Effects of postpartum corticosteroids in patients with HELLP syndrome

Ž .International Journal of Gynecology & Obstetrics 61 1998 141]148

Article

Effects of postpartum corticosteroids in patients withHELLP syndrome

O.T. YalcinU, T. Sener, H. Hassa, S. Ozalp, A. Okur

Department of Obstetrics and Gynecology, Osmangazi Uni¨ersity School of Medicine, Eskisehir, Turkey

Received 3 November 1997; received in revised form 23 January 1998; accepted 27 January 1998

Abstract

Objecti¨e: To evaluate the effect of corticosteroid treatment on the postpartum recovery of parturients withHELLP syndrome. Method: Thirty cases with HELLP syndrome were randomly assigned to a study or a controlgroup, each including 15 patients. A total dose of 30 mg intravenous dexamethasone was given to the study groupduring the 36 h following the childbirth, while the control group did not receive any steroid medication. Arterialblood pressure, urine output, hematocrit ratio, platelet count, serum alanine and aspartate aminotransferases anduric acid levels were monitored during the first 48 h postpartum. The data were analyzed by unpaired t-test, x 2 orFisher’s exact tests. Result: Before the treatment, no significant difference was observed between the two groups. Thestudy group showed statistically significant improvement in mean arterial blood pressure, mean serum aspartate

Ž .aminotransferase level, mean urine volume per hour and mean platelet count P-0.05 . Length of hospitalizationŽ .was also shorter in the study group P-0.01 . Conclusion: Early postpartum high-dose corticosteroid treatment

accelerates the recovery and shortens the hospitalization of the parturients with HELLP syndrome. Q 1998International Federation of Gynecology and Obstetrics

Keywords: HELLP syndrome; Corticosteroid treatment; Preeclampsia]eclampsia

1. Introduction

HELLP syndrome characterized by hemolysis,hepatic dysfunction and thrombocytopenia is an

U Corresponding author. Tel.: q90 222 2392979, ext. 7167;fax: q90 222 2398412.

atypical complicated form of severe pre-w xeclampsia]eclampsia 1]3 . The incidence of this

syndrome among patients with severepre-eclampsia]eclampsia is reported to be

w x4.0]18.9% 2]4 . Pregnancies complicated byHELLP syndrome are at a higher risk of seriousmaternal complications such as disseminated in-travascular coagulopathy, acute renal failure, se-

0020-7292r98r$19.00 Q 1998 International Federation of Gynecology and ObstetricsŽ .P I I S 0 0 2 0 - 7 2 9 2 9 8 0 0 0 3 6 - 8

( )O.T. Yalcin et al. r International Journal of Gynecology & Obstetrics 61 1998 141]148142

vere ascites, pulmonary and cerebral edema,pleural effusion and subcapsular hematoma or

w xrupture of the liver 1]5 . Maternal mortality dueto these complications is reported to be as low as1.1% in well equipped intensive care units withexperienced staff, however, this rate can reach upto 24.0% in others which do not possess these

w xfacilities 2]5 .The management of the patients with HELLP

syndrome is a difficult challenge. Although au-thors of the larger series conclude that immediatedelivery and conventional medical managementof pre-eclampsia]eclampsia usually leads to rela-tively rapid resolution of the HELLP syndrome,patients with delayed recovery, who also usuallyhave higher mortality and morbidity, represent a

w xmanagement dilemma 2,3,6,7 . Specific treatmentmeasures are currently not available as the patho-physiology of the disease has not been definedyet. Plasmapheresis has been advocated by someauthors, but this therapy is invasive, expensive

w xand also has questionable benefit 2,8 .A temporary arrest or recovery of HELLP syn-

drome has been observed after administration ofcorticosteroids given for a misdiagnosis of au-toimmune disease or in an effort to accelerate

w xfetal lung maturity 9]13 . Moreover, Magann etw xal. 14 recently reported that accelerated recov-

ery from HELLP syndrome was achieved by ashort course of postpartum corticosteroid ther-apy.

As more rapid resolution of this syndrome isdesirable to reduce maternal complications anddecrease hospital care cost, this prospective ran-domized study was initiated to investigate theeffect of corticosteroids on the recovery rate ofHELLP syndrome.

