Corticosteroids for HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome in pregnancy
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine, from the best available evidence, the effects of corticosteroids on maternal and perinatal mortality and morbidity in women with HELLP syndrome.
Background
Description of the condition
Pre‐eclampsia (also referred to as gestational hypertension with proteinuria, toxemia, or proteinuric hypertension) is a serious complication of pregnancy characterised by increased blood pressure and protein in the urine. It develops in 5% to 7% of pregnancies and is associated with poor maternal and perinatal outcomes. Although the cause has not been definitively determined, the final common pathway is vascular endothelial dysfunction with activation of the clotting cascade (Roberts 2000).
The syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP) is a severe manifestation of pre‐eclampsia and complicates approximately 20% of these pregnancies (Weinstein 1985). For HELLP syndrome to be diagnosed, there must be microangiopathic haemolysis, thrombocytopenia and abnormalities of liver function. There is no consensus, however, on the specific thresholds of hematologic and biochemical values to use in establishing the diagnosis of HELLP syndrome. Sibai has used the following criteria: haemolysis as evidenced by an abnormal peripheral smear, lactate dehydrogenase (LDH) greater than 600 IU/L or total bilirubin 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 (Sibai 1993). Martin defines HELLP syndrome as haemolysis as evidenced by a falling hematocrit, LDH over 164 IU/L or a bleeding diathesis; elevated liver enzymes as evidenced an AST greater than 48 IU/L and alanine transaminase greater than 24 IU/L and platelets less than 100,000 mm3 (Martin 1991).
Trials will be considered for inclusion in this review if they specify a definition of HELLP syndrome which includes generally accepted diagnostic criteria for haemolysis, elevated liver enzymes and thrombocytopenia.
The presence of HELLP syndrome is associated with significant maternal mortality and morbidity including acute renal and liver failure, disseminated intravascular coagulopathy, pulmonary edema, cerebrovascular accident and sepsis (Sibai 1993). Additionally, perinatal morbidity and mortality are also markedly high and are related primarily to the complications of prematurity and growth restriction (Visser 1995). Approximately 70% of pregnancies complicated by HELLP syndrome require preterm delivery with 15% occurring at extremely preterm gestational age (before 27 completed weeks' gestation) (Abramovici 1999).
Description of the intervention
The intervention to be evaluated is the use of corticosteroids for the treatment of maternal HELLP syndrome. Various regimens have been reported using dexamethasone or betamethasone. The purpose of this review is to summarise the evidence from randomised controlled trials examining the maternal and perinatal effects of corticosteroid administration in women with HELLP syndrome.
How the intervention might work
Since adverse perinatal outcomes are increased at preterm gestations, interventions that would allow the potential for pregnancy prolongation without negatively impacting the maternal condition could result in increased fetal maturity and subsequently decreased perinatal morbidity and mortality. Corticosteroids have been well established in controlled trials to decrease perinatal morbidity and mortality in the context of preterm birth, specifically by decreasing the risk of respiratory complications (Roberts 2006). Although the goal of corticosteroid administration in this setting is to promote fetal pulmonary maturation, improvements in maternal platelet count have also been reported (Vigil‐De Gracia 1997).
Why it is important to do this review
HELLP syndrome is a severe complication of pregnancy with considerable maternal and perinatal morbidity and mortality. There are suggestions from observational studies that steroid treatment in HELLP syndrome may improve disordered maternal hematological and biochemical features and perhaps perinatal mortality and morbidity (Clark 1986; Magann 1993; Yeast 1987)
The Cochrane review by Matchaba and Moodley was last updated in 2004 (search date 2003), and two of the seven trials identified were awaiting translation/more information (Matchaba 2004). The five studies reviewed showed improved biochemical profiles with steroid therapy, but were insufficient in numbers to address clinical outcomes adequately. Further research was called for as a matter of urgency.
For more information on eclampsia and HELLP syndrome, please refer to the 'Interventions for treating pre‐eclampsia and its consequences: generic protocol' (Duley 2009).
Objectives
To determine, from the best available evidence, the effects of corticosteroids on maternal and perinatal mortality and morbidity in women with HELLP syndrome.
Methods
Criteria for considering studies for this review
Types of studies
All published, unpublished and ongoing randomised controlled trials. Quasi‐randomised trials (e.g. those randomised by date of birth or hospital number) will be excluded from the analysis due to a high potential for bias. Studies published only as abstracts will be examined and included only if they contain enough information to meet the inclusion criteria.
Types of participants
Women with HELLP syndrome, as determined clinically or based on biochemical markers, both during pregnancy and after delivery, and their babies.
