Corticosteroids for HELLP syndrome in pregnancy

Comparison 01 Dexamethasone plus standard treatment versus standard treatment alone, Outcome 03Mean platelet counts over 48 hours.. Comparison 01 Dexamethasone plus standard treatment ve

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Corticosteroids for HELLP syndrome in pregnancy (Review)

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T A B L E O F C O N T E N T S

1ABSTRACT

2PLAIN LANGUAGE SUMMARY

2BACKGROUND

3OBJECTIVES

3CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW

3SEARCH METHODS FOR IDENTIFICATION OF STUDIES

3METHODS OF THE REVIEW

4DESCRIPTION OF STUDIES

4METHODOLOGICAL QUALITY

4RESULTS

5DISCUSSION

6AUTHORS’ CONCLUSIONS

6POTENTIAL CONFLICT OF INTEREST

6ACKNOWLEDGEMENTS

6SOURCES OF SUPPORT

7REFERENCES

8TABLES

8Characteristics of included studies

12ANALYSES

12Comparison 01 Dexamethasone plus standard treatment versus standard treatment alone

13Comparison 02 Dexamethasone versus betamethasone

14INDEX TERMS

14COVER SHEET

15GRAPHS AND OTHER TABLES

15Analysis 01.01 Comparison 01 Dexamethasone plus standard treatment versus standard treatment alone, Outcome 01Maternal deaths

15Analysis 01.02 Comparison 01 Dexamethasone plus standard treatment versus standard treatment alone, Outcome 02Postpartum sepsis

16Analysis 01.03 Comparison 01 Dexamethasone plus standard treatment versus standard treatment alone, Outcome 03Mean platelet counts over 48 hours

16Analysis 01.04 Comparison 01 Dexamethasone plus standard treatment versus standard treatment alone, Outcome 04Mean hospital stay post randomisation (days)

17Analysis 01.05 Comparison 01 Dexamethasone plus standard treatment versus standard treatment alone, Outcome 05Neonatal deaths

17Analysis 01.06 Comparison 01 Dexamethasone plus standard treatment versus standard treatment alone, Outcome 06Neonates with intraventricular hemorrhage

18Analysis 01.07 Comparison 01 Dexamethasone plus standard treatment versus standard treatment alone, Outcome 07Neonates with respiratory distress syndrome

18Analysis 01.08 Comparison 01 Dexamethasone plus standard treatment versus standard treatment alone, Outcome 08Neonates with 5 minute Apgars less than 7

19Analysis 01.09 Comparison 01 Dexamethasone plus standard treatment versus standard treatment alone, Outcome 09Weight at birth in grams

19Analysis 01.10 Comparison 01 Dexamethasone plus standard treatment versus standard treatment alone, Outcome 10Neonates with retrolental fibroplasia

20Analysis 01.11 Comparison 01 Dexamethasone plus standard treatment versus standard treatment alone, Outcome 11Number of cesarean section deliveries

20Analysis 01.12 Comparison 01 Dexamethasone plus standard treatment versus standard treatment alone, Outcome 12Time interval (hours) from randomisation to delivery

20Analysis 02.01 Comparison 02 Dexamethasone versus betamethasone, Outcome 01 Mean arterial pressure: adjusted

time-averaged change from baseline

i Corticosteroids for HELLP syndrome in pregnancy (Review)

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21Analysis 02.02 Comparison 02 Dexamethasone versus betamethasone, Outcome 02 Urinary output (mL/h): adjustedtime-averaged change from baseline

21Analysis 02.03 Comparison 02 Dexamethasone versus betamethasone, Outcome 03 Platelet count (10-9 cells/L):

adjusted time-averaged change from baseline

21Analysis 02.04 Comparison 02 Dexamethasone versus betamethasone, Outcome 04 LDH activity (U/L mean): adjustedtime-averaged change from baseline

22Analysis 02.05 Comparison 02 Dexamethasone versus betamethasone, Outcome 05 AST activity (U/L): adjusted time-averaged change from baseline

22Analysis 02.06 Comparison 02 Dexamethasone versus betamethasone, Outcome 06 Number of mothers with oliguria(less than 30 ml/hour for 2 hours)

23Analysis 02.07 Comparison 02 Dexamethasone versus betamethasone, Outcome 07 Maternal pulmonary edema

23Analysis 02.08 Comparison 02 Dexamethasone versus betamethasone, Outcome 08 Number of participants needing

acute antihypertensive therapy

24Analysis 02.09 Comparison 02 Dexamethasone versus betamethasone, Outcome 09 Neonates with a 5 minute Apgar

less than 7

24Analysis 02.10 Comparison 02 Dexamethasone versus betamethasone, Outcome 10 Neonates needing ventilatory

support

25Analysis 02.11 Comparison 02 Dexamethasone versus betamethasone, Outcome 11 Neonates with respiratory distresssyndrome