2. Materials and methods

Thirty-two patients admitted to a tertiary uni-versity hospital with a diagnosis of HELLP syn-drome were eligible for this prospective ran-domized study. The diagnosis of HELLP syn-drome was based on the presence of clinicalsymptoms and signs consistent with a diagnosis ofsevere pre-eclampsia]eclampsia in associationwith laboratory findings of hemolysis, elevated

Žliver enzymes aspartate aminotransferase G48.IUrl or alanine aminotransferase G24 IUrl and

Ž .low platelet count F100 000rml without evi-dence of another disorder primarily causative of

w xthe clinical and laboratory findings 1]5 . Plateletcounts and serum analysis of liver enzymes wereperformed by autoanalyzer. Burr cells androrschistocytes obtained in blood smears, elevatedindirect bilirubin, hematuria andror fallinghematocrit concurrent with worsening thrombo-cytopenia were accepted as evidence of intravas-

w xcular hemolysis 1]3,6 .After admission to the intensive care unit, all

patients were assessed serially for progress ofdisease by worsening clinical signs and symptomsand laboratory investigations including liver func-tion tests, complete blood count, coagulation pro-file and renal function tests. All patients wereroutinely put on intravenous magnesium sulfatetherapy to prevent and control eclampsia. Fol-lowing a bolus of 4 g of magnesium sulfate injec-tion over 5 min, controlled continuous infusion of1 grh was given to all patients until 48 h postpar-tum. As parenteral antihypertensives were not

Ž .available, sublingual nifedipine 10 mg wasŽadministered to treat hypertension blood pres-

.sure G180r110 mmHg . Oral alpha methyldopawas administered to all patients with an initialdose of 250 mg t.i.d and increased as needed to amaximum dose of 500 mg q.i.d to maintain ac-

Žceptable arterial blood pressures blood pressure.-160r110 mmHg .

Fetal well-being of all patients was assessed bynon-stress test and biophysical profile testing af-ter maternal stabilization. Cesarean section wasperformed for ‘fetal distress’ or unfavorable cervixfor induction. Induction of labor was initiated inall patients with favorable cervix, regardless oftheir gestational age. Delivery in all patients oc-curred within 72 h of admission.

Ž .Two 6.3% maternal deaths occurred beforedelivery, so these patients were not included inthe study. Both patients were referred to thecenter in hypotensive shock with severe coagula-tion abnormalities, profuse vaginal bleeding andadult respiratory distress syndrome. Respiratoryand cardiac arrest occurred during the first 12 hand resuscitation attempts were not successful.

( )O.T. Yalcin et al. r International Journal of Gynecology & Obstetrics 61 1998 141]148 143

Following delivery, the remaining 30 patientswere randomly assigned to the study or controlgroup. Fifteen patients randomized to each group.Immediately postpartum, patients in the studygroup received 10 mg of dexamethasone intra-venously, followed by 10 mg at 12 h, 5 mg at 24 hand 5 mg at 36 h after delivery, for a total dose of30 mg. Patients in the control group did notreceive any steroid medication. All patients inboth groups were carefully monitored by meanarterial blood pressure and urinary output every2 h, hematocrit and platelet count every 6 h andserum levels of aspartate and alanine aminotrans-ferases and uric acid every 12 h for the first 48 hpostpartum.

All patients remained in the intensive care unituntil remission was believed to have occurred.Criteria for recovery included urinary output ex-ceeding 100 mlrh for more than 1 day in theabsence of diuretic or fluid bolus administration,systolic blood pressure -140 mmHg and diastolicblood pressure -90 mmHg with or without beingon antihypertensive therapy, platelet count)100 000rml, normal liver and renal functions

w xand no evidence of hemolysis 1]3,6,13 .The data obtained from the study and control

groups were analyzed by unpaired t-test, x 2 orFisher’s exact tests.

3. Results

Fifteen patients in the study group had a meanŽ .maternal age of 26.1"8.9 years 16]34 years , a

mean gestational age at delivery of 35.1"2.9Ž .weeks 29]38 weeks , a mean gravidity of 3.0"1.6

Ž . Ž .1]6 and a mean parity of 0.7"0.8 0]3 . TheseŽ .data were 25.6"8.1 years 17]32 years 35.5"2.6

Ž . Ž .weeks 30]38 weeks , 2.7"1.5 1]5 and 1.0"0.7Ž .0]3 , respectively, for 15 patients in the controlgroup. These data were not significantly different.

Ž .Five 33.3% patients in the study group and 6Ž .40.0% patients in the control group were multi-

Ž .para n.s. . Medical histories of the patients re-Ž .vealed that two 13.3% of the patients in the

Ž .study group and three 20.0% of the patients inthe control group had pre-existing hypertensionŽ .n.s. . These patients were diagnosed to have su-perimposed pre-eclampsia]eclampsia.

