Interventions for treating painful sickle cell crisis during pregnancy
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effectiveness and safety of different regimens of packed red cell transfusion, oxygen therapy, fluid replacement therapy, analgesic drugs, and steroids for the treatment of painful sickle cell crisis during pregnancy.
Background
Sickle cell disease (SCD) is a group of genetic haemoglobin disorders ‐ abnormal structure of the haemoglobin ‐ (Bunn 1997; Pauling 1949; Serjeant 2001) which have their origins in sub‐Saharan Africa and the Indian sub‐continent (Stuart 2004; Weatherall 2006). The term SCD includes sickle cell anemia (Hb SS); haemoglobin S combined with haemoglobin C (Hb SC); haemoglobin S associated with ß Thalassemia (Sß0 Thal and Sß+ Thal) and other double heterozygous conditions which cause clinical disease (Saunthararajah 2004; Serjeant 2001; Weatherall 2006). Haemoglobin S combined with normal haemoglobin (A), known as sickle trait (AS), is asymptomatic and therefore not part of this review. Population mobility has spread haemoglobin disorders through Europe, Asia and the Americas. It means that millions of people have SCD worldwide. In Africa, the number of newborns affected by SCD is estimated at 200,000 per year (Diallo 2002); all over the world, about 300,000 children with SCD are born each year (Serjeant 1997).Thus SCD is a major health problem.
Recently, the pathophysiology of SCD has been reviewed (Hebbel 2004; Steinberg 2006; Stuart 2004; Weatherall 2006). Although SCD is primarily a defect of red blood cells (a haematological defect), changes in the red blood cells result in chronic vasculopathy (damage to blood vessels) (Hebbel 2004). The most frequent complication of SCD is vaso‐occlusive or painful crises; this is a process of vascular obstruction in very small and, sometimes, large vessels that is initiated by sickle erythrocytes (Steinberg 2006). The remarkable symptom is severe or moderate bone pain, which indicates a haematological emergency. Acute sickle cell pain episodes are the most common cause of hospitalisation of patients with SCD (Ballas 2005). Up to 58% of patients with SCD have been described with this complication (Babela 2005; Odum 2002).
In 1941, Kobak et al were pioneers in describing the complications associated with pregnancy and SCD (Kobak 1941). Pregnancy in women with SCD is a high‐risk situation (Rajab 2006; Sun 2001). It is associated with increased incidence of maternal and fetal morbidity and mortality (Adam 1996; Leborgne‐Samuel 2004; Serjeant 2004); however, in Hb SC females, pregnancy outcome is generally benign compared with SS disease (Serjeant 2005). Vaso‐oclusive sickle cell crisis tends to occur more frequently during pregnancy (Adam 1996) and is the most common maternal complication in pregnancy associated with sickle haemoglobinopathies (Martin 1986). The management of sickle cell crisis during pregnancy should be based on multidisciplinary management involving an obstetrician, a haematologist, an anaesthetist, and a haemoglobinopathy specialist nurse (Oteng‐Ntim 2006). The painful crisis in people with SCD could require several interventions: packed red cell transfusion, fluid replacement therapy, analgesic drugs, oxygen therapy and steroids; but the approach is not standardised.
Therefore, the primary aim of this review will be to examine the evidence for the effectiveness of the interventions, including the safety of their use, for painful sickle cell crisis during pregnancy.
Objectives
To assess the effectiveness and safety of different regimens of packed red cell transfusion, oxygen therapy, fluid replacement therapy, analgesic drugs, and steroids for the treatment of painful sickle cell crisis during pregnancy.
Methods
Criteria for considering studies for this review
Types of studies
We will consider randomised clinical trials that compare interventions with any other treatment for sickle cell crisis in pregnant women, irrespective of their publication status (we will consider trials published in abstract form or letters), language or country. We will only consider quasi‐randomised controlled trials to evaluate the adverse events.
Types of participants
Pregnant women with all types of SCD irrespective of age, or setting.
Types of interventions
Randomised trials in which non‐surgical approaches have been compared. Non‐surgical treatment includes: packed red cell transfusion, oxygen therapy, fluid replacement therapy, analgesia (nonsteroidal anti‐inflammatory agents or opiates agents), and steroids (prednisone, dexamethasone, or methylprednisolone).
Types of outcome measures
Primary outcomes
We will choose outcome measures pertinent to the woman's experience of acute sickle pain (Dunlop 2006):
(1) patient observer‐rated pain intensity, pain relief or both;
(2) duration of pain (hours).
Secondary outcomes
(1) Number of days of analgesic use.
(2) Number of days off work.
(3) Normal daily activities.
(4) Numbers and type of analgesics use (e.g. opiates).
(5) Days in hospital and other measures of health resources used (e.g. intensive care).
(6) Obstetric management (e.g. induction of labour).
(7) Apgar score.
Adverse events
We will use the following definition of adverse events as "any untoward medical occurrence not necessarily having a causal relationship with the treatment, but having resulted in the discontinuation of treatment" (ICH‐GCP 1997).
Search methods for identification of studies
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:
(1) quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
(2) monthly searches of MEDLINE;
(3) handsearches of 30 journals and the proceedings of major conferences;
(4) weekly current awareness search of a further 36 journals plus 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 'Search strategies for identification of studies' section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are given a code (or codes) depending on the topic. The codes are linked to review topics. The Trials Search Co‐ordinator searches the register for each review using these codes rather than keywords.
In addition, we will search the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register, EMBASE (1988 to current), LILACS (1982 to current), ISI Web of Science (1993 to current), ClinicalTrials.gov (http://www.clinicaltrials.gov), Current Controlled Trials (http://controlled‐trials.com/) and Clinical Study Results.org (http://www.clinicalstudyresults.org/).
