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Sickle cell trait

Sickle cell trait
Author:
Elliott P Vichinsky, MD
Section Editor:
Michael R DeBaun, MD, MPH
Deputy Editor:
Jennifer S Tirnauer, MD
Literature review current through: Dec 2022. | This topic last updated: Sep 09, 2022.

INTRODUCTION — Sickle cell trait is a benign carrier condition, usually with none of the symptoms of sickle cell anemia or other sickle cell diseases. However, knowledge of sickle cell trait is important in many settings, such as preconception counseling and evaluation of rare complications.

The screening, diagnosis, potential complications, and routine management of sickle cell trait are discussed here.

Homozygous sickle cell disease (Hb SS) and other sickle cell disease variants including sickle cell beta-thalassemia and hemoglobin SC disease are discussed separately.

SCD clinical features – (See "Overview of the clinical manifestations of sickle cell disease".)

SCD diagnosis – (See "Diagnosis of sickle cell disorders".)

SCD management – (See "Overview of the management and prognosis of sickle cell disease".)

Compound SCD syndromes – (See "Overview of compound sickle cell syndromes".)

GENETICS AND EPIDEMIOLOGY — Sickle cell trait is a generally asymptomatic carrier condition in which one allele of the beta globin gene carries the sickle hemoglobin mutation and the other allele is normal, producing hemoglobin AS (Hb AS). If the other beta globin allele carries the sickle mutation or another mutation (eg, for beta thalassemia), the individual will have a sickle cell disease (sickle cell anemia, sickle-beta thalassemia).

The gene for the sickle hemoglobin mutation is distributed throughout the world, with especially high frequency in sub-Saharan Africa, Mediterranean countries (especially Greece), the Middle East, and parts of India. This high prevalence in certain regions of the world appears to reflect the protective effect of the variant against severe falciparum malaria. (See "Protection against malaria in the hemoglobinopathies", section on 'Falciparum malaria and hemoglobin S'.)

Prevalence of sickle cell trait in various regions around the world includes the following:

African Americans – 7 to 10 percent [1-4]

Sub-Saharan Africa – approximately 30 percent [5]

Latinos – 0.2 to 6.3 percent [3,6,7]

India – up to 13 percent [8,9]

Middle East – 0.2 to 27 percent [10-12]

Greece – 1.5 to 7.5 percent [13,14]

Caribbean countries – 4 to 10 percent [15,16]

In the United States, results of comprehensive newborn screening have demonstrated an incidence of sickle cell trait of 1.6 percent overall; ethnicity and race information is available in a subset of 13 states, which found incidence rates of 7.3 percent in Black people and 0.7 percent in Hispanic peoples [3]. The incidence varied among states, from 0.08 percent in Montana to 3.4 percent in Mississippi. The incidence of sickle cell trait in White people was as high as 0.4 percent in some states. A study in blood donors found similar prevalences (7 percent in Black Americans and 1.7 percent in the blood donor population as a whole) [17].

A 2019 study from the state of Michigan in 33,404 newborns with sickle cell trait identified the following associations [18]:

Black people – 26,791 (80 percent of newborns with sickle cell trait)

White people – 2345 (7 percent)

Unknown racial/ethnic background – 1960 (5.87 percent)

Multiracial – 1750 (5.25 percent)

Hispanic ancestry – 688 (2.05 percent)

Arab ancestry 248 – (7.4 percent)

Native American ancestry – 233 (0.7 percent)

Asian/Pacific Islander peoples – 74 (0.22 percent)

These data translate to sickle cell trait in approximately 300 million people in the world and 2.5 million people in the United States.

SCREENING

Newborn screening — In many parts of the world, newborns are screened routinely for the presence of sickle hemoglobin using isoelectric focusing (IEF), high performance liquid chromatography (HPLC), or hemoglobin electrophoresis, performed on a blood sample obtained during the birth hospitalization. This testing will detect sickle cell disease and sickle cell trait. All states in the United States have been mandated to offer testing since 2006, and the proportion of parents opting out of screening is extremely low [3]. (See "Diagnosis of sickle cell disorders", section on 'Newborn screening'.)

Despite widespread testing, the reporting of the results to families and pediatricians is highly variable, and many parents of children with sickle cell trait are unaware of their newborn screening results [19]. As examples:

In a series of 100 mothers who were contacted regarding a positive result for sickle cell trait from newborn screening, fewer than half knew their sickle cell status prior to conception; only 34 of 60 (57 percent) with sickle cell disease or sickle cell trait had received professional hemoglobinopathy counseling; and only 23 of 100 (23 percent) reported prenatal discussions about newborn screening [20]. Most strikingly, 41 parents of a child with sickle cell trait (41 percent) first learned this result from the study recruiter rather than their pediatrician, birth hospital, or state Department of Public Health.

In a survey of 282 individuals in various neighborhoods in the United States, only 45 (16 percent) knew their sickle cell trait status [21].

In a survey of United States clinicians and families, only 37 percent of families were notified of sickle cell trait status [22].

