Académique Documents
Professionnel Documents
Culture Documents
www.ajog.org
EDITORS’ CHOICE
School of Public Healtha and School of Medicine,b Universidad del Valle; Department of Gynecology and Obstetrics,
Hospital Universitario del Valle,c Cali, Colombia; Department of Obstetrics and Gynecology, The Toledo Hospital,
Medical College of Ohio, Toledo, OHd
Received for publication March 15, 2005; revised April 4, 2005; accepted July 5, 2005
KEY WORDS Objective: The purpose of this study was to determine the efficacy of dexamethasone for
Dexamethasone treatment of HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome.
HELLP (hemolysis, Study design: A prospective, double-blind clinical trial was conducted among 132 women with
elevated liver HELLP syndrome who were assigned randomly to treatment or placebo groups. Pregnant women
enzymes and low in the experimental group received 10-mg doses of dexamethasone intravenously every 12 hours
platelet count) until delivery and 3 additional doses after delivery. Puerperal women received 3 10-mg doses of
syndrome dexamethasone after delivery. The same schedule was used in the placebo group. The main
Clinical trial outcome variable was the duration of hospitalization. In addition, we evaluated treatment effects
on the time to recovery of laboratory and clinical parameters and on frequency of complications.
Results: The mean duration of hospitalization of patients who received dexamethasone therapy
was shorter than in the placebo group (6.5 vs 8.2 days), but this difference was not statistically
significant (P = .37). No significant differences were found in the time to recovery of platelet
counts (hazard ratio, 1.2; 95% CI, 0.8-1.8), lactate dehydrogenase (hazard ratio, 0.9; 95% CI, 0.5-
1.5), aspartate aminotransferase (hazard ratio, 0.6; 95% CI, 0.4-1.1) and to the development of
complications. The results were found in both pregnant and puerperal women.
Conclusion: The results of this investigation do not support the use of dexamethasone for
treatment of HELLP syndrome.
Ó 2005 Mosby, Inc. All rights reserved.
0002-9378/$ - see front matter Ó 2005 Mosby, Inc. All rights reserved.
doi:10.1016/j.ajog.2005.07.037
1592 Fonseca et al
HELLP 1 (%50,000 platelets/mm3), HELLP 2 (between All patients received 1 to 1.5 g/hr of magnesium
50,000 and 100,000 platelets/mm3), and HELLP 3 (be- sulfate intravenously. Nifedipine, 10 mg orally every
tween 100,000 and 150,000 platelets/mm3).6 6 hours, was administered to women with diastolic
Treatment of HELLP syndrome usually is restricted arterial pressure O100 mm Hg. Another antihyperten-
to measures of support and treatment of complications. sive medication (clonidine and amlodipine) was admin-
However, since a first report in 1993,7 several clinical istered if the diastolic pressure remained elevated. In
trials have suggested that corticosteroids, mainly dexa- addition, patients received 1000 mL of normal saline
methasone therapy, can ameliorate and stabilize the solution during the first 2 hours and 1000 mL of normal
disease in the antepartum period and accelerate recovery saline solution every 6 hours afterwards. If the urinary
after delivery.8-11 However, these studies were not dou- output remained !30 mL/hr, an additional 500 mL of
ble-blind or placebo-controlled trials and had small normal saline solution was given during 1 hour; if
sample size, and there is a definite need for additional oliguria persisted, 20 mg of furosemide was adminis-
randomized clinical trials.5 For this reason, we con- tered intravenously. Renal failure was diagnosed if the
ducted a study that was aimed to determine the efficacy serum creatinine level was O1.5 mg/dL and if pulmo-
of dexamethasone for the treatment of HELLP nary edema was diagnosed by physical examination and
syndrome classes 1 and 2. chest radiography. When surgery was indicated, 8 units
of platelets were transfused to women with platelet
counts !50,000/mm3. Because the standard of care of
Material and methods the community is interruption of pregnancy after diag-
nosis of HELLP, induction of labor or cesarean delivery
This was a double-blind, placebo-controlled randomized were performed, depending on the maternal and fetal
clinical trial that involved pregnant and puerperal condition. If the gestational age was between 26 to 34
women who were admitted to the Hospital Universitario weeks, betamethasone (12 mg intramuscularly) was
del Valle in Cali, Colombia, between October 2001 and given every 24 hours for up to 2 doses before delivery.