25Analysis 02.12 Comparison 02 Dexamethasone versus betamethasone, Outcome 12 Neonatal sepsis

26Analysis 02.13 Comparison 02 Dexamethasone versus betamethasone, Outcome 13 Neonatal hyperbilirubinemia

26Analysis 02.14 Comparison 02 Dexamethasone versus betamethasone, Outcome 14 Fetal or neonatal death

27Analysis 02.15 Comparison 02 Dexamethasone versus betamethasone, Outcome 15 Neonate time to discharge (days:

mean)

ii Corticosteroids for HELLP syndrome in pregnancy (Review)

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Corticosteroids for HELLP syndrome in pregnancy (Review)

Matchaba P, Moodley J

This record should be cited as:

Matchaba P, Moodley J Corticosteroids for HELLP syndrome in pregnancy Cochrane Database of Systematic Reviews 2004, Issue 1.

Art No.: CD002076 DOI: 10.1002/14651858.CD002076.pub2

This version first published online: 26 January 2004 in Issue 1, 2004.

Date of most recent substantive amendment: 31 October 2003

A B S T R A C T Background

Hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome is a severe form of pre-eclampsia Pre-eclampsia is a multi-systemdisease of pregnancy associated with an increase in blood pressure and increased perinatal and maternal morbidity and mortality Eightyper cent of women with HELLP syndrome present before term There are suggestions from observational studies that steroid treatment

in HELLP syndrome may improve disordered maternal hematological and biochemical features and perhaps perinatal mortality andmorbidity

Data collection and analysis

The two authors independently applied inclusion criteria, assessed trial quality and extracted relevant data

Main results

Of the five studies reviewed (n = 170), three were conducted antepartum and two postpartum Four of the studies randomisedparticipants to standard therapy or dexamethasone One study compared dexamethasone with betamethasone

Dexamethasone versus control

There were no significant differences in the primary outcomes of maternal mortality and morbidity due to placental abruption,pulmonary oedema and liver hematoma or rupture Of the secondary maternal outcomes, there was a tendency to a greater plateletcount increase over 48 hours, statistically significantly less mean number of hospital stay days (weighted mean difference (WMD) -4.50,95% confidence interval (CI) -7.13 to -1.87), mean interval (hours) to delivery (41 ± 15) versus (15 ± 4.5) (p = 0.0068) in favour ofwomen allocated to dexamethasone

There were no significant differences in perinatal mortality or morbidity due to respiratory distress syndrome, need for ventilatorysupport, intracerebral hemorrhage, necrotizing enterocolitis and a five minute Apgar less than seven The mean birthweight wassignificantly greater in the group allocated to dexamethasone (WMD 247.00, 95% CI 65.41 to 428.59)

Dexamethasone versus betamethasone

There were no significant differences in all the maternal and perinatal mortality and in primary morbidity outcomes

1 Corticosteroids for HELLP syndrome in pregnancy (Review)

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Women randomised to dexamethasone fared significantly better for: oliguria, mean arterial pressure, mean increase in platelet count,mean increase in urinary output and liver enzyme elevations.

(hy-B A C K G R O U N D

Hemolysis, elevated liver enzymes and low platelets (HELLP)

syn-drome is a severe form of pre-eclampsia (Pritchard 1954)

Pre-eclampsia is a condition associated with an increase in blood

pres-sure, protein loss via the urine, and oedema in pregnancy and

occurs in 5% to 8% of all pregnancies Its cause is not known,

but it remains a major cause of perinatal and maternal morbidity

and mortality (Duley 1992) HELLP syndrome occurs in about

20% of severely pre-eclamptic women and does so before term

in 80% of cases; 10% of these occur before 27 weeks’ gestation

(Sibai 1993) Premature delivery contributes to the very high rate

of perinatal morbidity and mortality About a third of the cases

are diagnosed for the first time postpartum (Sibai 1993)

Although it is agreed that hemolysis, liver dysfunction and

throm-bocytopenia must be present to make a diagnosis of HELLP

syn-drome, there is disagreement over the specific biochemical and

hematological criteria to be used For the purposes of this

re-view, the criteria specified by Sibai (Sibai 1986) and Martin

(Mar-tin 1991) will be used Sibai’s criteria include hemolysis as

evi-denced by an abnormal peripheral smear, lactate dehydrogenase

(LDH) greater than 600 IU/L or Total Bilirubin (TB) greater

than 1.2 ULN; elevated liver enzymes as evidenced by an aspartate

transaminase (AST) greater than 70 IU/L and platelets less than

100 000/mm³ Martin’s criteria include hemolysis as evidenced by

a falling hematocrit, LDH greater than 164 IU/L or a bleeding

diathesis; elevated liver enzymes as evidenced an AST greater than

48 IU/L and alanine transaminase (ALT) greater than 24 IU/L

and platelets less than 100 000 mm³

Maternal mortality (1% to 3.5%) and morbidity are increased

by the hypertensive complications of pre-eclampsia, the bleeding

tendency that results from the low platelets and liver dysfunction(Sibai 1993; Weinstein 1985; Martin 1991)