In a survey of 15 primary care pediatrics practices in the United States, 28 percent did not actively seek the results of newborn screening, even though the information was generally accessible [23,24]. Subsequent surveys suggest families would like more detailed information concerning sickle cell-related complications following newborn screening, with additional counseling as the child ages [25].

Even if people are informed of their child's result, they may be unaware of the implications. In one study, 27.5 percent of families undergoing follow-up interviews believed their baby with sickle cell trait might develop sickle cell symptoms, indicating the ongoing misconceptions that persist in families given limited counseling [26].

Communication of a screening result consistent with sickle cell trait should always be accompanied by appropriate counseling about the implications for the individual and family members. (See 'Information/counseling to be provided with results' below.)

Adolescents and adults — Despite routine newborn screening, some individuals may not be screened at birth (eg, immigrants from countries without routine screening), and many others may be unsure of their screening results due to variability in reporting. In a 2018 sample of older adults (ages 40 to 69) who participated in the Southern Community Cohort Study, self-report of sickle cell disease and sickle cell trait status was not always concordant with results of DNA sequencing [27]. As an example, of 75 who reported not having sickle cell disease, 9 (12 percent) had sickle cell trait and none had sickle cell disease; of 51 who reported they did have sickle cell disease, 32 (63 percent) had sickle cell trait and three (6 percent) had sickle cell disease. In a 2022 study from the United Kingdom Biobank, 409 of the 527 individuals (78 percent) identified as having sickle cell trait by exome sequencing data did not have the diagnostic billing code for sickle cell trait in their medical record [28].  

Other studies have reported similar findings with sparse general understanding about sickle cell disease and sickle cell trait and incomplete knowledge of their own diagnosis [29,30].

Based on the available studies, publications, and our clinical experience, we believe that any individual who does not have definitive information regarding their sickle cell status and who might benefit from this information (individuals planning a pregnancy, individuals planning intensive exertion at high altitudes) should be offered screening. Ethnicity cannot be used as a routine criterion to eliminate the possibility of sickle cell trait. Screening should be planned, elective, and linked to meaningful counseling, which should include appropriate and accurate information regarding the implications of a positive result. Screening of asymptomatic individuals who are unaware of their status is generally deferred until late adolescence/early adulthood because this is optimal for obtaining informed consent and providing counseling regarding the implications of a positive result. (See 'Information/counseling to be provided with results' below.)

Information about sickle cell trait status in asymptomatic individuals is most important for preconception counseling. Some individuals may also benefit from this information in other settings, such as prior to strenuous athletic participation. These benefits are weighed against potential harms, including risks related to loss of insurance, employment, athletic participation, and other forms of discrimination. (See "Genetic testing", section on 'Practical issues'.)

We generally offer screening in the following settings:

Reproductive counseling – Preconception counseling and screening for sickle cell trait should be offered to all individuals of childbearing age and to all couples wishing to have a child. Many people with sickle trait often do not receive complete education on reproductive options, especially in vitro fertilization (IVF) with preimplantation genetic testing (PGT). New educational materials that incorporate stakeholders' comments have been developed, and these materials should be made available to at-risk communities, accompanied with counseling [31].

Targeted counseling and screening policies are often ineffective and problematic. Ethnicity cannot be used as a deciding factor in carrier testing [32,33]. (See "Prenatal screening and testing for hemoglobinopathy".)

Athletic pursuits/physical training – We favor voluntary rather than mandatory screening for sickle cell trait for individuals pursuing intense physical training, with decisions based on the potential benefits and risks of screening for the individual [34]. This is consistent with the approach of many professional societies that favor voluntary screening for selected individuals rather than mandatory screening. A universal preventative measure for all athletes, without mandatory screening, is recommended by the American Society of Hematology (ASH), the Sickle Cell Disease Association of America (SCDAA), the American Public Health Association (APHA), the Association of Public Health Laboratories (APHL), the American Society of Clinical Pathology (ASCP), and the American Society of Pediatric Hematology-Oncology (ASPHO). (See 'Intensive exercise/physical training' below.)

There are ongoing discussions by different professional groups regarding routine screening of athletes for sickle cell trait [35,36]. In the United States, the National Collegiate Athletic Association (NCAA) requires mandatory testing (or confirmation from newborn screening) for sickle cell trait, with a written opt-out provision, for all student athletes participating in Division I and II (college level) sports [37]. This policy is highly controversial. Each branch of the US military has its own policies on screening [38]. The US Army has abolished universal screening in favor of universal precautions; the US Marine Corps continues to test all recruits. A review of 377 cases of exertional rhabdomyolysis in individuals in the Air Force suggest this complication remains a potential problem to all service people exposed to high-risk activities. However, with universal precautions as a policy, these results suggest that individuals with sickle cell trait were at no greater risk of severe rhabdomyolysis than those without sickle cell trait [39].

Some athletes may receive a diagnosis of sickle cell trait from screening. As is standard clinical care for non-athletes, any athlete identified as having sickle cell trait should receive formal genetic counseling regarding the risk of having a child with sickle cell trait (and implications for other relatives).

