron or anti-depressants at antenatal booking, whichwere all independently associated with morbidityafter adjustment.1 Prior to 1980, the mortality asso-ciated with AFLP was in excess of 80%, and)25%

for the HELLP syndrome. Mortality has since beenreduced, which is thought to be due to earlierrecognition, prompt effective treatment, and referralto specialist centres when required. Hyperemesisgravidarum and cholestasis of pregnancy will not bereviewed, as they are usually benign conditions thatdo not cause severe hepatic impairment.

The thrombophilias are a distinct group ofabnormalities that induce a pro-coagulant state.

Association of Physicians 2002

Address correspondence to Dr T.M. Rahman, Department of Intensive Care Medicine, St Thomas Hospital, Lambeth

Palace Road, London SE1 7EH. e-mail: [email protected]

Q J Med2002; 95:343357

byguestonApril4,2012

http://qjmed.oxfordjournals.org

/

Dow

nloadedfrom
http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/http://qjmed.oxfordjournals.org/


2/15

These may present with recurrent spontaneous mis-carriages, venous and arterial thrombosis duringthe course of pregnancy, affecting hepatic vessels,causing hepatic failure and threatening the preg-nancy.2 Amongst the pro-coagulant disorders are,hereditary conditions such as protein S, protein C,

and anti-thrombin III deficiency; mutations andpolymorphisms for factor V Leiden, methylene-tetrahydrofolate reductase (MTHFR), angiotensin-converting enzyme and prothrombin genes;hyperhomocysteinaemia; and combinations ofthese pathologies.3,4 Other pro-coagulant disorderscommonly seen are those associated with systemiclupus erythematous (SLE). SLE is associated withanticardiolipin antibodies, lupus anticoagulant,and anti-b2-glycoprotein antibodies (anti-b2-GPI),which are all associated with the antiphospholipidsyndrome, and hepatic abnormalities that arise

from hepatic infarction and venous embolisms.5

Other causes of hepatic abnormality in preg-nancy include the viral hepatides. These are rare inthe UK and more commonly seen in the Far East,although there has been increasing awareness therisks of contracting of hepatitis C (HCV) in preg-nancy and the rates of vertical carriage to the childupon delivery. One study examined hepatitismarkers in 127 pregnant females: 73/127 (57.5%)had hepatitis E (HEV) infection, and 58% of theseHEV-infected pregnant females developed acutehepatic failure (AHF). Hepatitis B infection (HBV)

was observed in 19%

, and 20%

remained non-reactive for seromarkers of HAVHEV. Mortalityduring the pregnancy was highest (56%) amongHEV-infected AHF cases during third trimester ofpregnancy.6 This study is not typical of the UK.

Normal liver in pregnancyPhysiological changes that take place in pregnancyhave effects on all organs in the body. The increasein plasma volume has been well-documented asincreasing by about 40%, and this is associatedwith an increase in the cardiac output and heart ratewhich peaks at 32 weeks. The blood flow in theliver itself remains the same or in some studiesdecreases (35% of the cardiac output in non-pregnant females and 28% of cardiac output inpregnant females).

Abnormal or normal for pregnancy laboratorytests have been recognized. In 1997, a prospec-tive analysis of AST, ALT, bilirubin and GGT in430 pregnant women found that these testswere about 20% lower in pregnant women com-pared to laboratory reference ranges. Lunzer and

others have found increased alkaline phosphatase(ALP), triglycerides, cholesterol, caeruloplasmin,

transferrin, anda1- and a2-globulins, and reducedserum albumin, urea and uric acid concentrationsin the third trimester.7,8

Significant changes also occur in the haemato-logical adaptation to pregnancy. The increasedplasma volume may indicate a spurious anaemia.

Anaemia seen in pregnancy is usually associatedwith a raised mean corpuscular volume, and ismacrocytic with a normoblastic bone marrow. Theplatelet count and mean platelet volume remainunchanged during the gestational period.9,10 Innormal pregnancy, the coagulation cascade isin a state of activation, based on the increasedconcentrations of clotting factors and raised high-molecular-mass fibrinogen complexes. The meas-ured prothrombin time and partial thromboplastintimes remain unchanged. Levels of anti-thrombin IIIand protein C are essentially unchanged in normal

pregnancy, in contrast with the level of protein S,which serves as a cofactor to activated protein C.This decreases to levels similar to those ofcongenital protein S deficiency.4,11

Pre-eclampsia/eclampsiaPre-eclampsia is characterized by the presenceof hypertension, proteinuria and non-dependentoedema. It affects about 57% of all women duringpregnancy and a subset of these patients (as high as

65% in one series12

) may also have HELLPsyndrome. Pre-eclampsia usually occurs in thesecond and third trimesters, but is also seen,less frequently, before 20 weeks gestation. Com-plications include maternal hypertensive crises,renal impairment, hepatic rupture, infarction andneurological complications including seizures,cerebro-vascular accidents and increased perinatalmorbidity and mortality.8,13

Aetiology

The available evidence suggests that there areseveral distinct origins of pre-eclampsia, each withits own pathological characteristics and naturalhistory, but placental ischaemia offers a unifyinghypothesis.

Uteroplacental ischaemia

Changes in the uteroplacental circulation transformthe vascular supply to a low-pressure high-flowsystem. Disturbed penetration of the trophoblastinto the spiral arteries leads to hypoperfusion andlocal hypoxia, activating the endothelium with

abnormal expression of integrins, cadherins andother immunoglobulin superfamily members,

T.M. Rahman and J. Wendon344



/

Dow

nloadedfrom


3/15

which are involved in the pathophysiology ofpre-eclampsia.14

Endothelial dysfunction

Placental hypoperfusion leads to activation of theendothelium, with alteration of vasomotor tone,initiation of the coagulation cascade, increasedadhesiveness to platelets and greater thrombo-genicity.15,16 Nitric oxide has a critical role in vaso-motor homeostasis and upregulation of the nitricoxide synthase pathways has been demonstratedin normal pregnancy.17,18

Cytotoxic factors

Uterine tissue from pre-eclamptic patients hashigher levels of thromboxanes, isoprostanes andlipid peroxides and reduced prostacyclin(PGI2).19 Maladaptation has been described inpre-eclamptic women, with an imbalance of thePGI2: thromboxane ratio facilitating increasedvascular sensitivity, increased systemic resistance,reduced plasma volume and reduced cardiacoutput.20

Genetic

Studies have demonstrated a familial association inthe occurrence of pre-eclampsia. Several studieshave demonstrated increased risk of pre-eclampsiaamongst sisters, daughters and grandparents. Morerecently human leukocyte antigen (HLA-DR) ana-lysis of compatibility between pre-eclampticwomen and their partners showed a statisticallyhighly significant increase of the female-to-malecompatibility (p= 0.0003) and a lower but signific-ant male-to-female compatibility in comparisonwith controls (p= 0.014). This suggests that HLA-DR homozygosity and reduced antigenic disparityare associated with a major risk of pre-eclampsia.21

Histopathology

The liver in pre-eclampsia shows peri-portalfibrin deposition, haemorrhage and hepatocellularnecrosis. This may be due to focal segmentalhepatic vasospasm. AFLP and pre-eclampsia havesimilar histological patterns, and both developmicrovesicular steatosis.12

Clinical course

Most patients present following routine screeningwhere they have been found to be either hyper-tensive and or passing protein in the urine. Magannet al. (Table 1) demonstrated that nausea, vomitingand epigastric pain in association with admission

laboratory values in excess of the cut-offs for lactatedehydrodgenase, aspartate aminotransferase, and

uric acid concentrations, predict high morbidity inpatients with severe pre-eclampsia.13 These factorsare independent of, and additive with, the risingmaternal risk associated with decreasing platelet

counts.22

Uric acid remains one of the best markersfor assessing disease severity and progression, andthis will increase as gestation proceeds.