September 2003. Women who were at O20 weeks of Withholding steroids was considered unacceptable by
gestation or during the first 3 days of puerperium were the investigators and the Institutional Review Board.
asked to participate in the study if hypertension devel- Duration of hospitalization was measured from ran-
oped during the pregnancy or the puerperium and met domization to discharge. The duration of hospitaliza-
the criteria for complete HELLP syndrome as defined tion of the 4 maternal deaths was excluded for the
by Sibai12: platelet count, %100,000/mm3; aspartate calculation of mean and median but was included and
aminotransferase (AST), O70 U/L; lactate dehydrogen- treated as censored data in survival analysis. Criteria for
ase (LDH), O600 U/L. Exclusion criteria were oral discharge included a platelet count O100,000/mm3,
temperature O37.5(C and diabetic ketoacidosis. Be- regardless of AST or LDH levels. However, if evidence
cause of the potential for spontaneous recovery, puer- of organ damage or other clinical complications was
peral women were excluded if randomization was not present, the patients remained in the hospital until
accomplished in the first 24 hours after diagnosis. The recovery.
study was approved by the Institutional Review Boards Measurements of blood pressure and urine output
of the Hospital and the Medical School. were carried out every 2 hours. Baseline and follow-up
Pregnant and puerperal women were assigned ran- laboratory studies included platelet count, AST, LDH,
domly to treatment or placebo groups, with the use of and serum creatinine measurements every 12 hours.
stratified and random permuted blocks of 4. The Platelet counts were performed by automated counting;
assignment was kept inside consecutively numbered LDH and AST were processed at 25(C, with a reference
opaque envelopes that were labeled as pregnant or pattern of 120 to 240 U/L and 0 to 18 U/L, respectively.
puerperal and that were opened after informed consent Medical personnel were trained on protocol proce-
had been obtained. Pregnant women in the experimental dures for enrollment and follow-up of patients. Quality
group received 10-mg doses of dexamethasone sodium checks of clinical and laboratory forms were carried out
phosphate (Oradexon) intravenously every 12 hours before data entry. After entry, programs were run to
until delivery and 3 additional doses after delivery. verify the consistency of responses within each ques-
Puerperal women received 3 10-mg doses after delivery. tionnaire. Any detected inconsistencies were resolved by
The same schedule was used in the control group to correction against original data sheets.
administer sterile water as placebo. Dexamethasone and Sample size was calculated by the duration of hospi-
placebo were packed in identical vials in sealed boxes talization, as defined earlier.13 We assumed an average
that were labeled with the corresponding treatment hospital stay of 6 days in the control group and
codes. Codes were not broken until the end of the considered as significant a 33% decrease in stay for
univariate analysis. Treatment was to be discontinued if the experimental group, with a significance level of .01
oral temperature rose above 37.5(C. and a power of 90%. The required sample size was
Fonseca et al 1593
67 subjects per group. Analysis was carried out on the was performed with linear, logistic, or Cox regression,
basis of intention to treat. A planned subgroup analysis correspondingly. In addition to treatment (ie, the expo-
was performed according to pregnant and puerperal sure of interest), other variables were considered in the
strata. An additional, unplanned subgroup analysis was final model if their probability values were !.2 in the
conducted by severity of clinical presentation at diag- univariate analysis.14-16 Antepartum use of betametha-
nosis. We carried out an interim analysis, at a sample sone up to 2 weeks before randomization was also
size of 50 individuals, with no differences with final considered during modeling. Where appropriate, results
results. Continuous variables were analyzed with un- are presented as relative risk with 95% CI, odds ratio,
paired t-test or Mann-Whitney test, according to their and hazard ratio.
distribution. If needed, transformations were carried out
to allow for normal based statistics. Time to recovery of Results
laboratory parameters (platelets, LDH, and AST) and
duration of hospitalization was analyzed by Kaplan- A total of 144 patients were considered eligible and were
Meier. Categoric variables were compared by chi- invited to participate in the study. Two patients (1.4%)
squared test or Fisher’ s exact test. Multivariate analysis were excluded because of fever, and 2 patients (1.4%)
1594 Fonseca et al
Figure 2 Cumulative risk of (A) discharge, (B) platelet recovery (count O100,000), (C) LDH recovery (!600 U/L), (D) AST
recovery (!70 U/L) according to treatment received.