If there is a possibility of a child, the partner and the athlete should also receive genetic counseling about the couple having a child with sickle cell disease. In addition, the athlete should be informed of the medical risks associated with sickle cell trait.

A common misconception in informal genetic counseling and among individuals who have not received any genetic counseling is that if the individual has sickle cell trait and the partner does not have sickle trait, the couple cannot have a child with sickle cell disease. These assumptions are incorrect, as the partner may be heterozygous for another beta globin variant such as Hb C, beta thalassemia trait, Hb D, Hb E, or other beta globin variants that can lead to a child with compound heterozygous SCD. Other less common causes of SCD such as maternal or paternal uniparental disomy may also occur. Although maternal and paternal disomy are rare, it is important not to assume nonpaternity merely because the father does not have a hemoglobinopathy variant identified [40]. (See 'Information/counseling to be provided with results' below.)

There are no prospective studies indicating that screening for sickle cell trait decreases adverse events. Potential benefits of screening (or discussions about screening) include the opportunity to review and reinforce healthy practices for all individuals such as adequate hydration and avoidance of exertional heat illness or metabolic abnormalities during intensive physical activity. While sickle cell trait is a risk factor for exertional rhabdomyolysis, the risk is modest and similar to other risk factors such as obesity, tobacco use, and medications including statins and antipsychotic agents (hazard ratio 1.54; 95% CI 1.12-2.12). However, a military study involving 47,000 Black soldiers found that those with sickle cell trait did not have a higher risk of death than those without sickle cell trait [4] (table 1). (See 'Rhabdomyolysis and sudden death during strenuous physical activity' below and "Exertional heat illness in adolescents and adults: Management and prevention", section on 'Prevention of exertional heat illness'.)

The potential benefits of screening must also be weighed against potential harms, including risks related to loss of insurance, employment, athletic participation, and other forms of discrimination. In addition to risks of discrimination, professional groups have raised concerns that mandatory screening without adequate counseling could lead to additional adverse effects. These benefits and harms of screening are discussed separately. (See "Overview of preventive care in adults" and "Genetic testing", section on 'Genetic discrimination'.)

Appropriate laboratory testing — Sickle cell trait cannot be detected by measuring hemoglobin level, hematocrit, reticulocyte count, red blood cell indices such as mean cell volume (MCV), or review of the peripheral blood smear, as these are all normal in individuals with sickle cell trait.

Screening for sickle cell trait can be done with isoelectric focusing (IEF), hemoglobin electrophoresis, high performance liquid chromatography (HPLC), or genetic testing. Screening should not be done with the sickledex test, which often gives inaccurate results (false positives).

Hemoglobin electrophoresis is increasingly available in resource-limited countries. Hemoglobin electrophoresis is increasingly available in resource-limited countries. Advances in point-of-care testing for sickle cell disease and sickle cell trait should enable clinical hemoglobinopathy testing throughout sub-Saharan Africa [41,42]. (See "Diagnosis of sickle cell disorders", section on 'Laboratory methods' and "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Point-of-care assays'.)

The presence of sickle cell trait (rather than sickle cell disease) is established by the finding of both hemoglobin A (Hb A) and hemoglobin S (Hb S), with the amount of Hb A greater than Hb S (figure 1).

Age ≥6 months – Typically, individuals with sickle cell trait have approximately 50 to 60 percent Hb A and 35 to 45 percent Hb S (may be lower with concomitant alpha thalassemia). The percent Hb S increases with age and plateaus at approximately two years, due to switching from fetal hemoglobin (Hb F) to Hb A; Hb A uses the beta globin chain that is affected by the sickle mutation, whereas Hb F does not. The co-inheritance of other hemoglobinopathies such as alpha thalassemia or beta thalassemia may also affect the percent Hb S (table 2 and table 3). (See "Diagnosis of thalassemia (adults and children)", section on 'Overview of subtypes and disease severity'.)

Age <6 months – In some newborns and infants <6 months, it may not be possible to distinguish the FAS pattern (greater percentage of Hb A than Hb S, indicative of sickle cell trait; "F" stands for Hb F) from the FSA pattern (greater percentage of Hb S than Hb A) indicative of a compound state such as sickle-beta thalassemia or Hb SC disease. Repeat testing at age three to six months, or molecular testing (DNA analysis) is generally used to distinguish these conditions. (See "Diagnosis of sickle cell disorders", section on 'FAS and FSA patterns'.)

Genetic testing in an individual with sickle cell trait will demonstrate the sickle mutation in one allele of the hemoglobin beta locus (from one parent) and normal sequence (absence of the sickle mutation or other beta globin mutation such as Hb C or a beta thalassemia variant) in the other. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Molecular genetic (DNA-based) methods'.)

Other screening tests are less helpful and are generally avoided. Examples include the sickle prep test (microscopic evaluation for sickled cells from blood treated with sodium metabisulfate), which is less reliable and should not be used. Sickle solubility testing has a lower sensitivity than electrophoresis or HPLC, and it is not used in infants <6 months of age because Hb S levels are lower in young infants; results from this testing should be confirmed using electrophoresis or HPLC [43].