The use of aspirin in prevention of pre-eclampsiais controversial; however, a recent metanalysisconcluded that low-dose aspirin therapy reducedthe incidences of pre-eclampsia among womenwith poor obstetric histories and among high-risknulliparous women, but was ineffective amongwomen with underlying medical illness. It wasmarginally effective among low-risk nulliparouswomen, and benefit for women with multiple

gestations remained unclear. The differential effectsof low-dose aspirin therapy in the various riskgroups are probably a result of varying roles in thegroups of abnormal arachadonic acid metabolismin mediating pre-eclampsia.23,24

More recently, a meta-analysis examined the useof antiplatelet drugs in pre-eclampsia in 39 trials(30 563 women). Use of antiplatelet drugs wasassociated with a 15% reduction in the risk of pre-eclampsia, and an 8% reduction in the risk ofpreterm birth. There were no significant differencesin other measures of outcome. The authors con-cluded that antiplatelet drugs, largely low-doseaspirin, have low-to-moderate benefits when usedfor prevention of pre-eclampsia.25

Hypertension

Control of hypertension reduces the morbidityand mortality associated with this conditionfor both mother and fetus. Commonly used anti-hypertensives include methyldopa and beta-blockers, of which labetalol is commonlyused (combined a- and b-blocker, also reducesvasoconstriction).26

Calcium channel blockers (nifedipine) wererecently recommended as possible first-line

Table 1 Risk factors for severe pre-eclampsia and HELLPsyndrome34

Clinical Laboratory tests

Epigastric pain Platelets -50 000/mm3

Nausea Creatine phosphokinase )200 IU/lVomiting Lactate dehydrogenase )1400 IU/l

Aspartate transaminase )150 IU/lAlanine transaminase )100 IU/lUric acid )7.8 mg/dlSerum creatinine )100 mg/dl4qDipstick urine

Severe hepatic dysfunction in pregnancy 345



/

Dow

nloadedfrom


4/15

agents. However, careful clinical observation isrequired when administering magnesium sulphate,which may result in profound hypotension.Hydralazine is used for acute management ofhypertensive emergencies, reducing peripheralresistance, and improving cardiac output. Resistant

hypertension, severe proteinuria and hyperemesiswill require admission to hospital.7,27,28

Seizures

These may be related to focal cerebral vasospasmand cerebral hypoperfusion. The incidence ofseizures in pre-eclampsia is 4.9/10 000 maternities,in the UK. Pereiraet al. reported that 25% of thepre-eclamptic patients admitted in the Kings serieshad seizures; all were treated with anticonvulsanttherapy, including diazepam, phenytoin and mag-

nesium sulphate.29

In the Collaborative Eclampsiatrial, magnesium sulphate was superior to phenytoinand/or diazepam at preventing seizures.30 Patientstreated with magnesium sulphate also demon-strated a lower incidence of mechanical ventila-tion, pneumonia and fewer neonatal intensivecare admissions. It is thought to act as a mem-brane stabilizer, reducing intracerebral ischaemia.Care should be taken to monitor levels of mag-nesium sulphate; high plasma concentrations(e.g. in renal failure) may cause respiratory arrestwith paralysis of respiratory muscles. Other side-

effects include areflexia, weakness, nausea, flushes,somnolescence, diplopia and slurred speech.

Renal dysfunction

This occurs in two stages. The first involvesimpairment of tubular function, and is reflected bya reduction in uric acid clearance and developmentof hyperuricaemia. The second involves the impair-ment of glomerular filtration, with resulting inter-mediate selectivity proteinuria (albumin, transferrin,c-globulin). Gross proteinuria occurs late in thepregnancy and (at )0.5 g/day) may lead to man-datory delivery. The systemic consequences arehypoalbuminaemia and reduced plasma oncoticpressure. The loss of the selectivity of the glom-erular tubules resolves after delivery. Acuterenal failure may result from placental abruptionreducing renal blood flow.13,31

Haematological factors

Thrombocytopaenia and an increase in the meanplatelet volume have been described.9 Severalstudies have also demonstrated increased platelet

activation in pre-eclampsia, and this has beencorrelated with proteinuria and a raised serum

creatinine, suggesting a link between plateletactivation and renal microvascular damage.

Increased levels of factor-VIII-related antigen andfibrinopeptides may encourage platelet aggregationand clot formation, as has been demonstrated inpre-eclamptic women. Anti-thrombin III, protein C

and protein S are all reduced in pre-eclampsia,exacerbating the hypercoagulable state.11,32,33 Theprothrombin time and the partial thromboplastintime may remain normal.

Liver function tests

These are abnormal in 2030% of patients withpre-eclampsia,12 and are thought to reflect liverdysfunction resulting from vasoconstriction of thehepatic vascular bed, as demonstrated by Dopplerstudies in pre-eclamptic women. Alkaline phos-

phatase, which is often elevated in pregnancy, maybe further increased, likewise the transaminases.In severe cases of pre-eclampsia, with or withoutHELLP syndrome, abnormal transaminases may bepresent.34

Indications for delivery

After 36 weeks, fetal maturity can be assumed andcontinuation of the pregnancy has no benefit. Modeof delivery will be dictated by clinical circum-stances, but vaginal delivery is the preferred

route.

29

Severe pre-eclampsia may require early deliverydue to the increased risk to both mother and fetus(see Figure 1a and b). Premature delivery is asso-ciated with increased fetal mortality due to inade-quate lung maturation. Sibaiet al.35 investigated thepossibility of buying time or expectant manage-ment of patients at 2832 weeks with severe pre-eclampsia. Ninety-five women were randomized toexpectant management or prepared for delivery.It was possible to prolong the pregnancy for anaverage of 2.6 days to 15.4 days in the expectantgroup by optimization of hypertension, coagulo-pathy and the use of corticosteroids to enhance fetallung maturity. This significantly improved neonatalmortality without significantly increasing maternalmortality. Similar improvement has been seen inthe pre-term delivery of patients with HELLPsyndrome.3638

Intrapartum care

Meticulous fluid resuscitation may require theneed for central venous monitoring. Pre-eclampticpatients have increased sensitivity to volume shifts,

due to low plasma oncotic pressure, raised hydro-static pressure due to hypertension, and increased




/

Dow

nloadedfrom


5/15

capillary permeability reflecting endothelial dys-function, increasing susceptibility to pulmonaryoedema. Central venous pressure )10 cm ofwater indicates a risk of pulmonary oedema. Morecomplex patients will require admission to intensivecare for invasive intravascular haemodynamicmonitoring.