Since HELLP syndrome is common before term, any interventionthat prolongs the time from diagnosis to delivery by stabilising theclinical condition, may decrease perinatal morbidity and mortal-ity Steroids have been shown in observational studies (Magann1993; Clark 1986; Yeast 1987) to improve the deranged maternalbiochemical and haematological indices associated with the syn-drome This benefit has also been shown in HELLP syndromediagnosed postpartum (Martin 1997; Yalcin 1998) However, itmay be argued that delaying delivery may worsen the maternalmorbidity and increase both maternal and fetal mortality

Glucocorticoids have been shown to improve fetal lung ration, decreasing the occurrence and severity of respiratory dis-tress syndrome and the overall fetal morbidity and mortality afterpreterm birth (Crowley 1999) Dexamethasone at doses up to atotal of 48 mg over a 48 hour period may be given intramuscu-larly in order to improve fetal lung function However, the steroiddosing regimens that have been suggested for HELLP syndromeare different from the one used for fetal lung maturation The ma-ternal and fetal effects of such a regimen have not been quantified.Also, the number of women with HELLP syndrome who havebeen treated with steroids is probably small

matu-This review therefore aims to summarise existing evidence of theeffects of steroids in HELLP syndrome Any effects may be dif-ferent according to the gestational age, severity of disease, parityand whether the mother is antepartum or postpartum The effectestimates will be explored for these factors

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O B J E C T I V E S

(1) To evaluate the effects of corticosteroids in women with

HELLP syndrome during pregnancy or shortly after delivery

The following primary hypothesis will be tested:

In comparing women given steroids with control/placebo groups,

there will be no difference in:

(a) maternal morbidity and mortality;

(b) perinatal morbidity and mortality

(2) In addition, we will explore whether the possible effects of

steroids on the mother differ according to:

(a) gestational age at treatment; and

(b) whether the mother is antepartum or postpartum

C R I T E R I A F O R C O N S I D E R I N G

S T U D I E S F O R T H I S R E V I E W

Types of studies

All randomised controlled trials and trials which used

pseudo-randomised methods, such as alternate allocation

Types of participants

All antepartum and postpartum women diagnosed clinically and

by biochemical parameters as having the HELLP syndrome

Types of intervention

Any corticosteroid versus placebo or no treatment

Types of outcome measures

Primary outcomes

(1) maternal mortality;

(2) perinatal mortality;

(3) maternal morbidity, namely:

• presence of liver hematoma and rupture;

• pulmonary oedema;

• renal failure;

• abruptio placentae;

(4) perinatal morbidity, namely:

• respiratory distress syndrome and ventilatory support required;

• intracerebral haemorrhage;

• necrotizing enterocolitis

Secondary outcomes

(1) Maternal

After randomisation, the

• average time taken to return to normal biochemical and

haema-tological parameters;

• average time taken to return to a normal urine output;

• average time taken to return to a normal blood pressure;

• average time to delivery;

• mode of delivery

(2) Neonatal

• the mean gestational age and weight at birth;

• the mean Apgar scores at birth

1 quarterly searches of the Cochrane Central Register ofControlled Trials (CENTRAL);

2 monthly searches of MEDLINE;

3 handsearches of 30 journals and the proceedings of majorconferences;

4 weekly current awareness search of a further 37 journals.Details of the search strategies for CENTRAL and MEDLINE,the list of handsearched journals and conference proceedings,and the list of journals reviewed via the current awareness servicecan be found in the ’Search strategies for identification of studies’section within the editorial information about the CochranePregnancy and Childbirth Group

Trials identified through the searching activities described aboveare given a code (or codes) depending on the topic The codesare linked to review topics The Trials Search Co-ordinatorsearches the register for each review using these codes rather thankeywords

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• number of women;

• women’s characteristics including ethnic origin, parity, whether

the women were antepartum or postpartum, gestational age at

diagnosis, number of babies in current pregnancy, the mode of

delivery and time from diagnosis to delivery;

• the haematological and biochemical results;

• morbidity and mortality outcomes;

• the type, dose and duration of steroid used;

• other medication used

Babies’ characteristics including ethnic origin, gestational age at

birth, weight, Apgar scores and morbidity and mortality outcomes

It was intended to explore whether any heterogeneity of effect was

explained by whether the woman was antepartum or postpartum,

the gestational age, severity of disease and parity

D E S C R I P T I O N O F S T U D I E S

Seven published studies were identified that met the inclusion

criteria One of the studies (Kadanali 1997) has not been included

in the data analysis because it is being translated into English

and another (Isler 2003) has not been included because we have

asked for the original data Of the five studies that have been

analysed, four have compared steroid use (dexamethasone) with

placebo (Isler 2001; Magann 1994a; Magann 1994b; Yalcin 1998:

Vigil-De Gracia 1997) One study compared two different steroid

regimens (Isler 2001) The total number of trial participants in

the five studies is 170

Three of the reviewed studies were conducted antepartum (Isler

2001; Magann 1994b; Vigil-De Gracia 1997) The other two were

conducted postpartum (Magann 1994a; Yalcin 1998)

M E T H O D O L O G I C A L Q U A L I T Y

Three studies employed adequate randomisation and

alloca-tion concealment methods (Isler 2001; Magann 1994a; Magann

1994b) However, in Magann 1994b, women allocated to

stan-dard treatment (control) had higher mean platelet counts than

those allocated to steroid treatment

In the two other studies (Yalcin 1998; Vigil-De Gracia 1997), there

was no mention of the randomisation method used, nor whether

allocation concealment was implemented Furthermore in

Vigil-De Gracia 1997, the groups randomly allocated to standard

ther-apy differed in the maternal platelet count when compared with

the group allocated to steroid therapy, the platelet count being

lower in the group randomly allocated to receive steroids None

of the trials were placebo-controlled

In none of the five included studies was blinding described in themethods section

There was significant loss to follow up in one study (Magann1994a) Only 25 of the original 40 participants randomised wereaccounted for in the results section Intention to treat analysis wasnot performed in this study The other studies had no loss to followup

(Ma-ii) Respiratory distress syndrome events occurred in one study(Magann 1994b) and there was no statistically significant differ-ence (RR 1.00, 95% CI 0.25 to 4.00)

iii) Retrolental fibroplasia occurred in one neonate allocated toplacebo (Magann 1994b) but the difference was not statisticallysignificant (RR 0.36, 95% CI 0.02 to 8.05)

No intracerebral hemorrhagic events nor necrotizing enterocolitiswere recorded

Trial that compared dexamethasone and betamethasone

There was only one study with this design (Isler 2001, n = 40)

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Maternal morbidity

There were no cases of liver hematoma or rupture, pulmonary

oedema, or abruptio placentae in either group There was a

statis-tically significant difference in maternal oliguria (RR 0.06, 95%

CI 0.00 to 0.93) in favour of participants randomised to

dexam-ethasone

Perinatal morbidity

There was a tendency for fewer neonates allocated to

dexametha-sone to have ventilatory support or respiratory distress syndrome

when compared with those allocated to betamethasone However,

this was not statistically significant (RR 0.54, 95% CI 0.19 to

1.56) In this study, no cases of intracerebral hemorrhage and

necrotizing enterocolitis were recorded

2 Secondary outcomes

Trials that compared dexamethasone plus standard therapy

versus standard therapy alone

i) There was no statistically significant difference in postpartum

sepsis (RR 2.00, 95% CI 0.20 to 19.78) in one study (n = 30) and

cesarean sections (RR 0.93, 95% CI 0.66 to 1.31) between the

two groups (one study, n = 34)

ii) There was a tendency to a greater platelet count increase over

48 hours in participants allocated to dexamethasone (weighted

mean difference (WMD) 40.60, 95% CI -26.12 to 107.32) but

this result must be interpreted with caution because the data are

skewed and are derived from only one small study (Vigil-De Gracia

1997, n=34)

iii) There was a statistically significant difference in the mean

num-ber of hospital stay days postrandomisation (WMD -4.50, 95%

CI -7.13 to -1.87) in favour of participants allocated to

dexam-ethasone

iv) There was a significant difference in the mean interval (hours)

from randomisation to delivery (41 ± 15) versus (15 ± 4.5) (p =

0.0068) in favour of women allocated to dexamethasone in the

single study that looked at this outcome (Magann 1994b, n = 25)

Neonatal morbidity

The number of neonates with a five minute Apgar less than seven

did not differ significantly (RR 1.00 95% CI 0.25 to 4.00): one

study, n = 24 The mean weight at birth was significantly greater

in the group allocated to steroids (WMD 247.00, 95% CI 65.41

to 428.59)

Trial that compared dexamethasone and betamethasone

There was a statistically significant difference in favour of

partic-ipants allocated to dexamethasone in the adjusted time-average

change from baseline in the following secondary outcomes:

i) The mean arterial pressure decrease (WMD -7.50, 95% CI -8.37

ther-CI 0.12 to 0.73)

Neonatal morbidity

There were no statistically significant differences between the twogroups with regards to the number of neonates with a five minuteApgar less than seven (RR 0.95, 95% CI 0.22 to 4.14), neonatalsepsis (RR 4.76, 95% CI 0.24 to 93.19), neonatal hyperbiliru-binemia (RR 2.85, 95% CI 0.32 to 25.07) and mean time to dis-charge in days (WMD -5.40, 95% CI -19.53 to 8.73)

There was no trial that compared betamethasone plus standardtherapy versus standard therapy alone

D I S C U S S I O N Trials that compared participants randomised with steroid (dexamethasone) use and placebo (Magann 1994a; Magann

