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Iron stores in pregnant women with sickle cell disease: a protocol for a systematic review and meta-analysis
  1. Desmond Aroke1,2,
  2. Benjamin Momo Kadia3,
  3. Tsi Njim2
  1. 1Fontem District Hospital, Fontem, Cameroon
  2. 2Health and Human Development Research Network, Douala, Cameroon
  3. 3Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
  1. Correspondence to Dr Desmond Aroke; arokedess{at}


Introduction Sickle cell disease (SCD) is the most common inherited disease worldwide. The greatest disease burden is seen in sub-Saharan Africa. Early diagnosis and improved care of people living with SCD have led to an increase in the number of women with SCD reaching the reproductive age. Iron deficiency anaemia remains the most common cause of anaemia in pregnancy, affecting 51%–63% of pregnancies in Africa. However, the unavailability of guidelines on supplementation of iron in this pregnant subpopulation often leaves clinicians in a fix. We propose to conduct the first systematic review and possibly a meta-analysis on the prevalence, associated factors and maternal/fetal outcomes of iron deficiency anaemia among pregnant women with SCD.

Methods and analysis We will search the following electronic databases for studies on the iron status of pregnant women with SCD: PubMed, MEDLINE, EMBASE, Google Scholar, African Journals Online, African Index Medicus, Popline and the Cochrane Library. After the selection of eligible studies from the search output, review of full text, data extraction and data synthesis will be performed. Studies obtained from the review shall be evaluated for quality, risk of bias and heterogeneity. Appropriate statistical methods shall be used to pool prevalence estimates for matching studies globally and in subpopulations. This protocol has been reported as per the 2015 guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols.

Ethics and dissemination There is no requirement for ethical approval as the proposed study will use published data. The findings of this study will be published in a peer-reviewed journal and will be presented at conferences.

Trial registration number CRD42018109803.

  • sickle cell disease
  • iron status
  • pregnancy
  • protocol
  • systematic review/meta-analysis

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Strengths and limitations of this study

  • This review will be the first to summarise published data on the iron status of pregnant women with sickle cell disease.

  • This systematic review will reduce the risk of bias by using an independent review process.

  • The meta-analysis to be performed will improve the precision of the prevalence of iron deficiency anaemia in women with sickle cell disease.

  • Most studies on iron deficiency in people with sickle cell disease are likely to be done in resource-limited settings, so the pooled prevalence may not reflect reality in other settings.

  • Considering that this review will include various study designs, there is a potential risk of heterogeneity in the results.


Sickle cell disease (SCD) is a disease caused by inheritance of a defective haemoglobin gene resulting in red blood cells changing shape in hypoxic conditions and subsequent chronic haemolysis.1 SCD is the most common inherited disease worldwide. The WHO reports that approximately 60% of the world’s 229 countries are endemic for haemoglobin disorders.2 About 85% of sickle cell disorders and 70% of SCD-affected births occur in Africa.2

Over 7% of pregnant women worldwide carry a significant haemoglobin gene variant.2 Pregnancies in women with SCD have been shown to be associated with adverse maternal and fetal outcomes.3 Maternal mortality in a previous report was shown to be about 29 times higher in pregnant women with SCD when compared with pregnant women without SCD.4

Better understanding of the disease pathology and improved patient care have led to more women with SCD reaching reproductive age. Factors capable of influencing the morbidity of this condition need to be properly reviewed to guide clinical case management.

The low adult female iron body stores in tandem with increased pregnancy iron requirements often put pregnant women at risk of iron deficiency anaemia.5–8 Iron deficiency anaemia in pregnancy is a known significant contributor to maternal mortality. Daily iron supplementation in pregnancy is recommended by WHO as a proactive measure to reduce anaemia and its associated complications in pregnancy.9 However, there are no clear guidelines on iron supplementation in the SCD subpopulation. In the SCD subpopulation, chronic haemolysis leads to recurrent transfusions and a risk of iron overload.10 This risk of iron overload among patients with SCD and risk of iron deficiency in pregnancy make supplementation of iron in pregnant women with SCD a difficult decision. Several studies have been done to evaluate iron stores among pregnant women with SCD with varying outcomes.11–15 We previously provided recommendations on iron supplementation in this subpopulation.16 Harmonising published data in a systematic review and meta-analysis would provide better and more resilient recommendations on this issue.


We aim to systematically review existing data on iron stores among pregnant women with SCD. The following are the specific objectives:

  1. To estimate the prevalence of iron deficiency anaemia among pregnant women with SCD.

  2. To assess sociodemographic, obstetric and clinical factors associated with iron deficiency anaemia among pregnant women with SCD.

  3. To evaluate fetal (birth weight, anaemia, anomalies, stillbirth, neonatal death and infant death) and maternal (maternal anaemia, transfusion, preterm delivery, acute complications of SCD, oligohydramnios, caesarean delivery and maternal mortality) outcomes among pregnant women with SCD who are iron-deficient.