Postpartum care

In severe pre-eclampsia, intensive monitoring,correction of coagulopathy and thrombocytopaeniashould continue for 2472 h after delivery, as

patients are still susceptible to seizures, haemor-rhage and other complications including renal

failure, hepatic infarction, rupture and multi-organfailure.

HELLP syndromeThe haemolysis (H), elevated liver enzymes (EL) andlow platelets (LP) syndrome is a severe form of pre-eclampsia that threatens the patient and her fetus.Early reports described pre-eclampsia associatedwith microthrombi, thrombocytopaenia, coagulo-pathy and a poor prognosis.39 It may appear frommid-second trimester until several days postpartum.One study reports that two-thirds of patients will

be diagnosed antepartum, of which 10% will beidentified before 27 weeks, 20% in pregnancies

a

b

Figure 1. CT scans pre- (a) and post- (b) contrast of a 25-year-old woman presenting with pre-eclampsia. Following anelective caesarian section, she became encephalopathic and developed acute liver failure. Contrast-enhanced CT showsextensive necrosis throughout the right lobe with patchy necrosis also in the left lobe.




/

Dow

nloadedfrom


6/15

beyond 37 weeks and the majority between (70%)27 and 37 weeks. One third will develop HELLPsyndrome postpartum.40 There is an increasedincidence of HELLP in White women and multi-paras, which differs from pre-eclampsia. There is,however, an overlap, with a 412% incidence of

HELLP complicating pre-eclamptic disease. Pereiraet al.29 reported that all their patients with HELLPalso had pre-eclampsia.

Aetiology

The pathophysiology of normal pregnancy and pre-eclampsia are discussed above. HELLP syndromeand pre-eclampsia may well be part of the samespectrum of disease, with a common aetiology. Keyabnormalities include vasoconstriction, increasedvascular tone, platelet aggregation and an altera-

tion of the thromboxane : prostacyclin ratio. Thesechanges can be partly explained by the activationof complement and the coagulation cascade caus-ing multi-organ endothelial and microvascularinjury, and resulting in microangiopathic haemoly-tic anaemia, elevated liver enzymes (periportal andhepatic necrosis) and thrombocytopaenia.41

Clinical course

The presentation can often be non-specific withsubtle signs: most frequently nausea, epigastric

pain, or right upper quadrant pain, ranging infrequency from 3686%. A subset of patients withsevere pre-eclampsia present with symptoms ofheadache and visual changes. Hypertension may bepresent (16%) or absent (15%), and proteinuriamay be absent (6%) or just 1q on dipstick (9%).The majority of patients will present with hyper-tension and more severe signs and symptoms.42

Mortality amongst patients with HELLP has beeninvestigated: among 54 maternal deaths, 60% hadclass 1 disease, 35.6% had class 2 disease, and4.4% had class 3 disease. Events associated withmaternal deaths included cerebral haemorrhage(45%), cardiopulmonary arrest (40%), disseminatedintravascular coagulopathy (39%), adult respiratorydistress syndrome (28%), renal failure (28%), sepsis(23%), hepatic haemorrhage (20%), and hypoxicischaemic encephalopathy (16%). Delay in dia-gnosis of HELLP syndrome was implicated in 22 of43 deaths (51.1%).43

Several studies have tried to define theHELLP syndrome based on laboratory parameters(Table 2).42,44 Most classifications have attemptedto combine the elevation in hepatic enzymes andthe low platelet count. These parameters have also

been analysed to identify increased risk factorsassociated with severe disease.

Care must be taken to exclude other causes ofhaemolysis that may appear clinically similar,or that present laboratory data similar to HELLP.The differential diagnosis should include idio-pathic thrombocytopaenic purpura, systemic lupuserythematosis, haemolytic uraemic syndrome, and

AFLP (Table 3). HELLP syndrome carries a signif-icant risk to mother and fetus: about 13.5% for themother, with increased incidence of multi-organfailure, DIC and acute lung syndrome.45,46 Thehaematological abnormalities increase the risk ofspontaneous and post-partum haemorrhage, andthe need for blood products is 1050% for cor-rection of thrombocytopaenia and coagulopathy.Sibaiet al.42 reported eclampsia in 8% of patients,and in other series this had been as high as 30%.Other complications include pulmonary oedemaand acute renal failure, which are more common in

patients who develop HELLP postpartum.HELLP syndrome will affect the microvas-culature of the kidney and may lead to acute

Table 2 Two systems used to classify HELLP syndrome

Mississippi 3 Class System40 Tennessee System75

Class 1 Complete syndrome Platelets -50 000/mm3 AST and /or

ALT )40 IU/lClass 2Platelets-

100 000 mm3

Platelets 50000100 000/mm3

LDH )600 IU/lClass 3

AST )70 IU/lPlatelets 100000150 000/mm3

Incomplete syndromeHaemolysisqelevated

liver enzymesAny one or two

of the aboveLDH )600 IU/l

Table 3 The differential diagnoses when consideringHELLP syndrome

Differential diagnosis of HELLP syndrome

Thrombotic disordersThrombotic thrombocytopaenic purpuraHaemolytic uraemic syndromeSepsis and disseminated intravascular coagulopathy (DIC)Drug-induced haemolytic anaemias

Consumptive disordersAcute fatty liver of pregnancySepsis and DICHaemorrhage

OthersConnective tissue diseaseSystemic lupus erythromatous (SLE)Antiphospholipid syndromeProcoagulant disorders




/

Dow

nloadedfrom


7/15

tubular necrosis. This may be reversible; however,more permanent damage has been recordedwith severe cortical necrosis. Renal lesions aresimilar to that described in pre-eclampsia withglomerular enlargement, mesangial thickeningand capillary narrowing. Patients may require

temporary haemofiltration, or in the long term,haemodialysis.31

HELLP and AFLP both affect the liver, HELLPbeing more common, (1 : 5000 deliveries vs. AFLP1 : 1316 000 deliveries).29 AFLP usually occurslater in gestation and causes a reduction in thesynthetic function of the liver, resulting in hypo-glycaemia, elevated ammonia, and an increasedcoagulopathy. Disseminated intravascular coagulo-pathy is common to both AFLP and HELLP, butabnormal liver transaminases are commoner inHELLP. Histologically, periportal necrosis and vas-

cular microthrombi are present, as the disease pro-gresses there are more extensive areas of necrosisthat may lead to haematomas and eventually tohepatic rupture. This commonly occurs in theanterior aspect of the right lobe of the liver andhave been recorded as early as 16 weeks gestationto 3 days postpartum.