Information/counseling to be provided with results — Implications of sickle cell trait status should be communicated by a clinician who understands them, as there is a high prevalence of misleading information communicated during genetic counseling sessions for sickle cell trait by clinicians [44-47]. Counseling may decrease anxiety, facilitate understanding of clinical symptoms, and improve family planning decisions [48].

Counseling can be performed by primary care physicians, specialists, genetic counselors, and certified sickle cell trait community counselors; it is important that the individual providing counseling undergoes adequate training and that the family/caregivers have access to further education in the future.

The following information is appropriate to convey (table 4):

Sickle cell trait is a benign carrier state and not a disease.

There are implications for genetic counseling and a potential risk of having a child with sickle cell disease. (See 'Reproductive issues' below.)

Individuals with sickle cell trait have the same life expectancy as the general population.

Individuals with sickle cell trait are at risk for a few very rare life-threatening complications, including rhabdomyolysis and/or sudden death with prolonged physical activity (military boot camp, training for an athletic competition). In addition, risks are increased for a rare cancer (renal medullary carcinoma), complications of traumatic hyphema, and splenic infarction at high altitudes. Thus, it is important to seek medical attention promptly for hematuria, eye trauma, or severe abdominal pain, especially when traveling to high-altitude areas or in situations with low oxygen tension.

Individuals with sickle cell trait commonly develop hyposthenuria, increasing the risk of dehydration and associated complications. Therefore, counseling to maintain adequate fluid intake to prevent dehydration is a core necessity for sickle cell trait carriers [49]. (See 'Urologic and kidney disease' below.)

Additional resources are available for patients from the following sources:

Centers for Disease Control (CDC) (http://www.cdc.gov/ncbddd/sicklecell/traits.html)

Sickle Cell Disease Association of America (SCDAA) (https://www.sicklecelldisease.org/support-and-community/links-resources/)

"Toolkit" from the CDC, American Society of Hematology, and SCDAA (http://www.cdc.gov/ncbddd/sicklecell/toolkit.html)

Patient information provided in UpToDate (see 'Information for patients' below)

Additional counseling regarding reproductive issues, athletic participation and blood and hematopoietic stem cell donation is discussed below. (See 'Management and preventive care' below.)

The lack of adequate counseling of parents who have infants with sickle cell trait relative to other carrier states was illustrated in survey of 298 pediatricians and family practice physicians [50]. Parents of infants with sickle cell trait received counseling less often than parents of infants who were cystic fibrosis carriers (80 versus 92 percent).

CLINICAL FINDINGS

General health — The general health of people with sickle cell trait is comparable to individuals without sickle cell trait. Large population studies are not designed to look for rare or uncommon specific health events for which individuals with sickle trait are at risk. In Michigan, long-term follow-up of 18,257 children with sickle cell trait diagnosed in the newborn period found no increased risk of increased use of health care services and no increased incidence of common medical conditions over the rates of health care use and common disorders in 74,523 children who did not have sickle cell trait [51].

Inadequate evidence or conflicting results on the risk of hypertension, diabetes, heart disease, or stroke — Studies of cardiovascular conditions have produced conflicting results. As examples:

A 2022 study from the United Kingdom Biobank found an increased rate of multiple complications in individuals with sickle cell trait relative to other sickle cell trait studies [28]. The 2022 study evaluated 8019 Black individuals without sickle cell trait and 699 Black individuals with sickle cell trait (average age of the participants, 51 years) using ICD10 codes. In addition to previously reported potential risks, this study found increased rates of diabetes, hypertension, heart disease, chronic kidney disease, and retinopathy.

The CARDIA study (Coronary Artery Risk Development in Young Adults) was initiated in 1984 to study coronary artery disease risk factors in Black people and White people in four urban areas in the United States [52]. A 2017 report from the study analyzed data from 25 years of observation of 136 Black people with sickle cell trait and 1859 Black people without sickle cell trait [53]. This analysis revealed that after adjustment for age, sex, body mass index, and fitness, sickle cell trait was not associated with higher (or lower) rates of hypertension, diabetes, or metabolic syndrome (adjusted hazard ratios [HR], 1.2 [95% CI 0.9-1.7]; 1.5 [95% CI 1.0-2.3]; and 1.3 [95% CI 0.9-1.7]).

The complications are discussed in more detail below.

Hypertension — Several studies have evaluated systemic hypertension risk in sickle cell trait. Most were of moderate to low quality and did not find an association between sickle cell trait and increased risk of hypertension. The largest longitudinal study of 1590 African American adults (the CARDIA study) did not show an association between sickle cell trait and hypertension [53]. This study followed participants for >25 years with detailed laboratory and imaging testing. In a 2022 study from the United Kingdom Biobank that included 8019 Black individuals, 699 (8.7 percent) of whom had sickle cell trait, rates of hypertension were increased in those with sickle cell trait (56 percent) compared with controls (48 percent), with an odds ratio of 1.3, (95% CI 1.09-1.55) [28]. This was a cross-sectional analysis of patients who entered the project with a mean age of 51 years; the data were predominately collected by ICD10 codes and lacked the vigorous nature of the testing of the earlier study.