Table 1 describes the search strategies.
| Database | Dates | Search strategy |
| EMBASE | 1988 to current | Search strategy under development |
| LILACS | 1982 to current | Search strategy under development |
| ISI Web of Science | 1993 to current | heparin AND sickle AND pregnan* |
| Clinical Trials.gov (http://www.clinicaltrials.gov) | not applicable | sickle AND pregnan% |
| Current Controlled Trials (http://controlled‐trials.com/) | not applicable | (sickle AND pregnancy ) OR (sickle AND pregnant) |
| Clinical Study Results.org (http://www.clinicalstudyresults.org/) | not applicable | pregnancy (as the 'Studied indications or disease') AND (relevant drug names) |
We will search the abstract books of two major conferences: the European Haematology Association and the American Society of Hematology; and check the reference lists of all the trials identified by the above methods.
We will not apply any language restrictions.
Data collection and analysis
Data extraction
The authors will independently assess each reference identified by the searches to see if they meet the inclusion criteria.
We will examine the adequacy of the methods used to generate the allocation sequence; the concealment of allocation; and the level of blinding (clinician, participant or outcome assessor). For each trial the authors will classify the risk of bias as high, moderate or low. Overall, we will consider trials to be at low risk of bias if allocation concealment and blinding of participants are adequate.
We will also evaluate the risk of attrition bias, as estimated by the percentage of participants lost to follow up. We will exclude studies with total attrition more than 30%, or where the difference between groups exceeds 10%, or both, from the meta‐analysis, but include them in the review.
We intend to use the following definitions.
Generation of the allocation sequence
-
Adequate, if the allocation sequence was generated by a computer or random‐number table. We will consider drawing of lots, tossing of a coin, shuffling of cards or throwing dice adequate if a person who was not otherwise involved in the recruitment of participants performed the procedure.
-
Unclear, if the trial was described as randomised, but the method used for the allocation sequence generation was not described.
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Inadequate, if dates, names or admittance numbers were used for the allocation of participants. These studies are known as quasi‐randomised and we will exclude them from the efficacy analysis.
Allocation concealment
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Adequate, if the allocation of participants involved a central independent unit, on‐site locked computer, numbered drug bottles or containers of identical appearance prepared by an independent pharmacist or investigator, or envelopes consecutively sealed opaque were used.
-
Unclear, if the trial was described as randomised, but the method used to conceal the allocation was not described.
-
Inadequate, if the allocation sequence was known to the investigators who assigned participants or if the study was quasi‐randomised.
Blinding (or masking)
-
Adequate, if the participants of the trial were blinded to the intervention.
-
Unclear, if there is no information on blinding.
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Not performed, if the participants were not blinded to the intervention.
Follow up
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Adequate, if the numbers and reasons for dropouts and withdrawals in each group were described or if it was specified that there were no dropouts or withdrawals.
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Unclear, if the trial gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated.
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Inadequate, if the number or reasons for dropouts and withdrawals were not described.
We plan to extract the relative risk for each outcome. For continuous outcomes, we plan to record either mean change from baseline for each group or mean post‐treatment or intervention values and their standard deviation or standard error for each group. We also plan to calculate a pooled estimate of treatment effect by calculating the weighted mean difference. If statistical information is missing (such as standard deviations), we will try to extract them from other relevant information in the paper, such as P‐values and confidence intervals. We will also contact the first author of the paper for missing data. We will seek data on the number of participants by allocated treatment group, irrespective of compliance and whether or not the participant was later thought to be ineligible or otherwise excluded from treatment or follow up. If we are not able to do so, for each study we will record whether the results pertain to an intention‐to‐treat or to an available case analysis.
We will examine data for skewness using the means and standard deviations as described in the Cochrane Handbook of Systematic Reviews for Interventions (Higgins 2005). If data are skewed, we will present log‐transformed data.
We will quantify the impact of statistical heterogeneity using I2, which describes the percentage of total variation across studies that is due to heterogeneity rather than sampling error (Higgins 2003). If the identified studies are comparable enough, we will summarise their findings using a fixed‐effects model. In the case of significant heterogeneity, we will devote further research to identifying possible causes of heterogeneity by exploring the impact of the participants' and study's characteristics.
We anticipate clinical heterogeneity in the effect of the intervention for the following participant characteristics: age, severity of painful crisis, type of disease, type of interventions and gestational age. We will explore these sources of heterogeneity in the assessment of each outcome by subgroup analyses comparing, for example, mild and severe disease; disease type (i.e. SS type versus SC type); country and within country; teenage pregnant women with non‐teenage pregnant women; type of intervention and regimens.
We plan to conduct a sensitivity analysis by comparing the results of all studies to those of high methodological quality. We will also attempt to assess whether the review is subject to publication bias by using a funnel plot.
| Database | Dates | Search strategy |
| EMBASE | 1988 to current | Search strategy under development |
| LILACS | 1982 to current | Search strategy under development |
| ISI Web of Science | 1993 to current | heparin AND sickle AND pregnan* |
| Clinical Trials.gov (http://www.clinicaltrials.gov) | not applicable | sickle AND pregnan% |
| Current Controlled Trials (http://controlled‐trials.com/) | not applicable | (sickle AND pregnancy ) OR (sickle AND pregnant) |
| Clinical Study Results.org (http://www.clinicalstudyresults.org/) | not applicable | pregnancy (as the 'Studied indications or disease') AND (relevant drug names) |