Hepatic rupture has been reported as a spon-taneous event, but is more frequent in the pres-ence of HELLP or severe eclampsia/pre-eclampsia(Figure 2). Sibai et al.47 recorded an incidence of1% and this occurred in the setting of abruptio

placentae, leading to massive haemorrhage andshock in four patients. This requires emergency sur-gical treatment, and Pereiraet al.29 suggested thatthis may be an indication for liver transplantation.Hepatic infarction, subcapsular haematomas andintraparenchymal haemorrhage have also beenrecorded. The severity of complications has ledauthors to recommend early referral to specialistliver centres where adequate imaging, surgical andtransplantation facilities are available. The fetus isalso at risk, with a perinatal mortality rate of 56367per 1000 births. The onset of HELLP is before term,and so the greatest risk is prematurity. Mortality isdue to early-onset HELLP on the verge of viability ordue to placental abruption.

Several groups have attempted to study pro-gnostic indicators to assess the severity of disease,and to predict at an early stage those with a pooroutcome. Martin et al.40,48 examined the plateletnadir: on this basis, patients were classified asclass 1 (platelets -50 000/mm3), class 2 (platelets50 000100 000/mm3) and class 3 (platelets100 000150 000/mm3). Class 1 and class 2 hada higher incidence of postpartum haemorrhageand a longer, more complicated recovery. Prophy-

lactic platelet infusions did not reduce com-plications. Patients who developed superadded

DIC were at greater risk of complications. Morerecently, Haddadet al.44 found that among womenwith HELLP syndrome, AfricanAmerican race wasa risk factor for eclampsia. Both acute renalfailure and abruptio placentae were associatedwith disseminated intravascular coagulopathy.

Laboratory parameters of HELLP syndrome werenot independent risk factors for adverse maternaloutcome.

Pereira et al.29 described 17 patients out of 32with AFLP, two of whom had HELLP, all withevidence of DIC. Barton et al.49 examined thecorrelation between abnormal liver function testsand severity of disease. There appeared to be nostrong correlation between liver function tests,histopathology and radiological investigations, theonly finding being that patients with thrombocto-peania were at a higher risk of subcapsular

haemorrhage and hepatic rupture. There are casereports illustrating massive elevation of liver func-tion tests in association with hepatic rupture,infarction and subcapsular haematomas.50,51

The natural history of HELLP is similar to that ofsevere pre-eclampsia: the disease becoming pro-gressively more severe until delivery. Experiencefrom patients treated expectantly has illustrated thatsome in this group may be stabilized and delivereddays later, reducing fetal morbidity. Pereiraet al.29

described seven patients in their series of 46women admitted to the Kings College Hospital.

All seven also had pre-eclampsia, with demon-strated encephalopathy, jaundice, renal failure,median platelet count of 39000/mm3 (range1989 000/mm3) and a median platelet countnadir of 31 000/mm3 (range 666 000/mm3) 2 daysafter admission. The correlation of deterioratingplatelet counts and the liver function tests suggestsrapid disease progression. Following delivery, mostpatients got worse for a short period, followed byclinical improvement with platelet counts returningto normal. Martin et al.40 demonstrated that thepostpartum period sees a nadir in platelet counts2448 h after delivery.

Maternal risk

Management of HELLP syndrome will incorporatethe investigative and supportive care that hasalready been described for pre-eclampsia.Although these conditions may be part of thesame spectrum of disease, HELLP syndrome ismore common among older multiparous women,whereas pre-eclampsia is commoner in youngnulliparous women. Therefore it is important tobe aware of and recognize maternal risk factors

that may increase maternal and perinatal morbidityand mortality. Approximately 80% of patients




/

Dow

nloadedfrom


8/15

with HELLP and or pre-eclampsia will havehypertension, which requires pharmacologicalintervention. Prevention of seizures with magnesiumsulphate as an infusion should be commenced.This may also have an effect in reducing plateletclumping by relaxing central and peripheral vas-culature. If magnesium sulphate is contraindicated,then phenytoin is the drug of choice.

Laboratory investigations

Once the physician is aware of the diagnosis,

initial laboratory investigations can be appro-priately ordered and interpreted. Modest changes

in the hepatic transaminases, platelet counts andalso the lactate dehydrogenase may be exhibited inthe early phase, and these will mandate furtherinvestigations to exclude other differential dia-gnoses. Disseminated intravascular coagulopathymust be excluded, with decreased fibrinogen andfibrin degradation products not usually appear-ing until the platelet count is below between50 000100 000/mm3 (Table 4).

Fetal risk

Having established and assessed maternal risk, fetalrisk must also be examined. Severity of the maternal

a

b

Figure 2. Plain abdominal CT scan (a) and contrast-enhanced CT scan (b) of the liver. These are from a patient presenting inher third trimester with severe pre-eclampsia. Following an emergency caesarian section, she developed severe right upperquadrant pain and deteriorated rapidly. Contrast-enhanced CT (b) confirmed the presence of a large area of arterialinfarction, a secondary right subcapsular haematoma and segmental Budd-Chiari syndrome. She had a successful livertransplant 2 days later.




/

Dow

nloadedfrom


9/15

and fetal condition will influence where and whendelivery should take place. Once assessed, ifgestational age is )34 weeks and the motherdisplays the criteria for Class 1 HELLP syndrome,delivery should take place within 24 h.

Corticosteroids

These have been advocated to accelerate fetalmaturity in deliveries of all pregnancies between2434 weeks except in specified cases. This is thesame protocol as in pre-eclampsia. This mayprovide a 2448 h period of transient improvementin the maternal condition and would then alsoallow for maturation of the fetal lungs prior todelivery.37,52 A retrospective study found a signific-ant reduction in the number of neonatal episodes ofintubation and mechanical ventilation. Maternalhaematological status also improved, with improve-ment or stabilization of platelet counts, lactatedehydrodgenase and liver function tests in those

treated with steroids. The improvement of plateletcounts were maintained if steroids were also admin-istered after delivery to the mother; this avoideda rebound thrombocytopaenia with associatedcomplications.53,54

Fluid management

Multi-organ endothelial injury, increased vaso-motor tone and relative hypoalbuminaemia makethe mother less tolerant to volume shifts and resultsin a predisposition to pulmonary oedema. Careful

fluid management is needed to prevent a reducedintravascular volume exacerbating pre-renal renal

failure; in contrast, overzealous resuscitation maylead to pulmonary oedema, ascites and peripheraloedema. Good management may be achieved bycentral venous pressure monitoring and, if required,more invasive haemodynamic monitoring in thesetting of an intensive care unit. Daily evaluation

of electrolyte status will influence fluid choices.55

Thrombocytopaenia

Thrombocytopaenia will increase the risk ofspontaneous bleeding, and may also complicateboth vaginal and caesarean deliveries. Platelettransfusion will be required for mothers withplatelet counts -50 000/mm3 prior to delivery orany surgical procedure that may take place, anda platelet count -30 000/mm3 will also requiretransfusion to reduce the risks of spontaneous

haemorrhage. This must be continued after thedelivery has taken place, as retroperitoneal,abdominal, subcapsular hepatic haematomas andhepatic rupture may occur in the postpartumperiod.

Labour

The natural history of HELLP syndrome is of rapiddeterioration following hospital admission, carefulassessment of maternal and fetal risk is needed.

