Prophylactic versus selective blood transfusion for sickle cell disease in pregnancy

  • Protocol
  • Intervention


  • Babasola O Okusanya,

    Corresponding author
    1. Faculty of Clinical Sciences, College of Medicine, University of Lagos, Idi-Araba, Experimental and Maternal Medicine Unit, Department of Obstetrics and Gynaecology, Lagos, Nigeria
    • Babasola O Okusanya, Experimental and Maternal Medicine Unit, Department of Obstetrics and Gynaecology, Faculty of Clinical Sciences, College of Medicine, University of Lagos, Idi-Araba, Lagos, Nigeria.

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  • Olufemi T Oladapo

    1. Obafemi Awolowo College of Health Sciences, Olabisi Onabanjo University, Maternal and Fetal Health Research Unit, Department of Obstetrics and Gynaecology, Sagamu, Ogun State, Nigeria
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This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the benefits and harms of a policy of prophylactic versus selective blood transfusion in pregnant women with sickle cell disease (SCD).


Sickle cell disease (SCD) is an inherited disorder of haemoglobin S synthesis. The genetic defects of haemoglobin (Hb) are the most common genetic disorders worldwide and homozygous sickle cell anaemia (HbSS) is the most frequent (Hoffbrand 2011).  

Description of the condition

The inherited disorders of haemoglobin S are either in the homozygous form (HbSS) or in combination with another Hb variant such as haemoglobin C (HbSC), D (HbSD) or β-thalassaemia (HbSβo-thalassaemia and HbSβ+-thalassaemia). The homozygous form, HbSS (sickle cell anaemia), is the most common followed by HbSC and the HbSβ-thalassaemias (Hoffbrand 2011).

SCD is a relatively prevalent condition in Africa, the Mediterranean and the Caribbean; about 10% of the Jamaican population is estimated to carry Hb S. However, the disease prevalence now has a more global outlook as a result of immigration (RCOG 2011). Population estimates in the United States of America indicated that 72,000 to 98,000 people have SCD (Hassel 2010). Similarly, the United Kingdom currently has the largest population of people with SCD in Europe, a population that increased from approximately 5000 in 1995 (Howard 1995) to about 12,000 to 15,000 in 2011 (RCOG 2011).

Pregnancy in women with SCD carries significant risks of maternal and perinatal morbidity and mortality, particularly in resource-poor settings where facilities are lacking to adequately manage associated complications (Afolabi 2009; Odum 2002). Complications that may arise include various forms of crises resulting from haemolysis, vascular occlusion and sequestration (massive pooling) of damaged red blood cells in the liver and spleen, all having the potential to cause profound anaemia (Hoffbrand 2011). Another recognised complication, and an important cause of death in women with SCD, particularly in women with sickle cell anaemia is acute chest syndrome (ACS) which is characterised by cough, chest pain, dyspnoea, fever, increasing anaemia and fluid infiltrate on chest X-ray, all resulting from the sickling of red cells in the lungs. ACS is the most common cause of death in patients with SCD after puberty (Hoffbrand 2011), and it occurs in 7% to 20% of pregnant women with SCD (RCOG 2011). While all these complications are not specific to pregnancy in women with SCD, they are more frequent and exacerbated during pregnancy and are all major causes of severe ill health and death among women with the condition. Although the complications could arise in all forms of SCD, they are more frequent and severe among those with sickle cell anaemia (HbSS) (Nomura 2009; Odum 2002; RCOG 2011).

Pregnancy-specific complications include increased risk of spontaneous abortion (Serjeant 2004), urinary tract infection (Howard 1995) and proteinuric hypertension and thromboembolism (RCOG 2011). Pregnant women with SCD also have an increased risk of preterm birth, repeated antepartum hospitalisations, induction of labour, caesarean section and postpartum infection (ACOG 2007; Asnani 2011; Barfield 2010). As a result of chronic anaemia, women with SCD are also more likely to require blood transfusions (Grossetti 2009) and subsequent alloimmunisation of red cells which also increases the risk of haemolytic disease of the newborn. Fetal complications include intrauterine growth restriction, prematurity and its sequelae, low birthweight and death (ACOG 2007; Barfield 2010; Howard 1995).