1994b; Vigil-De Gracia 1997; Yalcin 1998)

HELLP syndrome is a severe form of pre-eclampsia (Pritchard1954), whose cause is unknown and remains a major cause of peri-natal morbidity and mortality (Duley 1992) In this review therewas no statistically significant difference in the primary outcome

of maternal mortality (relative risk (RR) 0.33, 95% confidenceinterval (CI) 0.01 to 7.65) There was one maternal death in thegroup allocated to placebo in a trial with a total of 34 partici-pants (Vigil-De Gracia 1997) Besides the small sample size of thistrial, the randomisation method used was not mentioned and themethodology used for allocation concealment is unclear Further-more the postrandomisation patient characteristics differed signif-icantly with regards to platelet count, before treatment was insti-tuted

There were four neonatal deaths in one small trial (Magann 1994b,

n = 25), which were not statistically significant (RR 0.36, 95%

CI 0.04 to 3.02) Although allocation concealment and sation were adequate in this trial, maternal platelet levels differedsignificantly postrandomisation before treatment commenced (p

randomi-= 0.034) and the ratio of black to female participants was 2:1.Maternal morbidity primary outcomes of pulmonary oedema,presence of a liver hematoma or rupture, renal and abruptio pla-centae did not differ significantly between the two groups of par-ticipants

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None of the primary perinatal morbidity outcomes, respiratory

distress syndrome, need for ventilatory support, intracerebral

hem-orrhage and necrotizing enterocolitis, differed significantly

The only secondary maternal morbidity outcome that was

sta-tistically significant in favour of steroid use was the mean

num-ber of days of hospital stay (weighted mean difference (WMD)

-4.50, 95% CI -7.13 to -1.87) The number of neonates with

Ap-gar scores less than seven after five minutes were not significantly

different The mean weight at birth differed significantly (WMD

247.00, 95% CI 65.41 to 428.59) in one study (Magann 1994b)

In summary, because of the small sample sizes in the trials

re-viewed, there is no evidence that either supports or refutes the use

of steroids in HELLP syndrome antenatally and in the

postpar-tum period in order to decrease or increase maternal and perinatal

mortality and the primary morbidity outcomes of interest in this

review

One trial compared dexamethasone use with betamethasone

(Isler 2001):

There were no maternal or neonatal primary outcome differences

with regards to death and maternal morbidity, with the exception

of oliguria (less than 30 ml urine/hour for two hours) (RR 0.06,

95% CI 0.00 to 0.93), in favour of dexamethasone

The main findings were in the maternal hematological and

bio-chemical parameters In all instances of adjusted time-average

change from baseline for mean arterial pressure decrease, mean

increase in the platelet count, mean decrease in lactate

dehydroge-nase and aspartate transamidehydroge-nase activity and the need for acute

an-tihypertensive therapy, women allocated to dexamethasone fared

better significantly than those allocated to betamethasone This

is supportive of the observational data referenced above that had

similar findings

There were no significant differences in the secondary neonatal

outcomes of Apgar score of less than seven after five minutes,

neonatal sepsis, hyperbilirubinaemia and time to discharge from

hospital

In summary, because of the small sample size there is no evidence

from this trial that indicates that when dexamethasone is given

intravenously (10 mg 12 hourly before delivery), that there is a

statistically significant difference in the maternal biochemical and

hematological parameters when compared with betamethasone

(12 mg intramuscularly every 24 hours)

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Until a large enough study that is adequately designed with

suffi-cient power to detect a significant difference in the primary ternal and neonatal outcomes of death and severe morbidity, there

ma-is no evidence to support the addition of dexamethasone or tamethasone to standard therapy in HELLP syndrome However,

be-it is important to note that glucocorticoids have been shown toimprove fetal lung maturity and overall fetal mortality and mor-bidity when the appropriate dosing regimens are used (Crowley1999)

Implications for research

The high maternal and perinatal mortality and morbidity ated with HELLP syndrome makes it imperative that a large studywith the appropriate design be done to determine the effect ofantenatal and postpartum steroids on the primary and secondaryoutcomes chosen in this review Steroids are relatively cheap and

associ-if found efficacious in decreasing the primary outcomes sought

in the review, they would provide a cost-effective intervention forHELLP syndrome Because HELLP syndrome is not very com-mon (Sibai 1993), a global multi-centre study design may be themost efficient study design to use in order to recruit sufficient pa-tients to adequately answer the review question

P O T E N T I A L C O N F L I C T O F

I N T E R E S T

We certify that we have no affiliations or involvement in any ganisation or entity with a direct financial interest in the subjectmatter of the review (e.g employment, consultancy, stock owner-ship, honoraria and expert testimony) The researchers wrote thisreview independently and Novartis Pharmaceuticals has no com-mercial or intellectual interest in the topic or products reviewed

or-A C K N O W L E D G E M E N T S

Contributions: Jim Neilson, Michel Boulvain, the Cochrane nancy and Childbirth Group’s panel of consumers