Types of interventions
Any corticosteroid versus placebo,no treatment, or other drug; or corticosteroid versus other corticosteroid or other dosage.
Types of outcome measures
Only outcomes with available data will appear in the analysis table. To avoid losing valuable data, trials that use acceptable variations of the definitions of primary and secondary outcomes specified below will also be included, as will those that do not state their definitions.
Outcome data that are not pre‐specified by the review authors, but which are reported by the trial authors, will be noted as non pre‐specified but not included in the analysis or used for the conclusions.
Primary outcomes
For the mother
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Maternal death or severe maternal morbidity, defined as any one of the following: presence of liver hematoma, rupture or persistent liver failure; pulmonary oedema; persistent renal failure; abruptio placentae; eclampsia; or cerebrovascular accident.
For the child
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Perinatal death: stillbirths (death in utero at or after 20 weeks' gestation), perinatal deaths (stillbirths plus deaths in the first week of life), death before discharge from hospital, neonatal deaths (death in the first 28 days after birth).
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Death or severe perinatal morbidity, defined as any one of the following: respiratory distress syndrome with/without ventilatory support required; intracerebral haemorrhage; necrotizing enterocolitis; care in a special care nursery for seven days or more; or severe neonatal encephalopathy.
Secondary outcomes
For the mother
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Presence of liver hematoma or rupture or liver failure.
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Pulmonary oedema.
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Renal failure.
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Abruptio placenta.
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Eclampsia.
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Cerebrovascular accident.
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Elective delivery: induction of labour or elective caesarean section.
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Caesarean section and caesarean section performed under general anaesthesia.
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Postpartum haemorrhage defined as blood loss of 500 mL or greater.
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Change in platelet count.
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Side‐effects or adverse events: any side‐effects or adverse events related to the intervention or intervention stopped due to side‐effects.
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Use of hospital resources: admission to intensive care unit, length of stay, cost of care, use of mechanical ventilation, dialysis.
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Woman's experience and views of the interventions: childbirth experience, physical and psychological trauma, postnatal depression, breastfeeding, mother‐infant interaction and attachment.
For the child
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Time from enrolment to birth.
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Respiratory distress syndrome with/without ventilatory support required.
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Intracerebral haemorrhage.
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Necrotizing enterocolitis.
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Care in a special care nursery for seven days or more.
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Preterm birth defined as birth before 37 completed weeks' gestation.
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Very preterm birth defined as birth before 33 completed weeks' gestation.
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Extremely preterm birth defined as birth before 27 completed weeks' gestation.
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Infection.
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Retinopathy of prematurity.
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Apgar score at five minutes: low (≤ seven) and very low (≤ four).
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Use of hospital resources: admission to special care nursery, length of stay, cost of care, endotracheal intubation, use of mechanical ventilation.
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Long‐term growth and development: blindness, deafness, seizures, poor growth, neurodevelopmental delay and cerebral palsy.
Search methods for identification of studies
Electronic searches
We will contact the Trials Search Co‐ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register.
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
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quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
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weekly searches of MEDLINE;
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handsearches of 30 journals and the proceedings of major conferences;
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weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
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 service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co‐ordinator searches the register for each review using the topic list rather than keywords.
In addition, we will search PubMed (1950 to current) and EMBASE (1980 to current) using the search strategies listed in Appendix 1.
We will not apply any language restrictions.
Data collection and analysis
Selection of studies
Two review authors will independently assess for inclusion all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, we will consult a third person.
Data extraction and management
We will design a form to extract data. For eligible studies, at least two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult a third person. Data will be entered into Review Manager software (RevMan 2008) and checked for accuracy.
When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.
Assessment of risk of bias in included studies
Two review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Any disagreement will be resolved by discussion or by involving a third assessor.
(1) Sequence generation (checking for possible selection bias)
We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.
We will assess the method as:
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adequate (any truly random process, e.g. random number table; computer random number generator);
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inadequate (any non random process, e.g. odd or even date of birth; hospital or clinic record number); or
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unclear.
(2) Allocation concealment (checking for possible selection bias)
We will describe for each included study the method used to conceal the allocation sequence in sufficient detail and determine whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
We will assess the methods as:
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adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
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inadequate (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
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unclear.
(3) Blinding (checking for possible performance bias)
We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. Studies will be judged at low risk of bias if they were blinded, or if we judge that the lack of blinding could not have affected the results. Blinding will be assessed separately for different outcomes or classes of outcomes.
We will assess the methods as:
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adequate, inadequate or unclear for participants;
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adequate, inadequate or unclear for personnel;
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adequate, inadequate or unclear for outcome assessors.