Once assessed, corticosteroids may be adminis-tered, and delivery will follow quickly. Provision forneonatal care is needed, especially if gestation is-34 weeks. Infants may require ventilation andresuscitation, because of their immature lungdevelopment. Intraventricular haemorrhage andnecrotising enterocolitis have also been reported.55

Vaginal delivery is the preferred route; however,as described in the pre-eclampsia section, this maynot always be possible, and caesarean section maybe needed. The caesarean section rate is high withHELLP syndrome: one study reported a rate of 68%at a gestational age of 3034 weeks.56 Complica-tions of caesarean delivery include haemorrhage,haematomas, wound infection and dehiscence.Rarer complications are seen in patients whopresent with ascites.57 Patients with large-volumeascites will be at increased risk of congestiveheart failure, infection, acute lung injury and adultrespiratory distress syndrome in the postpartumperiod.46 Admission to the intensive care unit,invasive haemodynamic monitoring and judiciousfluid replacement will be required in this smallsubset of patients.

Hepatic haemorrhage and rupture may occur in

the peri- and postpartum period. This may presentas right upper quadrant pain and hypotension.

Table 4 Some of the differences seen in early and lateHELLP syndrome and acute fatty liver of pregnancy

HELLP syndrome Acute fatty liverof pregnancy

EarlyPlatelets

50 000150 000/mm3Platelets)100 000/mm3

LDH 6001400 IU/l LDH normalBilirubin normal Bilirubin high qProthrombin time normal Prothrombin time

prolonged qqqUric acid high qqq

LatePlatelets-50 000/mm3

Platelets-100 000/mm3

LDH )1400 IU/l LDH -600 IU/lProthrombin time increasedBilirubin increased

Prothrombin timeprolonged qqq




/

Dow

nloadedfrom


10/15

As the liver ruptures, epigastric and right upperquadrant pain get worse, with radiation to theback, followed by signs of shock. The physicianmust be aware that this condition has a highmortality rate, and that the patient will requireintensive care and referral to a specialist liver

centre. The fetus must be delivered once the motherhas been resuscitated, but there is a very significantperinatal mortality. Computer tomography withcontrast studies are effective in assessing damageto the liver, and angiography and embolizationmay used to control hepatic bleeding if present.Haematoma formation may also impair venousoutflow. Based on the mothers clinical condition,supported by laboratory and radiological investiga-tions, it may be appropriate to refer the mother forliver transplantation.58

Postpartum care

Patients with severe HELLP will require ongoingsupportive care in a high-dependency/intensive-care setting. Care must be applied to the haemody-namic status of the patient as well as regularmonitoring and supplementation of electrolytesand blood products. Treatment of hypertension,seizure prophylaxis and the administration ofcorticosteroids should continue and until laboratoryinvestigations show a trend towards normal. Thephysician must always be aware of the possibility of

deterioration postpartum.The recurrence of HELLP in subsequent preg-

nancies has been investigated, and this informationwill be important in counselling parents withregards to family planning. Two studies showedan increased risk of hypertension and pre-eclampsiain subsequent pregnancies, with a rate approaching20% in one and 4243% in the other. The risk ofrecurrent HELLP is thought to be 327%. However,if the previous pregnancy ended before 32 weeks,the risk of recurrence of pre-eclampsia and anotherpremature gestation was 61%.42,45,59

Acute fatty liver of pregnancy(AFLP)This is an uncommon, potentially fatal disorder thatoccurs in the third trimester of pregnancy. The firstclinical descriptions came from Stander andCadden, who described acute yellow atrophy ofthe liver, a rare and fatal complication of preg-nancy, in 1934.60 The histological appearance ofa microvesicular fatty infiltrate, the clinicopatholo-

gical process and a mortality of 70% was soondescribed.61,62 In 1984, ten patients with AFLP

were reported by Pockros et al.,63 who illustratedthe clinical course, and found a mortality of 10%where patients were given careful clinical support.

Most studies have estimated the incidence ofAFLP as 1 : 10 00015 000 pregnancies, with mor-tality 1020%. Castro and colleagues64 performed a

retrospective analysis of pregnancies at their institu-tion from 1982 to 1997: only 28 cases werereported amongst 199767 births, giving an inci-dence of 1:6659 births. It is commoner in twinpregnancies and male births and also in nulliparousmothers.34

Aetiology

Recent molecular advances suggest that AFLP mayresult from mitochondrial dysfunction. The mito-chondria fatty acidb-oxidation spiral consists of a

series of multiple transport steps and four enzymicreactions. Fatty acids are transported to the mito-chondrial inner membrane by special carriertransporters. Beyond the inner membrane, theyare then broken down by a series of four enzymes.The third enzyme is long-chain 3-hydroxyacyl-CoAdehydrogenase (LCHA), deficiency of which resultsin the increased excretion and accumulationof medium- and long-chain fatty acids. Childrenborn with this defect fail to thrive and areprone to hepatic failure (microvesicular steatosis),hypoglycaemia and death.65

This defect has been localized to a G1528Cmutation in the exona-subunit leading to inactiva-tion of the catalytic domain.66 The prevalence ofthis mutation E474Q has been investigated inpopulation screening studies performed in Finland.This demonstrated a carrier rate of 1 : 150200.Further mutations have also been found, but E474Qaccounts for 6590% of the LCHAD patients.Evidence of clinical correlation between LCHADand AFLP came in 1991, Schoemanet al.67 report-ing an association between recurrent maternalAFLP. In 1993, Wilckenet al.68 and Treemet al.69

reported six families of children who had failureof fatty acid oxidation, which by now had beenlocalized to the long-chain 3-hydroxyacyl-CoAdehydrodgenase deficiency (LCHAD) in mito-chondria. All these children had been born tomothers who suffered from AFLP or HELLP syn-drome during pregnancy. Further retrospectivestudies have suggested an association betweenLCHAD and AFLP.70

Alternatively, pregnancy may itself affect mito-chondrial function. Animal studies demonstratereduced FAO and activity of the decarboxyliccycle in late-term rats and mice. Other hypotheses

favour above-normal (for pregnancy) level of oestro-gens potentiating the effects of an otherwise




/

Dow

nloadedfrom


11/15

tolerable hormonal insult to mitochondria in thethird trimester.

Clinical course

Clinical

Onset is between the 30th and 38th weeks ofgestation. It is sometimes preceded by a prodromalillness, but classically presents with malaise, nausea,vomiting, malaise, abdominal pain (right upperquadrant), fever, headaches and pruritus. Often

jaundice is only noticed after delivery has takenplace. Patients will require supportive care, fluidresuscitation, nutrition, correction of coagulo-pathies and thrombocytopaenia and hypertensionan seizure treatments.

Biochemistry

The biochemical changes have some similarity tothose in HELLP syndrome, and careful distinctionshould be made (Table 4). Elevated serum trans-aminases may also be associated with raised serumammonia, amino acid levels and lactic acidosis,uric acid, hyperbilirubin and hypoglycaemia. Theprothrombin and the partial thromboplastic timesare prolonged.

Histology

Microvesicular steatosis with sparing of zone 1.Hepatocytes have a foamy appearance with cen-trally dense nuclei. There is little inflammation andnecrosis and the liver architecture remains intact.In more severe cases, hepatocyte necrosis may beseen. Liver ultrasounds are frequently normal, sincethe fat is microvesicular in nature.