AST levels of !70 U/L were not reached by 53 (P = .32). A third antihypertensive drug was required in
patients (32 experimental patients and 21 control pa- 8 patients, 4 per treatment group.
tients), which included 2 of the maternal deaths and 51
patients who were discharged once their platelet counts
reached O100,000/mm3. Among patients with an AST Complications and blood transfusion
level of !70 U/L before discharge, there was a trend to
faster recovery among those patients who received There were 4 maternal deaths, 3 deaths in the dexa-
placebo (log rank test probability value, .07) that was methasone group and 1 death in the placebo group.
not significant after adjustment for renal failure, ethnic- Three of the maternal deaths occurred in women with
ity, and parity (hazard ratio, 0.7; 95% CI,0.4-1.1; Figure liver failure and severe hemolysis, with AST and LDH
2,D; Table III). levels of O2600 U/L and O6450 U/L, respectively. The
other death was due to a cerebrovascular accident. The
treatment groups were not different regarding develop-
Recovery of clinical parameters ment of complications or transfusion need (Table IV).
Interestingly, there were a higher number of infections
No significant differences in urinary output were found among those patients who received placebo, and mater-
between the 2 treatment groups. Furosemide was nal death and pulmonary edema were more frequent
required in 23 patients: 13 patients received placebo, among those women who received dexamethasone ther-
and 10 patients received dexamethasone therapy (rela- apy, even after adjustment. Infections were found to be
tive risk, 0.8; 95% CI, 0.4-1.6). All patients were associated independently with admission to the intensive
hypertensive, and 124 patients (93.9%) required nifed- care unit (odds ratio, 10.4; 95% CI, 2.2-48.2), renal
ipine therapy; therefore, we were not able to evaluate failure (odds ratio, 8.8; 95% CI, 1.9-38.8), and vaginal
changes in blood pressure, because they could have delivery (odds ratio, 6.7; 95% CI, 1.3-33.3). The higher
been associated with antihypertensive use. The addition odds of infection with vaginal delivery remained after
of a second antihypertensive drug was necessary in 30 adjustment for the occurrence of premature rupture of
patients, 13 of whom received dexamethasone therapy membranes and the use of antibiotics and steroids
1596 Fonseca et al
Table III Determinants of duration of hospitalization, platelet count, LDH and AST recovery by univariate Cox regression
Duration of hospitalization Platelets* LDHy ASTz
x x x
Hazard ratio 95% CI Hazard ratio 95% CI Hazard ratio 95% CI Hazard ratiox 95% CI
Treatment
Placebok 1 1 1 1
Dexamethasone 1.3 0.87-1.94 1.2 0.80-1.77 0.9 0.53-1.52 0.6 0.39-1.05
Steroid use up to 2 weeks before delivery
Nok 1 1 1 1
Yes 0.9 0.60-1.46 0.9 0.59-1.43 1.0 0.58-1.88 1.2 0.73-2.12
Delivery
Vaginalk 1 1 1 1
Cesarean 0.8 0.51-1.27 0.7 0.47-1.09 1.2 0.68-2.17 1.4 0.8-2.33
Class HELLP at admisión
HELLP 1k 1 1 1 1
HELLP 2 0.8 0.54-1.28 1.2 0.79-1.81 1.3 0.76-2.32 0.9 0.56-1.5
Acute renal failure at admission
Nok 1 1 1 1
Yes 0.3 0.15-0.44 0.5 0.22-0.99 0.3 0.07-1.17 0.5 0.17-1.36
Urinary output at admisión
!30 cc/hourk 1 1 1 1
31-100 cc/hour 4.7 1.94-11.52 2.4 1.07-5.17 1.2 0.47-3.26 1.3 0.50-3.46
O100 cc/hour 5.8 2.13-15.80 2.6 1.07-6.22 0.8 0.23-2.45 1.9 0.64-5.46
* Platelets above 100,000/mm3.
