The Journal of Maternal-Fetal and Neonatal Medicine, 2012; 25(12): 25972600

2012 Informa UK, Ltd.

ISSN 1476-7058 print/ISSN 1476-4954 online
DOI: 10.3109/14767058.2012.712571

 hoice of glucocorticoid in HELLP syndrome dexamethasone

C
versus betamethasone: revisiting the dilemma
Ahmet Basaran1, Mustafa Basaran2 & Cihat Sen3
1Obstetrics & Gynecology Department, ACIBADEM Kayseri Hospital, Kayseri, Turkey, 2Obstetrics & Gynecology Department, Konya

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Education and Research Hospital, Konya, Turkey, and 3Obstetrics & Gynecology Department, Division of Perinatology, Istanbul
University, Cerrahpasa School of Medicine, Istanbul, Turkey
Objective: Maternal corticosteroid administration has been
reported to improve the blood pressure, urine output, laboratory
values of liver enzymes and platelets in HELLP syndrome. In this
controversial subject, recently, Cochrane Database had updated
its systematic review and in the subgroup analysis they indicated
that dexamethasone was superior to betamethasone for the
improvement of platelet counts and liver enzymes. However,
there are several issues which need to be clarified about the
subgroup analysis and the consequent conclusion. Methods:
Systematic review and re-analysis of the indicated studies.
Results: In the subgroup analysis two studies were included,
which had used non-parametric methods for statistical analysis
and yielded insignificant p-values that showed indifference
between betamethasone and dexamethasone. However, the
Cochrane meta-analysis had used parametric methods in contradistinction to the included studies and indicated significant
difference between two steroids. Accordingly, results and conclusions of the Cochrane meta-analysis in this subgroup analysis
cannot be justified with the indicated two studies. Conclusion:
Here we can only urge further studies to provide frank evidence
about the comparison of dexamethasone and betamethasone in
HELLP syndrome. Until shown to be true, we doubt the credibility
of the subgroup analysis results of the Cochrane review and the
application of these subgroup results into clinical practice.
Keywords: Betamethasone, corticosteroid, dexamethasone,
HELLP syndrome

Introduction
HELLP syndrome is a serious and life-threatening complication
of pregnancy [1]. Hence, management of mothers with HELLP
syndrome is vital in order to prevent serious maternal morbidity
such as liver hematoma, liver rupture, pulmonary edema, cerebrovascular accident, and disseminated intravascular coagulopathy,
and more importantly maternal mortality. Besides other treatment options, corticosteroids may have the potential to intervene
the progression of the disease [1]. Because corticosteroid administration have been reported to improve the blood pressure, urine
output, laboratory values of liver enzymes and platelets, which
had been also debated [2]. In the context of this controversial
subject, recently, Cochrane Database had updated its systematic
review [3]. In this review authors concluded that there is insufficient evidence for the routine use of corticosteroids in HELLP

syndrome, but also added that the use of corticosteroids may be

justified in clinical situations in which increased rate of recovery
in platelet count is considered clinically worthwhile. As a matter
of fact decision to use corticosteroids in HELLP syndrome is at
the discretion of physicians. Moreover, in subgroup analysis of
this review, it was concluded that dexamethasone is superior to
betamethasone for the improvement of platelet counts and liver
enzymes. However, there are several issues need to be clarified
about the subgroup analysis and consequent conclusion.

Studies included for the comparison of

dexamethasone and betamethasone
Only two studies were included in the Cochrane review, which
were conducted by Isler et al. at 2001 and 2003 that evaluated
antenatal and postnatal commencement of the corticosteroids,
respectively [4,5]. When we look in depth to these two studies, we
saw that neither found significant difference between dexamethasone and betamethasone with respect to lactate dehydrogenase
(LDH), aspartate aminotransferase (AST), and platelet count
(Tables I and II) [4,5]. However, in their meta-analysis, Woudstra
et al. found statistically significant difference between dexamethasone and betamethasone both before and after pooling of the two
studies [3]. After contemplating on the three articles, we decided
to reanalyze the data to determine the source of the confusion and
to identify whether Islers original research or Woudstras metaanalysis was the cause of discrepancy.