Preg-S O U R C E Preg-S O F Preg-S U P P O R T External sources of support

• No sources of support supplied

Internal sources of support

• Medical Research Council SOUTH AFRICA

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R E F E R E N C E S References to studies included in this review

Isler 2001 {published data only}

Isler C, Barrilleaux P, Magann E, Bass J, Martin J A prospective,

randomized trial comparing the efficacy of dexamethasone and

be-tamethasone for the treatment of antepartum HELLP (hemolysis,

elevated liver enzymes, and low platelet count) syndrome [Un

estu-dio prospectivo, randomizado que compara la eficacia de la

dexam-etasona y betamdexam-etasona para el tratamiento anteparto del sindron de

hellp (hemolisis, elevacion de enzimas hepaticas y plaquetopenia)].

Revista Chilena de Obstetricia y Ginecologia 2001;66(3):248–50.

Isler CM, Barrilleaux PS, Magann EF, Bass JD, Martin JN A

prospec-tive, randomized trial comparing the efficacy of dexamethasone and

betamethasone for the treatment of antepartum HELLP (hemolysis,

elevated liver enzymes, and low platelet count) syndrome American

Journal of Obstetrics and Gynecology 2001;184(7):1332–7.

Magann 1994a {published data only}

Magann EF, Perry KG, Meydrech EF, Harris RL, Suneet PC,

Mar-tin JN Postpartum corticosteroids: accelerated recovery from the

syndrome of hemolysis, elevated liver enzymes, and low platelets

(HELLP) American Journal of Obstetrics Gynecology 1994;171(4):

1154–8.

Magann 1994b {published data only}

Magann EF, Bass D, Chauhan SP, Sullivan D, Martin RW, Martin

JN Antepartum corticosteroids: disease stabilization in patients with

the syndrome of hemolysis, elevated liver enzymes, and low platelets

(HELLP) American Journal of Obstetrics and Gynecology 1994;171:

1148–53.

Magann EF, Bass D, Chauhan SP, Sullivan DL, Martin RW,

Mar-tin JN Antepartum corticosteroids: disease stabilization in patients

with HELLP syndrome American Journal of Obstetrics and

Gynecol-ogy 1994;170:410.

Vigil-De Gracia 1997 {published data only}

Vigil-De Gracia P, Garcia-Caceres E Dexamethasone in the

post-partum treatment of HELLP syndrome International Journal of

Gy-necology & Obstetrics 1997;59:217–21.

Yalcin 1998 {published data only}

Yalcin OT, Sener T, Hassa H, Ozalp S, Okur A Effects of

postpar-tum corticosteroids in patients with HELLP syndrome International

Journal of Gynecology & Obstetrics 1998;61:141–8.

References to studies awaiting assessment

Isler 2003

Isler C, Magann E, Rinehart B, Terrone D, Bass J, Martin J Jr

Dex-amethasone versus betmethasone for postpartum hellp syndrome: a

randomized prospective clinical trial of comparative efficacy

Ameri-can Journal of Obstetrics and Gynecology 2000;182(1 Pt 2):S87.

Isler CM, Magann EF, Rinehart BK, Terrone DA, Bass JD, Martin JN

Jr Dexamethasone compared with betamethasone for glucocorticoid

treatment of postpartum hellp syndrome International Journal of

Gynecology & Obstetrics 2003;80(3):291–7.

Kadanali 1997

Kadanali S, Kucukozkan T, Bukam B Helpful effect of high-dose

corticosteroid use on Hellp syndrome Jinekoloji Ve Obstetrik Dergisi

1997;11:55–8.

Additional references Clark 1986

Clark SL, Phelan JR, Allen SH, Golde SR Antepartum reversal of hematologic abnormalities associated with the HELLP syndrome A

report of three cases Journal of Reproductive Medicine 1986;31:70–2.

Clarke 2000

Clarke M, Oxman AD, editors Cochrane Reviewers’ Handbook 4.1 [updated June 2000] In: Review Manager (RevMan) [Computer program] Version 4.1 Oxford, England: The Cochrane Collabora- tion, 2000.

Crowley 1999

Crowley P Prophylactic corticosteroids for preterm birth (Cochrane

Review) In: The Cochrane Library, 4, 1999 Oxford: Update software.

Duley 1992

Duley L Maternal mortality associated with hypertensive disorders of

pregnancy in Africa, Asia, Latin America and the Caribbean British

Journal of Obstetrics and Gynaecology 1992;99:547–53.

Magann 1993

Magann EF, Martin RW, Issacs JD, Blake PG, Morrison JC, Martin

JN Jr Corticosteroids for the enhancement of fetal lung maturity: impact on the gravida with preeclampsia and the HELLP syndrome.

Australian and New Zealand Journal of Obstetrics and Gynaecology

1993;33:127–31.