Diabetes — The United Kingdom Biobank study found a higher rate of diabetes associated with kidney and vascular disease with 19 percent prevalence [28]. In particular, type 2 diabetes was markedly increased in the sickle cell trait population (22 percent, versus 17 percent in controls); for an odds ratio of 1.38, (95% CI 1.12-1.68). Sickle cell trait increased the risk of end-stage kidney failure and rhabdomyolysis in the diabetes population.

In contrast, the CARDIA study did not find an association between sickle cell trait and diabetes [53]. There were slight differences in the CARDIA study's baseline data that disappeared over time, with both groups remaining similar. The overall prevalence of diabetes was 6.8 percent in the CARDIA study.

In a 2022 study of diabetes from Tanzania in individuals with or without HIV infection, individuals with sickle cell trait were more likely to have abnormal markers of pancreatic function than controls, including pancreatic beta cell dysfunction higher values on the 30-minute glucose tolerance test [54].

The effect of sickle hemoglobin on certain assay measurements of the HbA1c (glycosylated hemoglobin) and other issues related to HbA1c measurement in African Americans are discussed in separate topic reviews. (See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults", section on 'Diagnostic criteria' and "Measurements of glycemia in diabetes mellitus", section on 'Glycated hemoglobin (A1C)'.)

Heart disease — A 2021 study that longitudinally followed five large cohorts and included 23,197 African Americans, 1781 with sickle cell trait, found no increased risk of myocardial infarction or other coronary heart disease in those with sickle cell trait [55]. Likewise, the CARDIA study found no increased risk of heart disease [53].

A 2017 meta-analysis analyzed data from four population-based cohorts in the United States that were established to analyze cardiovascular risk factors (ARIC, Jackson Heart Study, MESA, and the Women's Health Initiative) [56]. Data on cardiac function and sickle cell trait status were obtained from study records, phone calls, and various genotyping methods. They included 1211 individuals with sickle cell trait and 14,153 controls (African Americans without sickle cell trait). Compared with controls, those with sickle cell trait had no increased risk of heart failure (HR, 1.0; 95% CI 0.8-1.3) or cardiovascular risk factors. This lack of association was confirmed in a 2018 systematic review of all available evidence [57].

Stroke — There are insufficient data to conclude whether sickle cell trait is an independent risk for ischemic stroke. Investigations of brain volume, cerebral blood flow, oxygen, metabolism, and vascular structure in sickle cell trait are not different than controls [58]. However, it is important for any individual with sickle cell trait who has a stroke to have a full evaluation for the cause and not to attribute stroke to sickle cell trait. In addition, it may be worthwhile to evaluate for a variant sickle cell syndrome such as Hb SC disease.

This approach of not attributing stroke to sickle cell trait is supported by a 2018 meta-analysis that assessed the association of sickle cell trait with ischemic stroke in 19,664 African-American individuals [59]. The crude incidence of ischemic stroke was 2.9 per person-years (95% CI, 2.2-4.0 per 1000 person-years) among those with sickle cell trait and 3.2 per 1000 person-years (95% CI, 2.7-3.98 per person-years) among those without sickle cell trait.

Additional large epidemiologic studies and smaller studies have reported either no increased risk or a very slight increased risk of stroke in individuals with sickle cell trait. As examples:

In a series that included over 10,000 African Americans, 2642 of whom had sickle cell trait, sickle cell trait was not associated with an increased risk of stroke 54.

In a population-based case-control study of early-onset ischemic stroke in young African-American individuals (ages 15 to 49 years) that evaluated 342 cases of ischemic stroke and 333 controls without ischemic stroke, there was no association between ischemic stroke and sickle cell trait [60].

The prospective Atherosclerosis Risk in Communities [ARIC] Study, which evaluated the risk of stroke in a population-based sample of 3497 African Americans for over two decades, found a slight increase in the risk of stroke in individuals with sickle cell trait compared with hemoglobin AA (13 versus 10 percent; hazard ratio [HR] 1.4; 95% CI 1.0-2.0; crude incidence rate 7.1 versus 5.3 events per 1000 person-years) [61]. These findings were of borderline significance and, even if true, do not imply causality. In a subsequent analysis, the minor effect of sickle cell trait on stroke incidence appeared amplified when concomitant CKD occurred [62]. In this report, the overall HR of ischemic stroke associated with sickle cell trait was 1.31 (95% CI 0.95-1.80). However, the HR was higher in individuals with concomitant CKD (HR 2.18; 95% CI 1.16-4.12) than in those without CKD (HR 1.09; 95% CI 0.74-1.61). This observation of sickle cell trait modifying stroke risk in kidney disease requires further investigation.

A small prospective study of 21 children with sickle cell trait versus controls without sickle cell trait found an increased prevalence of arterial tortuosity by brain imaging in those with sickle cell trait compared with controls, and the abnormalities seemed to correlate with percent of hemoglobin S 80.