Statistical reanalysis of the comparison subgroup

in the meta-analysis
We extracted the data from the studies of Isler et al. and reperformed the pooling with NCSS (NCSS, Kaysville, UT) [6]. We
had used different meta-analysis software other than RevMan
(The Cochrane Collaboration, Copenhagen) in order to confirm
the reliability and repeatability of the calculations [7]. Our reanalysis with parametric methods had yielded nearly identical results
with Woudstra et al. (Figures 1, 2 and 3).

Statistical reanalysis of the studies of Isler et al.

We had reanalyzed the provided data in the studies of Isler et al.
by using NCSS [6]. Isler and colleagues had indicated that all
tests were two sided and significance was assessed at the level of

Correspondence: Dr. Ahmet Basaran, Klarslan mah, Nurda Sk. Sinanoba sitesi, B-blok No:19, Seluklu, Konya/Trkiye. Tel: +90 532 777 83 13.
E-mail: dr_ahmetbasaran@yahoo.com; dr.ahmetbasaran@gmail.com

2597

2598 A. Basaran et al.

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Table I. Parameters and p values in the study of Isler et al. 2001 [4].
Adjusted time averaged
change from baseline
Dexamethasone Betamethasone
(mean SD)
(n = 19)
(n = 21)
p
MAP (mmHg)
15.61.4
8.11.4
<0.001
Urinary output (mL/h)
12.98.6
11.98.2
0.043
13.13.1
5.02.9
0.065
Platelet count (109 cells
count/L)
Lactate dehydrogenase
81.256.6
27.058.2
0.169
(U/L)
Aspartate aminotransferase
20.49.6
9.98.9
0.29
(U/L)
Table II. Parameters and p values in the study of Isler et al. 2003 [5].
Adjusted time averaged
change from baseline
Dexamethasone Betamethasone
(mean SD)
(n = 18)
(n = 18)
p
MAP (mmHg)
15.31.4
7.51.4
<0.001
Urinary output (mL/h)
64.211.5
56.011.5
0.619
33.84.2
30.14.2
0.537
Platelet count (109 cells
count/L)
Lactate dehydrogenase
318.759.3
223.959.3
0.281
(U/L)
Aspartate aminotransferase
51.48.9
44.18.9
0.570
(U/L)

Figure 2. Forrest plot of lactate dehydrogenase.

Figure 3. Forrest plot of aspartate aminotransferase.

Figure 1. Forrest plot of platelet counts.

0.05. In the reanalysis, we had used two sided t-tests with variance
assumption either met or not met (Table III). And we had found
that the indicated p values in the original studies were totally
different form our reanalysis. Consequently, two issues raised
concern;
Did the authors calculate or report incorrectly? If the authors
had used t-test for comparison, they should have had either
calculated or reported the results incorrectly. We think that
this is not the case.
Did the authors use non-parametric tests for comparison of
the means? Non-parametric statistics are less powerful (sensitive) than their parametric counterparts, and if it is important to detect even small effects one should be very careful
in the choice of a test statistic [8]. Non-parametric methods

are usually appropriate when the sample sizes are small [8].
However, if the sample size is large (n > 100) or the variable is
known to be normally distributed in the population, the parametric tests are an eligible option [8]. The number of patients
in the studies of Isler et al. was small. Therefore, Isler etal. had
probably used non-parametric tests in their analysis of raw
data (our reanalysis with parametric t-test showed significant
difference between the groups as in the meta-analysis). If the
authors had used non-parametric tests that were not able to
detect any significant difference between betamethasone and
dexamethasone, we should ask a second question that is which
approach should be the choice for pooling of these studies,
pooling of p values (for non-parametric tests) or pooling of
the data with parametric methods? In case of a meta-analysis
which included numerous studies, it would be more logical to
use pooling of data with parametric methods because a large
sample size will be reached in the meta-analysis. However, with
two small studies, as we come across here, the answer would be
pooling of the p values in our view, but our choice could be
debated by others. After all, we also pooled the p values from
the studies of Isler et al., according to Fishers method [9] and
the combined p values were 0.348, 0.413, and 0.223 for platelet
count, LDH, and AST, respectively. The combined p-values did
not indicate significant difference between dexamethasone and