This protocol has been written following the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 checklist,17 available in table 1. The protocol has been registered on the PROSPERO International Prospective Register of Systematic Reviews (registration ID: CRD42018109803). The study shall be carried out for a period of 6 months from the date of publication of this protocol.

Table 1

PRISMA-P 2015 checklist for the study protocol of a systematic review on iron stores in pregnant women with sickle cell disease

Eligibility criteria

We shall include all observational studies and clinical trials with evidence on the iron status in pregnant women with SCD, as illustrated in table 2.18 There will be no language limitation.

Table 2

Inclusion and exclusion criteria

Search strategy

The search for relevant studies will be done online.

Electronic sources

The following databases shall be searched for eligible studies: PubMed, MEDLINE, EMBASE, Google Scholar, African Journals Online, African Index Medicus, Popline and the Cochrane Library. We will search for all studies from inception to the present. The search will be done by combining relevant terms related to SCD, iron stores and pregnancy as illustrated in table 3.

Table 3

Search strategy for MEDLINE and adaptability to other databases

References in the identified studies shall be reviewed for articles with similar objectives. This will be done to identify additional data sources that were missed during the search in bibliographic databases.

Study screening

The literature search will be performed independently by two investigators (DA and BMK). The titles and abstracts will be reviewed, and the full texts of potentially eligible articles will be retrieved using EndNote V.X8 software. Preselected full texts will be screened for eligibility using a pretested predefined form created on Epi Info V. software. For studies with disagreements between the investigators, arbitration will be done by a third investigator (TN). Publications with ambiguous data shall be resolved by contacting authors by email for clarity.

Potentially eligible studies that are excluded will be documented with the various reasons for exclusion. A detailed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart shall be used to depict the selection process (figure 1).

Figure 1

Preferred Reporting Items for Systematic review and Meta-Analysis Protocols flow diagram.

Risk of bias assessment

Two reviewers (DA and BMK) will independently assess the methodological quality and the risk of bias for each included study. Assessment will be done using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies of the National Health Institute/National Heart, Lung, and Blood Institute (table 4) for observational studies, and the Cochrane Risk of Bias Tool for Randomized Controlled Trials (tables 5 and 6) for studies which used a randomised design.

Table 4

Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies

Table 5

Cochrane Risk of Bias Tool: Cochrane Collaboration modified tool for assessing risk of bias for randomised controlled trials, part I

Table 6

Cochrane Collaboration modified tool for assessing risk of bias for randomised controlled trials, part II

Data extraction

A data abstraction sheet produced on Epi Info V. statistical software and pretested by investigators will be used to extract data from selected studies. Data to be extracted will include the name of the first author, year of publication, country of study population, duration of study, study design and setting, mean or median age, sex distribution, sickle cell genotype, gestational age distribution, transfusion history, laboratory test used to measure body iron stores, iron status, mean cell volume, prevalence of iron deficiency anaemia, and the outcome of the fetus and the mother. For multinational studies we will separate the results and present them per country.

Data synthesis and analysis

The data will be analysed using STATA V.14 statistical software. Random-effects meta-analysis models will be reported over fixed-effects models due to the possibility of heterogeneity between the various studies retrieved. The χ2 test for heterogeneity and the I2 statistic will be used to assess the degree of heterogeneity among studies. Sensitivity analyses will be conducted to obtain pooled effects from different study designs (randomised controlled trials, cross-sectional, case–control and cohort study designs and the different diagnostic tests used to measure iron deficiency).

For objective 1, a pooled prevalence for the proportion of pregnant women with SCD will be obtained if two or more studies provide this measure. Prevalence of iron deficiency anaemia among pregnant women with SCD will further be categorised as per diagnostic method of iron stores. Subgroup analysis to determine the prevalence of iron deficiency anaemia in various regions (Africa, Europe, North America, South America, the Middle East and Asia) will also be performed.

Similarly, for objective 2, if two or more studies report on a factor associated with SCD in pregnancy and provide a measure of effect for this relationship (OR), a subgroup analysis will be carried out. The various maternal and fetal outcomes of SCD in pregnancy will be described qualitatively.

Presentation and reporting of results

The systematic review and meta-analysis will be presented according to the PRISMA 2015 guidelines using the PRISMA checklist, which will be published with the final report. No amendments are intended for this protocol; however, any amendments shall be clearly documented.

Patient and public involvement

There will be no involvement of patients or the public in this review.

Ethics and dissemination

We intend to publish the final manuscript as an original article in a peer-reviewed journal. Review findings will be presented at conferences to concerned institutions and submitted to relevant health authorities. Regular updates of this review will be done as needed.


There is controversial evidence regarding the role of iron supplementation in pregnant women with SCD and the associated pregnancy outcomes. Summarising existing data on this issue through a comprehensive review is of utmost importance as a majority of persons with SCD live in low-income areas, regions characterised by profligate use of iron supplements as well as an alarming lack of appropriate resources to guide clinicians on how to use these supplements in pregnant women with SCD.


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  • Contributors DA conceived the manuscript. DA, BMK and TN wrote and reviewed the manuscript. All authors approved the final version of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Ethical clearance is not required as the current review will be based on published data.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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