Among 28 patients with AFLP in a seriesdescribed by Castroet al.64 the commonest causefor admission was labour and hepatitis. Thediagnosis of AFLP was made in ten patients 48 hafter admission and in another ten 48 hs after birth.Almost all patients had abnormal liver functiontests, with elevated total bilirubin and prothrombin.Mean gestational age was 37.5 weeks (range 3142)and there was no reported maternal mortality.

This study contrasts with that of Pereira et al.29

who performed a retrospective analysis of pregnantwomen admitted to the Liver Failure Unit at KingsCollege Hospital. They reported 46 women (medianage 30 years, range 1741) admitted with severeliver impairment during pregnancy of whom 32 hadAFLP. Thirteen developed hepatic encephalopathyand other complications, including hypoglycaemia

(55%), renal insufficiency (50%) requiring haemo-filtration, coagulopathy (96%) and disseminated

intravascular coagulopathy (55%) and pre-eclamp-sia (50%). Four of the 32 with AFLP died dueto complications, including severe haemorrhage,sepsis, multi-organ failure and hepatic rupture andsubcapsular haematoma. The reported maternalmortality rate was 12.5% (see Figure 3).

Sepsis leads to significant morbidity and mortal-ity, as demonstrated by Pereira et al.,29 and theearly use of broad-spectrum antibiotics is suggested.Surgical procedures and/or haemhorragic complica-tions require correction of the coagulopathy withvitamin K, fresh frozen plasma and cryoprecipitate.In both series, most haemhorragic complica-tions resulted from surgical trauma that led tointra-abdominal and retroperitoneal bleeding andhaematomas.

The use of liver transplantation in AFLP iscontroversial. Case reports suggest some benefit in

specific cases, but in the majority this will not berequired. The deterioration of parameters such astransaminases and prothrombin time and concur-rent disseminated intravascular coagulopathy maybe explained by concomitant sepsis. Castroet al.64

suggested that patients often deteriorated in thepostpartum period and then began to improve.Pereiraet al.29 suggested that transplantation shouldbe reserved for those with liver rupture complic-ated by hepatic necrosis, as indicated by computertomographic findings, the presence of hepaticencephalopathy, and a severe metabolic acidosis,

together with worsening coagulopathy, and/orincreasing fresh frozen plasma requirements.It is uncommon for AFLP to recur in subsequent

pregnancies; to date, four cases are reported in theliterature.71,72 This may be an under-representation,as following the first occurrence of this syndrome,many women may refrain from having furtherpregnancies, undergo sterilization, or die beforethey can become pregnant again.

Conclusions

The three pathological processes described appearto overlap, and are regarded by many as represent-ing a spectrum of the same disease. Clearly, allthree have specific characteristics, but their closeclinical correlation supports this hypothesis. Recentreports suggest that the fetal inborn error of meta-bolism, long-chain fatty3-hydroxylacyl-coenzyme-Adehydrodgenase deficiency in mitochondria, lead-ing to a failure ofb-oxidation, may be responsiblefor the development of AFLP and possibly pre-eclampsia. Initial high reported mortality rates of70%62 have been reduced to zero mortality in the

Castro series.64 No specific treatments have beendeveloped for AFLP, and so this improvement




/

Dow

nloadedfrom


12/15

in mortality is due to improved awareness, earlyfetal monitoring, and fetal and maternal supportivecare. Early recognition of patients who may beat high risk of severe liver impairment will allowcounselling for future family planning.

The pathogenesis of pre-eclamptic liverdisease remains unclear, but is related in partto sympathetic over-activity and a marked increasein peripheral vascular resistance, which in turncauses increased blood pressure. The role of nitricoxide has been thought to be central to thepathogenesis of pre-eclampsia; however, recentclinical studies of NO donors in pre-eclampsiahave yielded conflicting results.73,74 Severe pre-eclampsia requires specific treatment of hyper-

tension, prevention of seizures and careful obstetricmanagement, optimizing both mother and fetus till

birth. HELLP syndrome also carries significant fetaland maternal morbidity and mortality.

Patients with severe AFLP, pre-eclampsia andHELLP should be treated in tertiary centres thatare prepared for all maternal and fetal complica-tions. All three conditions will require the obstetricmanagement to be optimized with a view to timingand choice of route of delivery. Close supervisionof these patients providing careful and judicioussupportive care may avoid many of the reportedcomplications. Early referral to a specialist unit isalso recommended, as deterioration is rapid andspecialist radiological, surgical, and transplantationfacilities may be required.

Several investigators have reported the use of

liver transplantation in grave situations of severehepatic impairment. This must be interpreted with

a

b

Figure 3. CT scan (a) and an ultrasound examination (b) of the liver of a pregnant woman who presented with obstructivejaundice. The CT scan shows generally low attenuation, however, the ultrasound examination shows marked parenchymalreflectivity consistent with fatty infiltration of the liver. Percutaneous liver biopsy confirmed acute fatty liver of pregnancy.




/

Dow

nloadedfrom


13/15

caution. Several larger series of patients with AFLPhave shown that often these patients will demon-strate deteriorating liver function tests for up to oneweek post-partum and will then make a recovery.Similarly, computer tomographic studies havedemonstrated that as a part of the natural history

of this disease the liver volume will also decrease,recovering some time post-partum. In the caseof HELLP and or pre-eclampsia, Pereira et al.29

have suggested that hepatic rupture in associationwith gross physiological derangement may be anindication for early listing for liver transplantation.

References1. Waterstone M, Bewley S, Wolfe C. Incidence and predictors

of severe osbtetric morbidity: case control study. Br Med J

2001;322:108993.

2. Deltrene P, Denninger MH, Hillaire S, et al. Factor VLeiden related Budd-Chiari syndrome. Gut2001; 48:2648.

3. Raziel A, Friedler S, Schacter M, Ron-El R, Kornberg Y,Sela BA. Hypercoagulable thrombophilic defects andhyperhomocysteinaemia in patients with recurrentpregnancy loss. Am J Reprod Immunol Microbiol2001;45:6571.

4. Dilley A, Austin H, El-Jamil M, et al. Genetic factorsassociated with thrombosis in pregnancy in a United Statespopulation.Am J Obstet Gynecol2000; 183:12717.

5. Petri M. Treatment of the antiphospholipid antibodysyndrome: progress in the last five years?Curr Rheumatol

Rep2000; 2:25661.

6. Jaiswal SP, Jain AK, Naik G, Chitnis DS. Viral hepatitis inpregnancy.Int J Gynaecol Obstet2001; 72:1038.

7. Hermida RC, Ayala DE, Mojon A, et al. Blood pressurepatterns in normal pregnancy, gestational hypertension,and preeclampsia.Hypertension2000; 36:14958.

8. Kaaja RJ, Moore MP, Yandle TG, Ylikorkala O,Frampton CM, Nicholls MG. Blood pressure and vasoactivehormones in mild preeclampsia and normal pregnancy.Hypertens Pregnancy1999; 18:17387.