The Journal of Maternal-Fetal and Neonatal Medicine

Choice of glucocorticoid in HELLP syndrome2599

Table III. Re-analysis of original studies by Isler et al. [4,5].
Adjusted time averaged change from
baseline (mean SD)
Isler 2001
Platelet count (109 cells count/L)
Lactate dehydrogenase (U/L)
Aspartate aminotransferase (U/L)
Isler 2003
Platelet count (109 cells count/L)
Lactate dehydrogenase (U/L)
Aspartate aminotransferase (U/L)

Recalculated p (95% CI of difference)

Variance assumption equal Variance assumption unequal

Dexamethasone

Betamethasone

13.13.1
81.256.6
20.49.6

5.02.9
27.058.2
9.98.9

0.0001 (6.1794; 10.0206)

0.005 (91.0223; 17.3777)
0.0001 (36.2214; 24.3786)

0.0001 (6.1710; 10.0290)

0.005 (90.9765; 17.4235)
0.0001 (36.2506; 24.3494)

33.84.2
318.759.3
51.48.9

30.14.2
223.959.3
44.18.9

0.0123 (0.8549; 6.5451)

0.0001 (34.9707; 54.6293
0,0191 (13.3290; 1.2710)

0.0123 (0.8549; 6.5451)

0.0001 (134.9707; 54.6293
0.0191 (13.3290; 1.2710)

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a debatable maternal benefit may lead to detrimental effects with

regard to fetal benefit.

Conclusion

Figure 4. Discrepant results with two different statistical methods.

betamethasone. In fact, we can see that two discrepant results

can be reached with different statistical methods (Figure 4).

Do distinction between dexamethasone vs.

betamethasone clinically relevant?
Glucocorticoids have genomic (mediated through nuclear steroid
receptors) and non-genomic (mediated through membrane
steroid receptors and interaction with cellular membranes) effects
[10]. It is classically known that dexamethasone and betamethasone are similar in pharmacologic activity in terms of potency
and equivalent dose for the genomic effects. However, these
drugs are not identical. When compared according to potentially unfavorable non-genomic effects dexamethasone is more
potent than betamethasone [11]. This issue becomes important
when we consider the patient population that will be treated with
these drugs. In case of HELLP syndrome, 53.1% of the patients
will have accompanying fetal growth restriction [12]. Therefore,
dexamethasone, if used, potentially may have more iatrogenic
harm risk to the fetus when compared to betamethasone. This
theoretical iatrogenic risk associated with dexamethasone can
be indirectly exemplified with the studies of betamethasone.
Findings in animal models of fetal growth restriction indicate
that betamethasone increases cerebral blood flow 13030%
and this in turn causes significant increase in oxidative damage
in the hippocampus and subcallosal area [13,14]. Umbilical
artery Doppler studies in growth-restricted human fetuses with
absent end-diastolic flow have shown that betamethasone causes
a transient return of end-diastolic flow [15,16]. Doppler studies
and animal experimentation with betamethasone clearly shows
that corticosteroids significantly alter the hemodynamics of fetal
circulation. Accordingly, with use of dexamethasone which has
more unfavorable effects than betamethasone, we may come
across with increased risk of iatrogenic harm to fetus [11]. When
we take into account the two studies and the methodology of
meta-analysis, favoring dexamethasone over betamethasone for

2012 Informa UK, Ltd.

We had perused two studies and the subgroup analysis in a metaanalysis. We come across with the result that authors of these two
included studies had probably used non-parametric methods that
yielded insignificant results (Figure 4). However, the Cochrane
meta-analysis had used parametric methods in contradistinction to the included studies and indicated significant difference
between the two steroids. Therefore, the subgroup conclusions
of the Cochrane meta-analysis cannot be justified with the indicated two studies and the statistical methods used for a choice
between betamethasone and dexamethasone. Here we can only
urge further large studies to provide frank evidence about the
comparison of dexamethasone and betamethasone in HELLP
syndrome. Until otherwise becomes true, we doubt the credibility of the subgroup analysis results of Cochrane review and
application of these subgroup results to clinical practice. When
the side-effect potential considered, favoring dexamethasone over
betamethasone for a debatable maternal benefit may lead to detrimental fetal effects.
Declaration of Interest: AB was responsible for conception of the
idea, acquisition of literature, analysis and interpretation of data,
drafting and revising the article. MB was responsible for analysis
and interpretation of data, acquisition of literature, drafting and
revising the article. CS was responsible for analysis and interpretation of data, drafting and revising the article. The authors report
no conflict of interest.