Ž .Five 33.3% patients in the study group andŽ .four 26.7% patients in the control group had

coagulation abnormalities characterized by pro-longed prothrombin time andror partial throm-boplastin time during the antenatal period. Thiscomplication was treated by parenteral vitamin Kand transfusion of at least two units of freshfrozen plasma before the initiation of the corti-costeroid therapy. A total of 10 patients including

Ž . Ž .six 40.0% patients in the study and four 26.7%patients in the control group required transfusionof packed red blood cells for anemia before deliv-

Ž .ery. Three 20.0% patients in the study groupŽ .and three 20.0% patients in the control group

developed acute renal insufficiency which resolvedspontaneously with conservative measures.

ŽPatients with antenatal complications coagula-tion abnormalities, anemia and acute renal fail-

. Ž .ure were similar in both groups n.s. . SevenŽ .46.7% patients in the study group and eightŽ .53.3% patients in the control group were deliv-ered by cesarean section for unfavorable cervix or

Ž .fetal distress n.s. .The mean arterial pressure, hematocrit, urine

output, platelet count, serum levels of liver en-zymes and uric acid of the study group obtainedimmediately postpartum before administration ofthe corticosteroids were not significantly different

Table 1The mean values of the clinical and laboratory parameters ofthe patients before the initiation of the corticosteroid treat-ment

Study group Control groupŽ . Ž .ns15 ns15

U UMean arterial pressure 130.2"13.8 129.1"16.1Ž .mmHg

U UUrine volume 19.2"10.1 21.8"12.3Ž .mlrh

U UŽ .Hematocrit % 31.2"3.8 29.8"3.0U UThrombocyte count 77.5"23.5 83.2"17.5

3Ž .=10 rmlU UAspartate aminotransferase 127.2"28.1 115.3"21.2

Ž .IUrlU UAlanine aminotransferase 132.8"16.1 130.6"19.6

Ž .IUrIU UUric acid 7.9"2.4 7.3"3.7

Ž .mgrdlU Non-significant.


Fig. 1. Graphic presentation of the average mean arterial blood pressure at 4-h intervals for the first 48 h postpartum for thesteroid-treated and the control groups.

Ž .from those of the control group Table 1 . Fol-lowing initiation of the dexamethasone therapy

Ž .the mean arterial blood pressure Fig. 1 and themean serum level of aspartate aminotransferaseŽ .Fig. 2 of the study group became significantlydecreased by 28 h and 36 h postpartum, respec-

Ž .tively P-0.05 . Meantime, compared to those ofthe control group, it was observed that both the

Ž .mean platelet count Fig. 3 and the mean urineŽ .output per hour Fig. 4 of the study group in-

creased significantly by 36 h and 20 h postpartum,Ž .respectively P-0.05 . Once present, the signifi-

cant differences in the mean values of theseparameters between the study vs. control grouppersisted from that point onward during the first48 h postpartum. There were no significant dif-

Fig. 2. Graphic presentation of the mean serum levels of aspartate aminotransferase at 12-h intervals for the first 48 h postpartumfor the steroid-treated and the control groups.


Fig. 3. Graphic presentation of the mean platelet counts at 6-h intervals for the first 48 h postpartum for the steroid-treated andthe control groups.

ferences in the mean hematocrit values, serumalanine aminotransferase and uric acid levelsbetween the study and control groups at any timeinterval during the first 48 h postpartum.

Complications of infection occurred in twoŽ .13.3% of the patients in the study and oneŽ .6.7% of the patients in the control group duringthe postpartum period. All responded to par-enteral antibiotic therapy.

The mean length of postpartum hospital stay

Ž .was 6.0"4.1 days 4]15 days for the steroid-Ž .treated patients and 10.5"3.2 days 6]21 days

Ž .for control patients P-0.01 .

4. Discussion

w xIn 1982, Weinstein 1 used the term HELLPsyndrome to describe an atypical presentation ofsevere pre-eclampsia]eclampsia with features of

Fig. 4. Graphic presentation of the mean urine volumerhour at 4-h intervals for the first 48 h postpartum for the steroid-treatedand the control groups.


hemolysis, elevated liver enzymes and low plateletcount. The diagnosis and management of HELLPsyndrome involves some controversy. The severityof disease has been classified, but HELLP syn-drome is often misdiagnosed as other medical or

w xsurgical disorders 1]10 .Most of the management plans reported in the

literature include immediate delivery regardlessof the gestational age with supportive care includ-ing transfusion of whole blood or its components

w xuntil the disease resolves postpartum 1,2,4]6 .This conventional management is reported to re-sult in relatively rapid resolution of the syndrome

w xin many of the patients 2]6,8 . However, patientscan have delayed recovery, which is associatedwith higher maternal mortality and morbidity. Asthe pathophysiology of the syndrome has not beendefined yet, specific and effective treatment mea-sures are not available to arrest the progressionor accelerate the recovery. Exchange plasma-pheresis with fresh frozen plasma has been used,

