, et al
Clinical outcomes associated with sickle cell trait: a systematic review
Ann Intern Med.
; doi:

Investigators from multiple institutions conducted a systematic review to assess clinical outcomes associated with sickle cell trait (SCT). Databases such as PubMed and the Cochrane Library were searched for English-language research articles published between 1970 and 2018 that reported on associations between SCT and 24 clinical outcomes grouped into 6 categories (exertion-related injury, renal, vascular, pediatric, surgery or trauma related, and overall mortality). Articles were excluded if they did not use a valid method of genotyping all study participants, did not have a non-SCT comparison group, or did not list outcomes for non-SCT carriers.

Two independent reviewers assessed all included articles for quality, with high-quality articles defined as those (a) involving a population-based observational cohort, (b) including a direct measure of the relevant outcomes and adjustment for relevant confounders, and (c) having precise findings and no suspected bias. Moderate- and low-quality articles lacked these characteristics to an increasing degree. Strength of evidence was also assessed for each outcome by consensus among all investigators based on the magnitude and consistency of association estimates.

There were 41 articles included in analysis. Among high-quality studies included, there was a positive association between SCT and proteinuria, chronic kidney disease, vascular thromboembolism, and pulmonary embolism. Among moderate-quality studies included, there was a positive association between SCT and exertional rhabdomyolysis and no association between SCT and deep venous thromboembolism, heart failure, stroke, and pediatric growth. There were only moderate- and low-quality studies included that reported on surgery- or trauma-related and overall mortality outcomes and, in most, there was no observed association between outcomes and SCT.

The investigators conclude that SCT is a risk factor for a few adverse clinical outcomes, particularly renal and vascular.

Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

SCT affects approximately 3 million individuals in the United States, including an estimated 8% of African Americans and <0.1% each for those of Hispanic, Mediterranean, Arab, or Southeast Asian descent. This heterozygous form of the beta-globin gene mutation confers a survival advantage with a 50%–90% reduction in Plasmodium falciparum density, decreasing malaria severity by a variety of proposed mechanisms. Unlike other countries, the United States began mandatory universal sickle cell newborn screening in 1990, which was adopted nationwide by 2006. However, reporting and providing education about SCT-related complications to pediatricians and parents are inconsistent.

Strengths of the current systematic review include a comprehensive search of the published literature using definitive inclusion criteria with standard SCT genotyping and non-SCT control subjects as comparison. Limitations include no meta-analysis, some heterogeneous study designs, publication bias excluding unpublished null data, and selection bias excluding non–English-language publications. Because of lack...

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