Martin 1991

Martin JN Jr, Blake PG, Perry KG, McCaul JF, Hess LW, Martin

RW The natural history of HELLP syndrome: patterns of disease

progression and regression American Journal of Obstetrics and

Gyne-cology 1991;164:1500–9.

Martin 1997

Martin JN, Perry KG Jr, Blake PG, May WA, Moore A, Robinette

L Better maternal outcomes are achieved with dexamethasone apy for postpartum HELLP (hemolysis, elevated liver enzymes and

ther-thrombocytopenia) syndrome American Journal of Obstetrics and

eclampsia American Journal of Obstetrics and Gynecology 1986;155:

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heamolysis, elevated liver enzymes, and low platelets (HELLP

syn-drome) American Journal of Obstetrics and Gynecology 1993;169:

1000–6.

Weinstein 1985

Weinstein L Preeclampsia/eclampsia with heamolysis, elevated liver

enzymes and thrombocytopenia Obstetrics and Gynecology 1985;66:

657–60.

Yalcin 1998

Yalcin OT, Sener T, Hassa H, Ozalp S, Okur A Effects of

postpar-tum corticosteroids in patients with HELLP syndrome International

Journal of Gynecology and Obstetrics 1998;61:141–8.

Yeast 1987

Yeast JD, Coronado S Hepatic dysfunction, thrombocytopenia and

late onset preeclampsia A report of three cases Journal of Reproductive

Intention to treat analysis done

Participants Randomisation antepartum done into dexamethasone and betamethasone groups

N = 41 (19 in the dexamethasone group and 21 in the betamethasone group)

No differences in the participant characteristics postrandomisation

All participants had labor induced after stabilisation unless a cesarean section was indicated

Interventions All groups:

1 Intravenous magnesium sulphate for seizure prophylaxis at study enrolment and continued for 24 hourspostpartum

10 mg dexamethasone sodium phosphate intravenously every 12 hours

Outcomes Primary endpoint was considered to be:

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Characteristics of included studies (Continued )

1 The impact of the steroid on laboratory values (platelet count, LDH activity, AST activity) MAP andurinary output, using adjusted time averaged change from baseline

Kaplan-Meier were generated to illustrate the cumulative distribution of time to delivery

2 Ancillary analyses considered the frequency of additional medications and treatments for patient tion

stabiliza-Both maternal and neonatal mortality and morbidity data were captured

Notes Adequate allocation concealment and randomisation method

Allocation concealment A – Adequate

Participants Randomisation postpartum done into steroid and control groups after ’disease remission was believed to

present’

At randomisation N = 40 There were no statistical differences in participants’ characteristics sation between the two groups

postrandomi-At analysis of results, 15 participants not accounted for (lost to follow up) Only 12 in the steroid group and

13 in the control group accounted for

Interventions Control group:

Magnesium sulphate 2 gm/hr intravenous infusion for 36 hours

No mention of antihypertensive therapy used

Treatment group:

1 Magnesium sulphate regimen as the control group

2 Dexamethazone 10 mg intravenously as a stat dose then, 10 mg after 12 hours, followed by 5 mg 12hourly at 24 hours and 36 hours Total steroid given 30 mg of Dexamethazone

Outcomes Data reported on 25 participants only instead of 40 (steroid: 12, and control: 13)

No tables of dichotomous or continuous data provided Only charted graphs provided

Conclusions:

1 No primary maternal or neonatal outcomes recorded or mentioned

2 Secondary outcomes: compared with the control group, in the steroid group:

i) The MAP became significantly decreased by 22 hours postpartum (p < 0.03) significantly different.ii) The urinary output increased significantly by 36 hours postpartum (p < 0.02)

iii) The platelet count had significantly increased by 24 hours postpartum (p < 0.05)

iv) Both the LDH and the aspartate aminotransferase decreased significantly by 36 hours (p < 0.04 and p <0.05) respectively

v) There were no differences in:

postpartum infectious morbidity;

abnormal uterine bleeding;

alanine aminotransferase and hematocrit values between the steroid treated group and placebo

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Notes Adequate allocation concealment

Loss to follow up greater than 37%

No blinding

Methods Randomisation:

computer generated with card enclosed in sealed opaque envelope

Allocation concealment: adequate

Blinding: not mentioned

Loss to follow up: none

Participants Antepartum randomisation of participants between 27 and 34 weeks gestation

N = 25 (steroid group = 12 and control group = 13)

1 Participant characteristics differed on the level of the maternal platelet count (p = 0.034) The authorsspeculate that the steroid group was perhaps a sicker group The other participant characteristics were notsignificantly different

2 The ratio of black to white participants was 2:1 in the placebo group compared with 1:1 in the placebogroup

Managed with standard HELLP protocol (drugs not mentioned)

Steroid group:

In addition to the above management, dexamethazone was administered intravenously at rate of 10 mg, 12hourly until delivery

Outcomes Maternal primary outcomes:

No maternal primary outcomes occurred (death, liver heamatoma or rupture, pulmonary oedema, renalfailure, abruptio placentae)