The 2022 study from the United Kingdom Biobank found no increased risk of ischemic stroke in individuals with sickle cell trait compared with controls (2.7 versus 1.9 percent; OR 1.46, 95% CI 0.86-2.34), but there was an increased risk of non-ischemic stroke that barely reached statistical significance (3.7 versus 2.5 percent; OR 1.6, 95% CI 1.02-2.41) [28].

It is also worth noting that African Americans have a higher prevalence of stroke and stroke risk factors than other groups [63]. Additional research is needed to determine definitively whether sickle cell trait further increases stroke risk.

Details of the evaluation and management of ischemic stroke are presented separately. (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis" and "Ischemic stroke in children: Management and prognosis" and "Initial assessment and management of acute stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack" and "Neuroimaging of acute stroke".)

Urologic and kidney disease — Individuals with sickle cell trait are at risk for certain urologic and kidney complications, although the true prevalence of these complications relative to the general population is not well characterized, and the benefit of screening individuals with sickle cell trait for these complications is unknown.

Additional details regarding the pathogenesis and laboratory evaluation of these complications are presented separately. (See "Sickle cell disease effects on the kidney", section on 'Routine surveillance and early detection'.)

Chronic kidney disease and hyposthenuria — Sickle cell trait likely has an increased risk of chronic kidney disease (CKD), a more rapid decline in estimated glomerular filtration rate (EGFR), and an increased incidence of albuminuria. Two large studies from 2022 analyzed the impact of sickle cell trait on CKD.

The United Kingdom Biobank study found a statistically significant association of sickle cell trait with CKD (prevalence, 5.6 percent in sickle cell trait compared with 3.5 percent in controls; OR 1.61, 95% CI 1.11-2.29) [28]. In addition to CKD, there was also an association of sickle cell trait with end-stage kidney disease (ESKD; 0.9 percent, versus 0.2 percent in controls; OR 4.2, 95% CI 1.45-10.36) and rhabdomyolysis (1.6 percent, versus 0.3 percent in controls; OR 5.1, 95% CI 2.14-11.37). Rhabdomyolysis is discussed below. (See 'Rhabdomyolysis and sudden death during strenuous physical activity' below.)

The Million Veteran Program includes a long-standing electronic health record of military veterans with a genetic biobank [64]. This dataset was used to determine the association of sickle cell trait with medical complications prior to the coronavirus disease 2019 (COVID-19) pandemic and during and post-COVID-19 infections. In the pre-COVID-19 analysis, sickle cell trait was associated with CKD, diabetic kidney disease, hypertensive kidney disease, pulmonary embolism, and cerebrovascular disease. While rates of COVID-19 were similar in individuals with and without sickle cell trait, individuals with sickle cell trait who developed COVID-19 had a higher risk of mortality than controls. Acute kidney failure was more common in the individuals with sickle cell trait and was a major factor in the increased mortality rate. Sickle cell trait was also associated with a greater risk of declining kidney function following COVID-19, both in individuals with preexisting CKD and those with previously normal kidney function.

A 2018 meta-analysis of sickle cell trait complications, which was informative but limited by the lack of high-quality data, found an increased risk of proteinuria and CKD in individuals with sickle cell trait [57]. In the one high-quality study evaluating proteinuria, individuals with sickle cell trait had a 32 percent risk of albuminuria, compared with 20 percent in those without sickle cell trait, a 1.86-fold increased risk. Two high-quality studies evaluated CKD and found an increased risk (relative risk [RR] 1.57; 95% CI 1.34-1.84). Among two high-to-moderate-quality studies evaluating dialysis-dependent ESKD, one reported an increased incidence of ESKD compared with individuals without sickle cell trait (hazard ratio [HR] 2.03; 95% CI 1.44-2.84); a similar study of moderate quality did not find any association between sickle cell trait and ESKD. More research is needed to determine composite effect of confounding conditions such as including diabetes and hypertension. (See "Sickle cell disease effects on the kidney", section on 'Pathogenesis'.)

African Americans also inherit genetic risk factors that predispose to CKD, such as the G1 and G2 alleles of APOL1 gene, a risk factor for ESKD. (See "Gene test interpretation: APOL1 (chronic kidney disease gene)".)

Hyposthenuria refers to an impairment in the ability to concentrate the urine; the risk is related to early CKD and is increased in individuals with sickle cell trait. Hyposthenuria is responsible for nocturnal enuresis in older children with sickle cell trait and increases the likelihood of dehydration in at-risk situations such as exertional rhabdomyolysis [57,65,66]. It occurs because the renal medulla has a hyperosmolar, acidic, hypoxic environment that can induce hemoglobin polymerization in sickle cell trait cells. This environment, together with a low flow state in the renal medulla, reduces the number of vasa recta and damages the normal vascular structure. It is important to counsel individuals with sickle cell trait about this risk so that they can ensure adequate fluid intake and prevent dehydration. (See 'Information/counseling to be provided with results' above.)

Screening for kidney disease in individuals with sickle cell trait is controversial, and the optimal screening is unknown, with issues similar to the general population. A reasonable approach is to screen individuals who have sickle cell trait and risk factors for CKD (hypertension, diabetes) with serum creatinine and urinalysis, with further evaluation based on the results. (See "Early detection of chronic kidney disease" and "Sickle cell disease effects on the kidney", section on 'Routine surveillance and early detection'.)