Painful crisis secondary to vascular occlusion is the most frequent manifestation of SCD which is often precipitated by conditions such as infection, stress, acidosis, dehydration and hypoxia (low oxygenation state) (Hoffbrand 2011). Furthermore, visceral sequestration crises as a result of pooling of blood within the reticuloendothelial system (liver and spleen), as well as haemolytic and aplastic crises, are all associated with worsening anaemia (Hoffbrand 2011) that often have to be corrected to avert severe morbidity and mortality.

In spite of these complications, successful pregnancy outcomes have been reported in up to 57% of women with HbSS and 85% of women with HbSC (Asnani 2011; Serjeant 2004). These outcomes have been achieved with interventions to improve the complications occurring in these women. Measures to improve pregnancy outcomes have included the use of analgesia, intravenous fluid replacement, antibiotics and packed red cell transfusion for treatment of vaso-occlusive complications (ACOG 2007; RCOG 2011). However, there is no compelling evidence from randomised trials that regimens comprising the various combination of these interventions actually improve pregnancy outcomes (Marti-Carvajal 2009).

Description of the intervention

Pregnancy in women with SCD requires management by a multi-disciplinary team of haematologists, obstetricians and anaesthetists to reduce the likely complications. Although longitudinal follow-up studies of women with HbSC have reported a relatively benign course of pregnancy (Serjeant 2005), complications occurred in 96.6% of HbSS pregnant women (Odum 2002). While pregnant women with HbSβ+-thalassaemia share similarly mild clinical behaviour with those with HbSC, the clinical course of pregnancy in HbSβo-thalassaemia is quite similar to women with sickle cell anaemia (Hoffbrand 2011).

Blood transfusion for women with SCD during pregnancy could either be selective or prophylactic. Selective blood transfusion is performed when conditions such as anaemia, pain crises, or ACS necessitates blood transfusion. On the other hand, prophylactic blood transfusion is performed with the aim of optimising the oxygen-carrying capacity of the blood and reducing complications related to sickling of the red cells and anaemia in an asymptomatic pregnant woman with SCD. Prophylactic blood transfusion is often started early in pregnancy and performed at intervals to reduce the chances of transfusion on an emergency basis. Whenever blood is transfused, it is aimed at reducing the proportion of HbS in the circulation to less than 40% and also to achieve an Hb concentration of 10 gram/decilitre (ACOG 2007; Grossetti 2009).

Prophylactic blood transfusion can either be simple "top-up" (transfusion without prior withdrawal of blood from the recipient) or exchange blood transfusion (Howard 1995). Prophylactic exchange blood transfusion was first proposed by Ricks in 1965 (ACOG 2007). He recommended exchange blood transfusion four to six weeks before the delivery date to optimise the woman's Hb level towards the end of pregnancy when complications are most frequent (ACOG 2007). Prophylactic transfusion reduces the risk of sickling by reducing maternal erythropoiesis and thereby, increasing the partial O2 pressure (Grossetti 2009). It has the advantage of avoiding the risk of alloimmunisation from transfusion of inadequately phenotyped red blood cells and the transfusion-related reaction or overload that could occur with emergency transfusion (Grossetti 2009). 

How the intervention might work

Depending on the institutional policy, prophylactic blood transfusion could be started during the first, second or beginning of the third trimester of pregnancy (Grossetti 2009; Howard 1995; Ngo 2010). When it commences during the third trimester of pregnancy, it preferably begins at 28 weeks (Gilli 2007) and repeated every two to four weeks until delivery. This intervention carries the risks of iron overload (from the woman's inability to adequately excrete iron released from sickled and dead red blood cells), blood-related infections and alloimmunisation (due to exposure to multiple sources of allogeneic blood) with significant cost implications, especially in resource-poor settings. Compliance to schedules of transfusion and the need for repeated hospitalisation are other issues of concern for affected women as well as health services (Makani 2007). On the other hand, selective blood transfusion which has a comparatively lower risk of transfusion-related morbidities, may become indicated and performed at a time when it is already too late to improve maternal, or fetal outcomes.