Maternal secondary outcomes:

Simple linear regression technique was used to model the hourly rates of change for the following parameters:

1 Mean urinary output increased in the steroid treated group compared with the control group (p < 0.0006)

2 Platelets significantly increased in the steroid treated group compared with the control group (p < 0.006)

3 LDH in the treatment group decreased significantly (p < 0.03) compared with the control group 4.Aspartate aminotransferase decreased significantly in the treatment group (p < 0.005) compared with thecontrol group, ’over time’

Postpartum maternal secondary outcomes were noted and the authors concluded that:

1 There was a significant difference in the time to delivery after randomisation

2 There was an immediate deterioration in the disease process in all patients (no significant differencesbetween the two groups)

2 There was resolution of the HELLP syndrome process by 96 hours postpartum and again there was nosignificant differences between the two groups

Neonatal primary outcomes:

1 Neonatal deaths were recorded in both groups

2 Neonatal morbidity (respiratory distress syndrome, intraventricular hemorrhage and retrolental fibroplasia)were recorded

3 Birthweight, and

4 Apgar scores after 5 minutes were also recorded

Notes Adequate allocation concealment

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Patient characteristics after randomisation not the same, mainly steroid allocated patients had a statisticallysignificant lower platelet count

The racial distribution (black and white) was unequal between the two groups)

Loss to follow up: nil

Participants Randomisation done antepartum

N = 34

Participant demographics after randomisation:

The two groups are not significantly different except in the platelet count which was statistically significant(p < 0.05); with lower counts in the treatment group

1 Hydralazine boluses given to control blood pressure

2 No MgSO4 given to prevent or control fits

Treatment groups:

1 Given the same treatment as the control group and

2 Dexamethazone 10 mg intravenously stat then 12 hourly until 30 mg dose given after 24 hours

3 All patients monitored for 72 hours and after delivery

Outcomes Maternal primary outcomes:

1 Death was the only primary outcome noted in the study

Maternal secondary outcomes:

1 The authors noted there was no significant differences between the steroid treated group and control forthe postpartum sepsis, metabolic disorders, blood pressure control, urinary output, LDH, AST and ALTvalues post delivery

2 Platelet count resolution was recorded and the rate of increase was found to be significantly different infavour of the steroid treated group at 30 hours postpartum (p < 0.01)

Notes Unclear allocation concealment

Randomisation method not stated

Post randomisation patient platelet levels significantly different

Allocation concealment B – Unclear

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Participants Randomisation done antepartum.

N = 34

Participant demographics after randomisation:

The two groups are not significantly different except in the platelet count which was statistically significant(p < 0.05); with lower counts in the treatment group

Interventions Control group given magnesium sulphate regimen for eclampsia prevention, nifedipine to decrease acute

blood pressure and methyl dopa as maintenance antihypternsive medication

Steroid group given the above treatment and: dexamethazone 10 mg intravenously as a stat dose, then 10

mg after 12 hours, followed by 5 mg at 24 and 36 hours respectively Total dexamethazone dose given was

30 mg in 36 hours

Outcomes The authors provided mean data without standard deviations but concluded that:

1 Following initiation of dexamethazone therapy the mean arterial pressure and mean serum level aspartateaminotransferase of the study group became significantly decreased by 28 hours and 36 hours respectively (p

< 0.05) and that compared with the control group, it was observed that both the mean platelet count and themean urine output per hour of the study group increased significantly by 36 hours and 20 hours postpartumrespectively (p < 0.05) These differences in effects lasted beyond the 48 hour observation period

2 They also concluded that there were no significant differences in the mean hematocrit values, serum alanineaminotransferase and uric acid levels between the two groups at any time interval during the first 48 hourspostpartum No data were provided

None of the primary outcomes (death, liver hematoma or rupture, pulmonary oedema, renal failure andabruptio) were noted in the two treatment groups postrandomisation

4 Maternal infectious morbidity postrandomisation was recorded and was not significant

5 Mean hospital length stay in days (with SD) was given and ranges 6.0 +/- 4.1 days (4-15) for the steroidtreated group and 10.5 +/- 3.2 days (6-21) for the control group (p < 0.01)

Neonatal outcomes were not recorded

Notes Allocation concealment unclear Randomisation method not stated No mention of blinding method or

whom was blinded

Allocation concealment B – Unclear

ALT: alanine transaminase

AST: aspartate transaminase

01 Maternal deaths 1 34 Relative Risk (Fixed) 95% CI 0.33 [0.01, 7.65]

02 Postpartum sepsis 1 30 Relative Risk (Fixed) 95% CI 2.00 [0.20, 19.78]

03 Mean platelet counts over 48

1 30 Weighted Mean Difference (Fixed) 95% CI -4.50 [-7.13, -1.87]

05 Neonatal deaths 1 25 Relative Risk (Fixed) 95% CI 0.36 [0.04, 3.02]

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