For individuals with sickle cell trait who have CKD and develop anemia, some data suggest that these individuals require higher doses of an erythropoiesis-stimulating agent (ESA) compared with controls [67]. (See "Overview of the management of chronic kidney disease in adults", section on 'Anemia'.)

Urologic complications

Hematuria – Episodes of hematuria are common in sickle cell trait. A 2018 systematic review found an approximately twofold increase compared with individuals without sickle cell trait (95% CI 1.5-2.6), although the quality of the evidence was low [57]. The mechanism generally is thought to be related to renal papillary infarcts. (See "Etiology and evaluation of hematuria in adults" and "Evaluation of microscopic hematuria in children".)

There is also an unlikely possibility of renal medullary carcinoma. Thus, hematuria without another obvious explanation should prompt evaluation for this malignancy, particularly among younger patients with sickle cell trait (or sickle cell disease). Imaging with computed tomography (CT) urography has replaced intravenous pyelography (IVP) in evaluating hematuria in these cases. (See 'Renal medullary carcinoma' below.)

Urinary tract infection – The frequency of urinary tract infections may be increased in sickle cell trait [68,69]. Routine management is similar to individuals without sickle cell trait.

Renal medullary carcinoma — Renal medullary carcinoma is a rare and aggressive form of non-clear cell renal cancer seen almost exclusively in individuals with sickle cell trait. It has been associated with the loss of SMARCB1, a tumor suppressor that has been noted in childhood cancers [70]. The United Kingdom Biobank study reported a trend towards an increased risk of renal medullary carcinoma in individuals with sickle cell trait that did not reach statistical significance; the number of cases was very low (0.4 percent with sickle cell trait, versus 0.2 percent in controls; OR 2.2, 95% CI 0.51-6.78) [28].

It is appropriate to evaluate patients with sickle cell trait who have unexplained hematuria or severe flank pain using imaging studies. Individuals with sickle cell trait presenting with hematuria should inform the clinician of their sickle cell trait status and the possibility of renal medullary carcinoma; however, we do not screen for this tumor in asymptomatic individuals with sickle cell trait [71].

Additional aspects of evaluation and management are discussed separately. (See "Sickle cell disease effects on the kidney", section on 'Renal medullary carcinoma'.)

Vaso-occlusive phenomena — A variety of vaso-occlusive phenomena can occur in individuals with sickle cell trait, although the incidence is low, and documentation is not definitive. Patients suspected of having any of these complications should be evaluated and treated by a specialist with expertise in their management.

Splenic infarction – Splenic infarction can develop at high altitude, including mountain climbing and flying in unpressurized airplanes [72,73]. It is possible that this complication is more likely to occur in White individuals than in Black individuals, but this has not been studied extensively [74]. This was illustrated in a review of 25 cases of high-altitude splenic infarction in individuals who were subsequently found to have sickle cell trait, in which the ratio of non-African Americans to African Americans was 1.4 to 1 [75]. Most of the affected individuals (all males) were unaware that they had sickle cell trait at the time of the event, especially the non-African Americans. Presenting symptoms included left upper quadrant pain and an elevated bilirubin.

The most comprehensive case report review identified 85 cases of splenic infarction in individuals with sickle cell trait [76]. All age groups were affected; as noted previously, most individuals were male. All ethnic groups were represented, and African Americans accounted for 26 percent of the cases. Both altitude level and the percentage of Hb S appeared to be risk factors. However, the altitude level at which splenic infarction occurred could not be clearly established, since 39 percent of the cases occurred at an altitude <3,000 meters. Hb S was >35 percent in 88 percent of the cases. Conservative treatment, including changing altitude, was therapeutic in most cases, though splenectomy was required in over a third of cases.

Splenic sequestration – Splenic sequestration crisis and acute pain episodes have been described in individuals with sickle cell trait, but these events are very rare and most often due to other concomitant medical problems or extreme conditions, such as high altitude, increased pressure (SCUBA diving), low oxygen, severe prolonged exercise, or dehydration.

Priapism – Although priapism has been reported in individuals with sickle cell trait, insufficient evidence exists to support a causal relationship, as the priapism generally occurred in the setting of other potential precipitating factors (drug use, heart transplant) [77-80]. It is unclear if the incidence of priapism is increased relative to the general population [5]. (See "Priapism and erectile dysfunction in sickle cell disease", section on 'Epidemiology'.)

Eye complications (traumatic hyphema, retinal complications) – Patients with sickle cell trait are at increased risk for serious complications of traumatic hyphema (entry of blood into the anterior chamber of the eye due to injury), including increases in intraocular pressure following the initial hyphema and rebleeding, and loss of vision. Testing for sickle cell trait is warranted for individuals with a traumatic hyphema. Individuals with sickle cell trait who develop traumatic hyphema should be evaluated by physicians familiar with medical and surgical approaches to traumatic hyphema and its complications [81,82]. (See "Traumatic hyphema: Management".)