Why it is important to do this review

Pregnant women with SCD are at increased risk of severe complications as a result of chronic anaemia, sickling of red cells and their consequences. Repeated blood transfusions to optimise the Hb level is an intervention to avert some of the complications seen, despite the potential morbidity that such practice constitutes. In spite of its use, the benefit of prophylactic blood transfusion to improve the outcome of pregnancy is uncertain. For instance, 11.6% of women who had prophylactic transfusion still needed emergency blood transfusion for severe anaemia during the same pregnancy. This is partly related to the lack of consensus among clinicians, hospital and even countries regarding the optimal transfusion regimen which makes evaluation of their impact on pregnancy outcomes difficult and the fact that the usefulness of the practice had been largely derived from observational studies that have inherent limitations for policy formulation on the subject (Cunningham 1983; Grossetti 2009; Howard 1995; Ngo 2010). The existing variation in the approaches to care requires a systematic evaluation of the evidence in order to balance effectiveness with safety. This systematic review will replace an outdated and withdrawn review (Mahomed 2006) and intends to evaluate the use of blood transfusion in pregnant women with SCD based on rigorous studies derived from up-to-date searches.


To assess the benefits and harms of a policy of prophylactic versus selective blood transfusion in pregnant women with sickle cell disease (SCD).


Criteria for considering studies for this review

Types of studies

All published randomised controlled trials (including those using a cluster-randomised design) evaluating the effects of prophylactic versus selective blood transfusion in pregnant women with SCD. We will also include quasi-randomised trials. Studies presented only as abstract will be included among studies awaiting further assessment pending their full publication.

Types of participants

Pregnant women with SCD (genotype HbSS, HbSC and HbSβ-thalassaemias). We will exclude studies of pregnant women with sickle cell trait (HbAS).

Types of interventions

Prophylactic blood transfusion to optimise Hb concentration to a specified level versus selective (emergency) blood transfusion when indicated by specific complication or a critically low level of Hb concentration. Studies will be included regardless of whether whole blood or packed red cells was transfused.

Types of outcome measures

Primary outcomes
  • Maternal death       

  • Severe maternal morbidity (e.g. organ failure, pulmonary embolism, fat embolism, stroke, intensive care unit admission or as defined by trial authors)     

  • Perinatal death

Secondary outcomes
  • Frequency of sickle cell crisis (due to vaso-occlusion, sequestration or haemolysis)

  • Total units of blood transfused 

  • Blood transfusion reaction (mild and severe)

  • Iron overload in the woman (as assessed by trial authors) 

  • Postpartum haemorrhage (> 500 mL blood loss or haemodynamic compromise following any degree of blood loss; or as defined by trial authors)

  • Cumulative duration of hospital stay

Infant ·        

  • Admission to neonatal intensive care (NICU)

  • Haemolytic disease of the newborn

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. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. weekly searches of MEDLINE;

  3. weekly searches of EMBASE;

  4. handsearches of 30 journals and the proceedings of major conferences;

  5. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and EMBASE, 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. 

Searching other resources

We will search the reference list of all relevant trials.

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 identified as a result of the search strategy. We will resolve any disagreement through discussion or if required, consult another review author within the Cochrane Pregnancy and Childbirth Group.

Data extraction and management

We will design a form as specified by the Cochrane Pregnancy and Childbirth Group to extract data. For eligible studies, the two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion or if required, consult another review author within the Cochrane Pregnancy and Childbirth Group. We will enter data into Review Manager software (RevMan 2011) and check for accuracy

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 2011). We will resolve any disagreement by discussion or by involving a third assessor as specified above.