y
LDH below 600 U/L.
z
AST below 70 U/L.
x
Non-adjusted Hazard ratio.
k
Reference category.
median duration was 4 days in both groups, and the study among patients with HELLP syndrome that
interquartile ranges were 3 to 4.5 days and 3 to 7 days report sample size estimation. The estimate was based
for dexamethasone therapy and placebo, respectively. on the duration of hospitalization because it has been
widely accepted that this outcome variable reflects the
development of complications and the rate of recovery
Subgroup analysis by severity of clinical and laboratory variables and because it is a
useful indicator for patients and clinicians. Other valu-
The time to recovery of the platelet count was found to
able features in this study that support its internal
be heterogeneous when the cases were stratified by
validity are the study design (stratified randomization
HELLP class at the time of enrollment (Mantel-Cox
in blocks and double blind) and the small number of
test: chi-squared test, 4.76; P = .03). Therefore, we
protocol violations that result in compliance with the
performed a subgroup analysis according to severity at
assigned treatment of O95%. The external validity of
enrollment. No differences were found among patients
this study is also high probably because of the large
who were classified as HELLP class 2 and control
number of eligible patients who accepted randomiza-
subjects; however, among 49 patients with HELLP
tion, the adoption of a widely accepted dose of dexa-
1 (28 patients with placebo and 21 patients with dexa-
methasone for the treatment group, the use of
methasone therapy), the conditional probability of
betamethasone in preterm deliveries, and the clinical
platelet recovery was higher in those patients who
relevance of the outcome measures.
received dexamethasone therapy (Figure 3), even after
A weakness of this study is that 28.03% of our
adjustment for potential confounders (hazard ratio, 3.4;
patients received betamethasone during the 2 weeks
95% CI, 1.3-8.5). Also, the duration of hospitalization
before delivery for the purpose of accelerating fetal lung
was shorter among women who received dexamethasone
maturity and preventing neonatal intracranial bleeding.
therapy when means (4.6 and 10.4 days), medians (3.5
However, analyses were carried out to adjust by previ-
and 5.0 days), and interquartile ranges were compared.
ous steroid administration (Table III). Furthermore,
This trend persisted after adjustment (P = .03).
analyses were carried out that included only women who
did not received other steroids before delivery (45
Comment women in the placebo group and 50 women in the
dexamethasone group; power, O90%; a, .05) with
Several randomized clinical trials have been published to similar results; therefore, previous administration of
evaluate the effect of dexamethasone therapy in women betamethasone did not affect final results.
with HELLP syndrome.9-11 Although they indicate that The results of this study indicate that the adminis-
dexamethasone therapy is beneficial, the strength of this tration of dexamethasone in patients with complete class
conclusion is limited because of small number of patients 1 and 2 HELLP syndrome, when compared with similar
in each trial, the lack of blinding and placebo controls, patients who received placebo, does not reduce the
the inclusion of women with mild forms of the disease, number of complications or the need for blood products
and the lack of an strict definition of the syndrome (Table administration or shorten platelets and LDH recovery.
V). Observational studies have also found better out- These results were consistent in global and planned
comes in patients with HELLP syndrome who received subgroup analysis. Contrasted with previous studies,
dexamethasone therapy. However, 2 of the studies were AST recovery was slower in patients who were assigned
retrospective, with historic control groups,17,18 and the to dexamethasone therapy than to placebo, and this
other 2 studies compared different steroids.19,20 finding remained in the subgroup analysis. Unfortu-
To the best of our knowledge, this is the largest nately, we cannot speculate about the clinical implica-
reported clinical trial to evaluate the use of dexameth- tions of the last finding, given that patient follow-up
asone therapy in HELLP syndrome and the first that is evaluations finished at the time of platelets recovery,
double blind and placebo controlled. This is also the first regardless of AST levels.
1598 Fonseca et al