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Rakhi P. Naik, MD
Although sickle cell trait (SCT) has been linked to adverse clinical outcomes in multiple studies, only a handful of associations have strong evidence supporting them, according to a systematic review.
Evidence was strongest for the association between SCT and venous and renal complications.
There was low-strength evidence supporting a link between SCT and exertion-related sudden death and moderate-strength evidence supporting a link between SCT and exertion-related rhabdomyolysis.
Most other associations between SCT and clinical outcomes had either low-strength evidence or insufficient data to support a link.
Rakhi P. Naik, MD, of Johns Hopkins University in Baltimore, Maryland, and her colleagues reported these findings in Annals of Internal Medicine.
The researchers’ systematic review was focused on 41 studies, most of which were population-based cohort or case-control studies.
The team rated the evidence quality of each study and grouped 24 clinical outcomes of interest into six categories: exertion-related injury, mortality, and renal, vascular, pediatric, surgery-, and trauma-related outcomes.
The researchers found low-strength evidence for a link between SCT and hematuria, end-stage renal disease, hypertension, myocardial infarction, retinopathy, diabetic vasculopathy, sudden infant death syndrome, surgery- and trauma-related injury, and overall mortality.
There was moderate-strength evidence for a link between SCT and pediatric height/weight, stroke, and heart failure/cardiomyopathy.
Exertion-related injury/death
The strength of evidence for a link between SCT and exertion-related death was low in this analysis, which included two studies of this outcome.
However, Dr. Naik and her colleagues did note that SCT may be associated with a small absolute risk of exertion-related death in extreme conditions, such as highly strenuous athletic training or the military.
There was moderate-strength evidence supporting the link between SCT and exertional rhabdomyolysis, based on two studies.
However, the researchers said the absolute risk of exertional rhabdomyolysis in SCT is small and probably occurs only in high-intensity settings, with risk modified by other genetic and environmental factors.
“We do concur with the American Society of Hematology statement recommending against routine SCT screening in athletics and supporting the consistent use of universal precautions to mitigate exertion-related risk in all persons, regardless of SCT status,” the researchers wrote.
Venous and renal outcomes
High-strength evidence linked pulmonary embolism, with or without deep-vein thrombosis, to SCT. In contrast, there was moderate-strength evidence showing no increased risk of isolated deep-vein thrombosis in individuals with SCT.
“The cause of this paradoxical observation is unknown but may be an increased risk for clot embolization in SCT,” the researchers wrote.
Renal outcomes were often attributed to SCT, and the researchers said there was high-strength evidence to support SCT as a risk factor for both proteinuria and chronic kidney disease (CKD).
Out of six studies of proteinuria, the one high-quality study showed a 1.86-fold increased risk for baseline albuminuria in African Americans with SCT versus those without. The other studies “showed a consistent direction of increased risk for proteinuria with SCT,” according to the researchers.
Out of four CKD studies, the two high-quality studies showed a 1.57- and 1.89-fold increased risk of CKD in African Americans with SCT.
Support for this review came, in part, from the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute. The authors reported disclosures related to Novartis, Addmedica, and Global Blood Therapeutics, among others.