(1) Random 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:

  • low risk of bias (any truly random process, e.g. random number table; computer random number generator);

  • high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);

  • unclear risk of bias.   

 (2) Allocation concealment (checking for possible selection bias)

We will describe for each included study the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We will assess the methods as:

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);

  • unclear risk of bias.   

(3.1) Blinding of participants and personnel (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. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes. If the blinding of study participants and personnel of included studies is poor or not done, this will be explained in the 'Risk of bias' table.

We will assess the methods as:

  • low, high or unclear risk of bias for participants;

  • low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes. If the assessment of outcomes of included studies are poorly blinded or unblinded, this will be included and explained further in the 'Risk of bias' table.

We will assess methods used to blind outcome assessment as:

  • low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

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 and 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:

  • low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

  • high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);

  • unclear risk of bias.

(5) Selective reporting (checking for 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:

  • low risk of bias (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);

  • high risk of bias (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);

  • unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

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:

  • low risk of other bias;

  • high risk of other bias;

  • unclear whether there is risk of other bias.

(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 2011). 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.

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 e.g. postpartum haemorrhage

Unit of analysis issues

Cluster-randomised trials

We will include cluster-randomised trials in the analyses along with individually-randomised trials. We will adjust their standard errors using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions using an estimate of the intracluster correlation co-efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster-randomised trials and individually-randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.

We will also acknowledge heterogeneity in the randomisation unit and perform a sensitivity analysis to investigate the effects of the randomisation unit. 

Dealing with missing data

For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.

For all outcomes, we will carry out analyses, 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, and all participants will be analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. 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 assess statistical heterogeneity in each meta-analysis using the T², I² and Chi² statistics. We will regard heterogeneity as substantial if the I² is greater than 30% and either the T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity. We will explore substantial heterogeneity if identified, by conducting sensitivity analysis based on trial quality.

Assessment of reporting biases

If there are 10 or more studies in the meta-analysis we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually.  If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

We will carry out statistical analysis using the Review Manager software (RevMan 2011). We will use fixed-effect meta-analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random-effects meta-analysis to produce an overall summary if an average treatment effect across trials is considered clinically meaningful. The random-effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful, we will not combine trials.

If we use random-effects analyses, the results will be presented as the average treatment effect with 95% confidence intervals, and the estimates of  T² and I².

Subgroup analysis and investigation of heterogeneity

If we identify substantial heterogeneity, we will investigate it using subgroup analyses and sensitivity analyses. We will consider whether an overall summary is meaningful, and if it is, use random-effects analysis to produce it.

We plan to carry out the following subgroup analyses for the primary outcomes.

  • Number of fetuses (singleton versus multiple).

  • Type/clinical severity of haemoglobinopathy (homozygous (HbSS) versus heterozygous (HbSC and or HbSβ+-thal).

  • Type of transfused blood (whole blood versus packed red cells).

We will assess subgroup differences by interaction tests available within RevMan (RevMan 2011).  We will report the results of subgroup analyses quoting the χ2 statistic and p-value, and the interaction test I² value.

Sensitivity analysis

We will perform sensitivity analysis based on trial quality, separating high-quality trials from those of low quality for the primary outcomes.


The contact author acknowledges the assistance of Reviews for Africa Programme (RAP) Nigeria run by the Nigerian Branch of the South African Cochrane Centre. RAP-Nigeria was funded by a grant from the Department for International Development (DFID) through the Research Programme Consortium at the Liverpool School of Tropical Medicine.

As part of the pre-publication editorial process, this protocol has been commented on by three peers (an editor and two referees who are external to the editorial team) and the Group's Statistical Adviser.

Contributions of authors

BO Okusanya prepared the first draft of the protocol and has overall responsibility for maintaining the review. OT Oladapo revised and contributed to the final draft of the protocol.

Declarations of interest

None known.