9. Chesley LC. Plasma and red cell volumes during pregnancy.Am J Obstet Gynecol1972; 112:44050.

10. Chesley LC. Cardiovascular changes in pregnancy.

Obstet Gynecol Annu1975; 4:7197.

11. Greer IA. Thrombosis in pregnancy: maternal and fetalissues.Lancet1999; 353:125865.

12. Burroughs AK. Pregnancy and liver disease.Forum Genova1998;8:4258.

13. Murphy DJ, Stirrat GM. Mortality and morbidity associatedwith early-onset preeclampsia. Hypertension in Pregnancy2000;19:22131.

14. Caniggia I, Winter J, Lye SJ, Post M. Oxygen and placentaldevelopment during the first trimester: implications forthe pathophysiology of pre-eclampsia. Placenta 2000;21(Suppl A):S2530.

15. Bussen S, Sutterlin M, Steck T. Plasma endothelin and bigendothelin levels in women with severe preeclampsia orHELLP-syndrome.Arch Gynecol Obstet1999;262:11319.

16. Bernheim J, Golan E. wEndothelial cells and preeclampsiaof pregnancyx wReviewx w36 refsx wHebrewx. Harefuah1998;134:7202.

17. Lowe DT. Nitric oxide dysfunction in the pathophysiologyof preeclampsia wReviewx w204 refsx. Nitric Oxide2000;4:44158.

18. Anumba DO, Robson SC, Boys RJ, Ford GA. Nitric oxideactivity in the peripheral vasculature during normotensiveand preeclamptic pregnancy. Am J Physiol1999;277:H84854.

19. Walsh SW, Vaughan JE, Wang Y, Roberts LJ. Placentalisoprostane is significantly increased in preeclampsia.FASEB J2000; 14:128996.

20. Borghi C, Esposti DD, Immordino V, et al. Relationshipof systemic hemodynamics, left ventricular structure andfunction, and plasma natriuretic peptide concentrationsduring pregnancy complicated by preeclampsia. Am JObstet Gynecol2000; 183:1407.

21. de LB, I, Battini L, Simonelli M, et al. Increased HLA-DRhomozygosity associated with pre-eclampsia. Human

Reproduction2000; 15:180712.22. Martin-JN J, May WL, Magann EF, Terrone DA,

Rinehart BK, Blake PG. Early risk assessment ofsevere preeclampsia: admission battery of symptomsand laboratory tests to predict likelihood of subsequentsignificant maternal morbidity. Am J Obstet Gynecol1999;180:140714.

23. Heyborne KD. Preeclampsia prevention: lessons fromthe low-dose aspirin therapy trials wReviewx w25 refsx.Am J Obstet Gynecol2000; 183:5238.

24. Rogers MS, Fung HY, Hung CY. Calcium andlow-dose aspirin prophylaxis in women at high risk ofpregnancy-induced hypertension. Hypertens Pregnancy1999;18:16572.

25. Duley L, Henderson-Smart D, Knight M, King L.Antiplatelet drugs for prevention of pre-eclampsia andits consequences: systematic review. Br Med J2001;322:32933.

26. Easterling TR, Carr D, Brateng D, Diederichs H,Schmucker B. Treatment of hypertension inpregnancy: effect of atenelol on maternal disease, pretermdelivery, and fetal growth. Am J Obstet Gynecol2001;98:42733.

27. Dekker A, Sibai BM. Primary, secondary and tertiaryprevention of pre-eclampsia. Lancet2001; 357:20915.

28. Chesley LC. The control of hypertension in pregnancy.Obstet Gynecol Annu1981; 10:69106.

29. Pereira SP, ODonohue J, Wendon J, Williams R. Maternaland perinatal outcome in severe pregnancy-related liverdisease.Hepatology1997; 26:125862.

30. Anonymous. Which anticonvulsant for women witheclampsia? Evidence from the Collaborative EclampsiaTrial wpublished erratum appears in Lancet 1995 July22;346(8969):258x. Lancet1995; 345:145563.

31. Selcuk NY, Odabas AR, Cetinkaya R, Tonbul HZ, San A.Outcome of pregnancies with HELLP syndrome complicatedby acute renal failure (198999). Renal Failure2000;22:31927.

32. Rubin PC. Magnesium sulphate in pre-eclampsiawletterx.Lancet1998; 352:1861.

33. Walker ID. Thrombophilia in pregnancywReviewx w88 refsx.J Clin Pathol2000; 53:57380.




/

Dow

nloadedfrom


14/15

34. Burroughs AK, Seong NH, Dojcinov DM, Scheuer PJ,Sherlock SV. Idiopathic acute fatty liver of pregnancy in12 patients. Q J Med1982; 51:48197.

35. Sibai BM, Mercer BM, Schiff ER, Friedman SA. Aggressiveversus expectant management of severe preeclampsia at28 to 32 weeks gestation. Am J Obstet Gynecol1994;171:81822.

36. Magann EF, Washburne JF, Sullivan CA, Chauhan SP,Morrison JC, Martin JN Jr. Corticosteroid-induced arrestof HELLP syndrome progression in a marginally-viablepregnancy.Eur J Obstet Gynecol Reprod Biol1995;59:21719.

37. OBoyle JD, Magann EF, Waxman E, Martin-JN J.Dexamethasone-facilitated postponement of delivery of anextremely preterm pregnancy complicated by the syndromeof hemolysis, elevated liver enzymes, and low platelets.Mil Med1999; 164:31618.

38. Abramovici D, Friedman SA, Mercer BM, Audibert F, Kao L,Sibai BM. Neonatal outcome in severe preeclampsia at24 to 36 weeks gestation: does the HELLP (hemolysis,elevated liver enzymes, and low platelet count) syndrome

matter? Am J Obstet Gynecol1999; 180:2215.

39. Weinstein L. Syndrome of hemolysis, elevated liverenzymes, and low platelet count: a severe consequenceof hypertension in pregnancy. Am J Obstet Gynecol1982;142:15967.

40. Martin-JN J, Magann EF, Blake PG. Analysis of 454pregnancies with severe preeclampsia/eclampsiaHELLP syndrome using the 3-class system of classification.Am J Obstet Gynecol1993; 68:38691.

41. Egerman RS, Sibai BM. HELLP syndrome.Clin ObstetGynecol1999; 42:3819.

42. Sibai BM, Ramadan MK, Usta I, Salama M, Mercer BM,Friedman SA. Maternal morbidity and mortality in

442 pregnancies with hemolysis, elevated liver enzymes,and low platelets (HELLP syndrome). Am J Obstet Gynecol1993;169:10006.

43. Isler CM, Rinehart BK, Terrone DA, Martin RW, Magann EF,Martin-JN J. Maternal mortality associated with HELLP(hemolysis, elevated liver enzymes, and low platelets)syndrome.Am J Obstet Gynecol1999; 181:9248.

44. Haddad B, Barton JR, Livingston JC, Chahine R, Sibai BM.Risk factors for adverse maternal outcomes among womenwith HELLP (hemolysis, elevated liver enzymes, and lowplatelet count) syndrome. Am J Obstet Gynecol2000;183:4448.