w xbut it is expensive and of uncertain value 2,6,8 .Antenatal corticosteroid administration has

provided some benefit in patients with HELLPw x w xsyndrome 9]13 . Thiagarajah et al. 9 reported

that five of the 13 patients with HELLP syndrometreated with antenatal corticosteroids for the mis-diagnosis of idiopathic thrombocytopenic purpuraor in an effort to accelerate fetal lung maturity.An improvement in liver function coincident withan increase in platelet count was seen in all of

w xthese steroid-treated patients 9 . A retrospectiveinvestigation of preterm pregnancies complicated

w xby HELLP syndrome by Magann et al. 11 con-cluded that corticosteroid therapy used to accel-erate fetal lung maturity was associated with anincreased maternal platelet count and decreasedmaternal serum liver enzymes. In a report by

w xGoodlin 10 , two patients with HELLP syndromeinitially misdiagnosed as having idiopathic throm-bocytopenic purpura and treated with corticos-teroids showed an increase in platelet count.However, the numbers of patients in these re-ports were too small to conclude whether thesefindings represented a mere coincidence or abeneficial effect of corticosteroids.

Maternal platelet count and serum level ofliver enzymes reflect the severity of the HELLP

w xsyndrome 2]5,14 . Maternal blood pressurestabilization and diuresis are two clinical criteriawhich reflect resolution of the disease processw x2]5,8,14 . Our findings confirmed that patientswith HELLP syndrome, who received shortcourse]high dose corticosteroids during the first36 h postpartum demonstrated significant changein most parameters reflecting severity or durationof disease compared to the control patients. Thecorticosteroid-treated patients had significantlydecreased mean arterial blood pressure and as-partate aminotransferase by 28 and 40 h postpar-tum, respectively. In addition urinary output andplatelet count of these patients were found to beincreased significantly by 36 and 20 h postpartum,respectively. These findings suggested thatsteroid-treated patients had more rapid resolu-tion of the disease and the clinical improvementoccurred earlier than the improvement of thelaboratory findings. This suggestion was also sup-ported by significantly shorter hospital stay of thesteroid-treated patients vs. that of the control

Ž .group P-0.01 . Similar results were also re-w xported by Magann et al. 14 in an another

prospective randomized study. However, thelength of the hospital stay of the steroid-treatedpatients was not reported in that study.

As the etiopathogenesis of pre-eclampsia]eclampsia and its atypical form HELLP syndromecurrently is not defined clearly, it is not possibleto explain the mechanism of action of these ben-eficial effects of corticosteroids on HELLP syn-drome. However, it is speculated that corticos-teroids could either promote the release ofplatelets from normally functioning bone marrowor inhibit removal by reticuloendothelial system

w xof platelets altered by vascular damage 8 . Otherpossible actions are thought to be decreasedplatelet adhesion or a direct endothelial mecha-nism that might include prevention of release ofplatelet activating substances from the damagedendothelial cells by stabilization cell membranew x14 . Recently some authors reported significantautoantibody abnormalities, especially increasedformation of antiphospholipid antibodies andantibodies to platelets in patients with preeclamp-

w xsia]eclampsia 15,16 . On the basis of these find-ings accelerated recovery from HELLP syndrome


might be explained by the well known immuno-suppressive effect of corticosteroids. Another pos-sible effect of corticosteroids is increased renalblood flow and glomerular filtration rate, whichmay also explain the improvement in renal outputin steroid-treated patients with HELLP syndromein this study.

In contrast to aspartate aminotransferase, ala-nine aminotransferase levels were not signifi-cantly different between the steroid-treated andcontrol patients at any time interval in this study.As high aspartate aminotransferaseralanineaminotransferase ratios are observed during themost active phase of the disease, aspartate amino-transferase appears to be the dominant transami-nase released into the peripheral circulation of

w xthe patients with HELLP syndrome 1]3,17 . Rel-atively stable serum levels of alanine aminotrans-ferase probably were not affected by the corticos-teroid treatment in this study. The hematocritvalues were also similar in the two groups ofpatients in this study. The effects of corticos-teroids on hematocrit values might be masked byeffective erythropoiesis and red blood cell releasefrom the bone marrow or increased hemaconcen-tration seen in these patients with HELLP syn-

w xdrome 3 .Although there has been fear of maternal in-

fection in patients treated with corticosteroidsdue to its immunosuppressive effect, many au-thors reported that steroid-treated patients hadno significantly increased infectious morbidityw x3,9,14,18 . No difference in the overall puerperalfebrile morbidity was also demonstrated betweenthe steroid-treated and control patients in thisstudy.