References
1. Barton JR, Sibai BM. Gastrointestinal complications of pre-eclampsia.
Semin Perinatol 2009;33:179188.
2. Fonseca JE, Mndez F, Catao C, Arias F. Dexamethasone treatment
does not improve the outcome of women with HELLP syndrome: a
double-blind, placebo-controlled, randomized clinical trial. Am J Obstet
Gynecol 2005;193:15911598.
3. Woudstra DM, Chandra S, Hofmeyr GJ, Dowswell T. Corticosteroids for
HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome in
pregnancy. Cochrane Database Syst Rev 2010;CD008148.
4. Isler CM, Barrilleaux PS, Magann EF, Bass JD, Martin JN Jr. A
prospective, randomized trial comparing the efficacy of dexamethasone
and betamethasone for the treatment of antepartum HELLP (hemolysis,
elevated liver enzymes, and low platelet count) syndrome. Am J Obstet
Gynecol 2001;184:13327; discussion 1337.
5. Isler CM, Magann EF, Rinehart BK, Terrone DA, Bass JD, Martin JN
Jr. Dexamethasone compared with betamethasone for glucocorticoid
treatment of postpartum HELLP syndrome. Int J Gynaecol Obstet
2003;80:291297.
6. Hintze J. NCSS 2007. Kaysville, Utah, USA; 2007.

2600 A. Basaran et al.

13.
14.

15.
16.

pre-eclampsia-associated intrauterine growth restriction. Mol Hum

Reprod 2007;13:281285.
Miller SL, Chai M, Loose J, Castillo-Melndez M, Walker DW, Jenkin G,
Wallace EM. The effects of maternal betamethasone administration on the
intrauterine growth-restricted fetus. Endocrinology 2007;148:12881295.
Miller SL, Supramaniam VG, Jenkin G, Walker DW, Wallace EM.
Cardiovascular responses to maternal betamethasone administration
in the intrauterine growth-restricted ovine fetus. Am J Obstet Gynecol
2009;201:613.e1613.e8.
Edwards A, Baker LS, Wallace EM. Changes in umbilical artery
flow velocity waveforms following maternal administration of
betamethasone. Placenta 2003;24:1216.
Robertson MC, Murila F, Tong S, Baker LS, Yu VY, Wallace EM.
Predicting perinatal outcome through changes in umbilical artery
Doppler studies after antenatal corticosteroids in the growth-restricted
fetus. Obstet Gynecol 2009;113:636640.

J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by HINARI on 03/14/15

For personal use only.

7. (RevMan) RM. Version 5.1 ed. Copenhagen: The Nordic Cochrane

Centre, The Cochrane Collaboration; 2011.
8. (Electronic Version): StatSoft Inc. Electronic Statistics Textbook. Tulsa,
OK: StatSoft; 2011.
9. Singh G. Conventional approach of combining p-values using chi-square
test: an essence of meta analysis. Internet J Med Inform 2007;3.
10. Buttgereit F, Brand MD, Burmester GR. Equivalent doses and relative
drug potencies for non-genomic glucocorticoid effects: a novel
glucocorticoid hierarchy. Biochem Pharmacol 1999;58:363368.
11. Vidaeff AC, Blackwell SC. Potential risks and benefits of antenatal
corticosteroid therapy prior to preterm birth in pregnancies complicated
by severe fetal growth restriction. Obstet Gynecol Clin North Am
2011;38:20514, ix.
12. Sziller I, Babula O, Hupuczi P, Nagy B, Rig B, Szab G, Papp Z, et
al. Mannose-binding lectin (MBL) codon 54 gene polymorphism
protects against development of pre-eclampsia, HELLP syndrome and

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