45. Sibai BM, Ramadan MK, Chari RS, Friedman SA.Pregnancies complicated by HELLP syndrome (hemolysis,

elevated liver enzymes, and low platelets): subsequentpregnancy outcome and long-term prognosis. Am J ObstetGynecol1995; 172:1259.

46. Mabie WC, Barton JR, Sibai BM. Adult respiratory distresssyndrome in pregnancy. Am J Obstet Gynecol1992;167:9507.

47. Sibai BM, Kustermann L, Velasco J. Current understandingof severe preeclampsia, pregnancy-associated hemolyticuremic syndrome, thrombotic thrombocytopenic purpura,hemolysis, elevated liver enzymes, and low plateletsyndrome, and postpartum acute renal failure: differentclinical syndromes or just different names? Curr OpinNephrol Hypertens1994; 3:43645.

48. Martin JNJ, Rinehart BK, May WL, Magann EF,Terrone DA, Blake PG. The spectrum of severepreeclampsia: comparative analysis by HELLP

(hemolysis, elevated liver enzyme levels, and low plateletcount) syndrome classification. Am J Obstet Gynecol1999;180:137384.

49. Barton JR, Riely CA, Adamec TA, Shanklin DR, Khoury AD,Sibai BM. Hepatic histopathologic condition does notcorrelate with laboratory abnormalities in HELLP syndrome(hemolysis, elevated liver enzymes, and low platelet count).

Am J Obstet Gynecol1992; 167:153843.

50. Schwartz ML, Lien JM. Spontaneous liver hematoma inpregnancy not clearly associated with preeclampsia: a casepresentation and literature review. Am J Obstet Gynecol1997; 176:132832.

51. Yagmurdur MC, Agalar F, Daphan CE. Spontaneous hepaticrupture in pregnancy. Eur J Emerg Med2000; 7:756.

52. Magann EF, Graves GR, Roberts WE, Blake PG, Morrison JC,Martin JN Jr. Corticosteroids for enhanced fetal lungmaturation in patients with HELLP syndrome: impact onneonates.Aust N Z J Obstet Gynaecol1993; 33:1315.

53. Magann EF, Perry KG Jr, Meydrech EF, Harris RL, ChauhanSP, Martin JN Jr. Postpartum corticosteroids: accelerated

recovery from the syndrome of hemolysis, elevated liverenzymes, and low platelets (HELLP). Am J Obstet Gynecol1994; 171:11548.

54. Tompkins MJ, Thiagarajah S. HELLP (hemolysis,elevated liver enzymes, and low platelet count)syndrome: the benefit of corticosteroids. Am J ObstetGynecol1999; 181:3049.

55. Magann EF, Martin JN Jr. Twelve steps to optimalmanagement of HELLP syndrome. Clin Obstet Gynecol1999; 42:53250.

56. Martin-JN J, Perry KG Jr, Roberts WE. Plasma exchange forpreeclampsia: III. Immediate peripartal utilization forselected patients with HELLP syndrome. J Clin Apheresis1994; 9:1625.

57. Woods JB, Blake PG, Perry KG Jr. Cardiopulmonarycomplications in the preeclamptic patient with the syndromeof hemolysis, elevated liver enzymes and low platelets.Obstet Gynecol1992; 80:8791.

58. Chan AD, Gerscovich EO. Imaging of subcapsular hepaticand renal hematomas in pregnancy complicated bypreeclampsia and the HELLP syndrome. J Clin Ultrasound1999; 27:3540.

59. Sullivan CA, Magann EF, Perry KG Jr, Roberts WE, Blake PG,Martin JN Jr. The recurrence risk of the syndrome ofhemolysis, elevated liver enzymes, and low platelets (HELLP)in subsequent gestations. Am J Obstet Gynecol1994;171:9403.

60. Stander H, Cadden B. Acute yellow atrophy of the liverin pregnancy. Am J Obstet Gynecol1934; 28:619.

61. Sheehan HL. Jaundice in pregnancy.Am J Obstet Gynecol1961; 81:42740.

62. Kunelis CT, Peters JL, Edmondson HA. Fatty liver ofpregnancy and its relationship to tetracycline therapy. Am JObstet Gynecol1965; 33:35977.

63. Pockros PJ, Peters RL, Reynolds TB. Idiopathic fattyliver of pregnancy: findings in ten cases. Medicine1984; 63:111.

64. Castro MA, Fassett MJ, Reynolds TB, Shaw KJ, Goodwin TM.Reversible peripartum liver failure: a new perspective onthe diagnosis, treatment, and cause of acute fatty liver ofpregnancy, based on 28 consecutive cases. Am J ObstetGynecol1999; 181:38995.




/

Dow

nloadedfrom


15/15

65. Wanders RJ, Vreken P, den Boer ME, Wijburg FA,Van Gennip AH, Ijlst L. Disorders of mitochondrialfatty acyl-CoA beta-oxidation. J Inherit Metab Dis1999;22:44287.

66. Ijlst L, Oostheim W, Ruiter JP, Wanders RJ. Molecularbasis of long-chain 3-hydroxyacyl-CoA dehydrogenasedeficiency: identification of two new mutations. J Inherit

Metab Dis1997; 20:4202.

67. Schoeman MN, Batey RG, Wilcken B. Recurrent acutefatty liver of pregnancy associated with a fatty-acidoxidation defect in the offspring. Gastroenterology1991;100:5448.

68. Wilcken B, Leung KC, Hammond J, Kamath R, Leonard JV.Pregnancy and fetal long-chain 3-hydroxyacyl coenzyme Adehydrogenase deficiency. Lancet1993; 341:4078.

69. Treem WR, Rinaldo P, Hale DE, et al. Acute fatty liverof pregnancy and long-chain 3-hydroxyacyl-coenzymeA dehydrogenase deficiency. Hepatology1994;19:33945.

70. Ibdah JA, Bennett MJ, Rinaldo P, et al. A fetal fatty-acidoxidation disorder as a cause of liver disease in pregnantwomen.N Engl J Med1999; 340:172331.

71. Visconti M, Manes G, Gianattasio F, Uomo G. Recurrenceof acute fatty liver of pregnancy. J Clin Gastroenterol1995;21:2435.

72. Barton JR, Sibai BM, Mabie WC, Shanklin DR. Recurrent

acute fatty liver of pregnancy. Am J Obstet Gynecol1990;163:5348.

73. Mushambi MC, Halligan AW, Williamson K. Recentdevelopments in the pathophysiology and managementof pre-eclampsia. Br J Anaesth1996;76:13348.

74. Sladek SM, Magness RR, Conrad KP. Nitric oxide andpregnancy.Am J Physiol1997; 272:R44163.

75. Audibert F, Friedman SA, Frangieh AY, Sibai BM.Clinical utility of strict diagnostic criteria for theHELLP (hemolysis, elevated liver enzymes, and lowplatelets) syndrome.Am J Obstet Gynecol1996;175:4604.




/

Dow

nloadedfrom

Documents

Severe Hepatic Dysfunction in Pregnancy