Our data would support clinical use of corticos-teroids given in high dose for 36 h following thedelivery of patients with HELLP syndrome. In alimited number of patients, this therapy short-ened the recovery phase resulting in less morbid-ity and lower hospital cost.

References

w x1 Weinstein L. Syndrome of hemolysis, elevated liver en-zymes and low platelet count: a consequence of hyper-

tension in pregnancy. Am J Obstet Gynecol1982;142:159]167.

w x2 Sibai BM, Ramadan MK, Usta I, Salama M, MercerBM, Friedman SA. Maternal morbidity and mortality in442 pregnancies with hemolysis, elevated liver enzymes

Ž .and low platelets HELLP syndrome . Am J ObstetGynecol 1993;169:1000]1006.

w x3 Martin JN, Blake PG, Perry KG, Martin RW. Thenatural history of HELLP syndrome: patterns of diseaseprogression and regression. Am J Obstet Gynecol1991;164:1500]1513.

w x4 Sibai GM, Taslimi MM, El-Nazer A. Maternal perinataloutcome associated with the syndrome of hemolysis,elevated liver enzymes and low platelets in severepreeclampsia]eclampsia. Am J Obstet Gynecol1986;155:501]509.

w x Ž5 Sibai BM. The HELLP syndrome hemolysis, elevated.liver enzymes and low platelets : much ado about

nothing? Am J Obstet Gynecol 1990;162:311]316.w x6 Martin JN, Blake PG, Lowry SL, Perry KG, Morrison

JG. Pregnancy complicated by preeclampsia]eclampsiawith the syndrome of hemolysis, elevated liver enzymesand low platelet count: how rapid is postpartum recov-ery? Obstet Gynecol 1990;76:737]741.

w x7 Weinstein L. Preeclampsiareclampsia with hemolysis,elevated liver enzyme and thrombocytopenia. ObstetGynecol 1985;66:657]660.

w x8 Martin JN, Jr, Files JC, Blake PG et al. Plasma ex-change for preeclampsia. I. Postpartum use for persis-tently severe preeclampsia]eclampsia with HELLP syn-drome. Am J Obstet Gynecol 1990;162:128]137.

w x9 Thiagarajah S, Bourgeois FJ, Harbert GM, Caudle MR.Thrombocytopenia in preeclampsia: associated abnor-malities and management principles. Am J Obstet Gy-necol 1984;150:1]7.

w x10 Goodlin GC. Severe preeclampsia; another great imita-tor. Am J Obstet Gynecol 1976;125:747]749.

w x11 Magann EF, Martin RW, Isaacs JD, Blake PG, Mor-rison JG, Martin JN, Jr. Corticosteroids for the en-hancement of fetal lung maturity: impact on the gravidawith preeclampsia and HELLP syndrome. Aust NZ JObstet Gynaecol 1993;33:127]131.

w x12 Clark SL, Phelan JP, Allen SH, Golde SR. Antepartumreversal of hematologic abnormalities associated withthe HELLP syndrome. J Reprod Med 1986;31:70]72.

w x13 Magann EF, Bass D, Chauhan SP, Sullivan DL, MartinRW, Martin JN, Jr. Antepartum corticosteroids: diseasestabilization in patients with the syndrome of hemolysis,elevated liver enzymes and low platelets. Am J ObstetGynecol 1994;171:1148]1153.

w x14 Magann EF, Martin JN, Jr, Blake PG, Perry KG, Mey-drech EF, Harris RL. Postpartum corticosteroids: accel-erated recovery from the syndrome of hemolysis, ele-

Ž .vated liver enzymes and low platelets HELLP . Am JObstet Gynecol 1994;171:1154]1158.


w x15 El-Roeiy A, Myers SA, Gleicher N. The relationshipbetween autoantibodies and intrauterine growth retar-dation in hypertensive disorder of pregnancy. Am JObstet Gynecol 1991;164:1253]1261.

w x16 Milliez J, Lalious HE, Medjadji M et al. The prevalenceof autoantibodies during third trimester pregnancy com-plicated by hypertension and idiopathic growth retarda-tion. Am J Obstet Gynecol 1991;165:51]56.

w x17 Romero R, Vizoso J, Emamian M. Clinical significanceof liver dysfunction in pregnancy-induced hypertension.Am J Perinatol 1988;5:146]151.

w x18 Taeush HW, Frigoletto F, Kitzmiller J. Risk of respira-tory distress syndrome after prenatal dexamethasonetreatment. Pediatrics 1979;63:64]72.

Documents

Effects of postpartum corticosteroids in patients with HELLP syndrome