(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)
We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re‐include missing data in the analyses which we undertake. We will assess methods as:
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adequate;
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inadequate:
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unclear.
We will consider adequate a level of missing data up to 20%. Studies missing greater than 20% of outcome data will be judged as inadequate
(5) Selective reporting bias
We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
We will assess the methods as:
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adequate (where it is clear that all of the study’s pre‐specified outcomes and all expected outcomes of interest to the review have been reported);
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inadequate (where not all the study’s pre‐specified outcomes have been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
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unclear.
(6) Other sources of bias
We will describe for each included study any important concerns we have about other possible sources of bias.
We will assess whether each study was free of other problems that could put it at risk of bias:
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yes;
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no;
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unclear.
(7) Overall risk of bias
We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses ‐ seeSensitivity analysis.
Measures of treatment effect
Dichotomous data
For dichotomous data, we will present results as summary risk ratio with 95% confidence intervals.
Continuous data
For continuous data, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.
Unit of analysis issues
Only individually randomised controlled trials will be included in this review.
For neonatal outcomes, the results for multiple pregnancies will be adjusted for clustering if sufficient information is available. If not, sensitivity analysis will be performed to assess the impact of assuming independence or non‐independence of the multiple birth babies.
For neonatal outcomes, the denominator will be the number of individual babies randomised rather than the number of pregnancies.
In the case of trials comparing more than one type or dose of drug with placebo, each drug will be compared individually with the placebo group. Where more than one comparison is included in the same analysis, the numbers in the placebo group will be divided by the number of comparisons to avoid double‐counting of cases.
Dealing with missing data
For included studies, levels of attrition will be noted. The impact of including studies with high levels of missing data in the overall assessment of treatment effect will be explored by using sensitivity analysis.
For all outcomes, analyses will be carried out, as far as possible, on an intention‐to‐treat basis, i.e. we will attempt to include all participants randomised to each group in the analyses. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing.
Assessment of heterogeneity
We will use the I² statistic to measure heterogeneity among the trials in each analysis. If we identify substantial heterogeneity we will explore it by pre‐specified subgroup analysis. Heterogeneity of greater than 50% as measured by the I² statistic will be considered substantial.
Assessment of reporting biases
Where we suspect reporting bias (see 'Selective reporting bias' above), we will attempt to contact study authors asking them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, the impact of including such studies in the overall assessment of results will be explored by a sensitivity analysis.
Data synthesis
We will carry out statistical analysis using the Review Manager software (RevMan 2008). We will use fixed‐effect inverse variance meta‐analysis for combining data where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. Where we suspect clinical or methodological heterogeneity between studies sufficient to suggest that treatment effects may differ between trials we will use random‐effects meta‐analysis.
If substantial heterogeneity is identified in a fixed‐effect meta‐analysis this will be noted and the analysis repeated using a random‐effects method.
Subgroup analysis and investigation of heterogeneity
We plan to carry out the following subgroup analyses.
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Gestation at trial entry: greater than 37 completed weeks' gestation, between 33 and 37 completed weeks' gestation, between 27 and 33 completed weeks' gestation, and less than 27 completed weeks' gestation.
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Type of intervention: type or class, dose or duration of corticosteroid.
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Corticosteroid versus no treatment, corticosteroid versus placebo.
The following outcomes will be used in subgroup analysis.
For the mother
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Maternal death (during pregnancy or up to 42 days after end of pregnancy) or severe maternal morbidity, defined as any one of the following: presence of liver hematoma, rupture or liver failure; pulmonary oedema; renal failure; abruptio placentae; eclampsia; or cerebrovascular accident.
For the child
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Perinatal death: stillbirths (death in utero at or after 20 weeks' gestation), perinatal deaths (stillbirths plus deaths in the first week of life), death before discharge from hospital, neonatal deaths (death in the first 28 days after birth).
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Death or severe perinatal morbidity, defined as any one of the following: respiratory distress syndrome with/without ventilatory support required; intracerebral haemorrhage; necrotizing enterocolitis; care in a special care nursery for seven days or more; or severe neonatal encephalopathy.
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Time from enrolment to birth.
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Severity of preterm birth.
For fixed‐effect meta‐analyses we will conduct planned subgroup analyses classifying whole trials by interaction tests as described by (Deeks 2001). For random‐effects meta‐analyses we will assess differences between subgroups by inspection of the subgroups’ confidence intervals; non‐overlapping confidence intervals indicate a statistically significant difference in treatment effect between the subgroups.
Sensitivity analysis
Sensitivity analysis will be used if any significant sources of bias are identified in the methods of this review or of included studies.