There is limited evidence to establish whether individuals with sickle cell trait have increased risk of retinal disease. In the 2022 study from the United Kingdom Biobank study that used ICD10 codes to identify complications, there was a higher rate of retinopathy in individuals with sickle cell trait (2.4 percent, versus 1.4 percent in controls) [57]. However, there was no significant difference in the rate of retinopathy in individuals with diabetes and sickle cell trait compared with controls with diabetes who did not have sickle cell trait. Three previous limited studies looking at retinopathy found no association.

Venous thromboembolism — There is increasing biologic and clinical evidence that individuals with sickle cell trait may have an increased risk of thrombosis in certain clinical settings. Experimentally, sickle trait red cells increase fibrin resistance to fibrinolysis by tissue plasminogen activator (TPA), resulting in a pro-thrombotic state [83,84].

A 2018 meta-analysis found two high-to-moderate-quality studies reporting an increased incidence of deep vein thrombosis (DVT) in individuals with sickle cell trait compared with those without sickle cell trait (9 versus 6 percent, respectively) [57]. Three high-to-moderate-quality studies from the meta-analysis found an increased risk for pulmonary embolism (PE).

While sickle cell trait may confer an increased risk of PE and possibly of DVT, the risk is not great enough to warrant differences in routine management solely on the basis of sickle cell trait [57,85,86]. Examples of some of the relevant studies include the following:

A prospective study of African Americans with sickle cell trait and age matched controls without sickle cell trait reported an increased risk of pulmonary embolism (HR 2.05; 95% CI 1.12-3.76) but not for DVT [87].

A case-control study that evaluated sickle cell trait status in 515 Black adults hospitalized with a PE or DVT compared with 555 Black outpatient controls also found an increased adjusted odds ratio (OR) for sickle cell trait in patients with PE (OR: 3.9; 95% CI 2.2-6.9) but not DVT (OR 1.1; 95% CI 0.65-1.9) [86].

A retrospective cohort study of 13,964 African Americans found a slightly increased risk for PE in those with sickle cell trait (adjusted relative risk [RR] 1.37; 95% CI 1.07-1.75) [88].

The risks of PE and DVT may be more pronounced in some settings. One area of concern is in pregnant and postpartum women. However, one of the largest analyses found a similar incidence of peripartum PE and DVT in non-Hispanic Black women with and without sickle cell trait (0.44 versus 0.49 percent) [89]. Additional studies are needed in this setting.

Rhabdomyolysis and sudden death during strenuous physical activity — Regular exercise is beneficial to individuals with sickle cell trait [90]. Routine fitness training does not increase the risk of mortality for individuals with sickle cell trait, and overall it appears that sickle cell trait has limited if any effect on the physiologic response to exercise [85,91-98]. However, concerns have been raised about an increased risk for rhabdomyolysis and/or sudden death during prolonged physical conditioning and extreme exercise (eg, military training, competitive sports) in individuals with sickle cell trait [35,99-102]. This has also been referred to as "exercise collapse associated with sickle cell trait" (ECAST) [103]. Proposed contributing factors include heat exposure, dehydration, myocardial ischemia, and arrhythmias.

The best available evidence suggests that individuals with sickle cell trait have a slightly increased risk of rhabdomyolysis but not an increased risk of death with strenuous physical activity, as long as proper measures to prevent heat illness are taken. These measures include gradual acclimatization, breaks for hydration and cooling, and prompt intervention for concerning symptoms, as discussed in detail separately. (See "Exertional heat illness in adolescents and adults: Management and prevention" and 'Intensive exercise/physical training' below.)

Evidence for an increased risk of rhabdomyolysis but not increased mortality comes from a 2016 cohort of 47,944 Black soldiers who served in the United States army during the years 2011 to 2014 for whom data on sickle cell trait status were available [4]. Sickle cell trait status and clinical findings were obtained from medical records, laboratory data, billing codes, and death records.

Rhabdomyolysis – There were 391 episodes of rhabdomyolysis during the study period. The magnitude of increased risk attributable to sickle cell trait was relatively small (hazard ratio [HR] 1.54, 95% CI 1.12-2.12). In comparison, the HRs for rhabdomyolysis attributable to smoking, obesity, antipsychotic medications, and statin agents were 1.4, 1.5, 3.0, and 2.9, respectively. Age and male sex also were associated with increased risk. These other risk factors are discussed separately. (See "Rhabdomyolysis: Epidemiology and etiology".)

Mortality – There were 96 deaths from all causes during the study period. The risk of death for those with sickle cell trait was similar to those without sickle cell trait (HR 0.99, 95% CI 0.46-2.13). Causes of death for the seven individuals with sickle cell trait included battle injuries and other (unrelated) medical conditions. The sole individual who died from an episode of rhabdomyolysis did not have sickle cell trait.

The finding of increased rhabdomyolysis is consistent with data from two large population-based studies involving approximately two million military recruits undergoing basic training from 1977 to 1981 and approximately two million college athletes studied from 2004 to 2008 [99,104]. Both studies found an increased rate of sudden death in individuals with sickle cell trait (eg, 32.2 per 100,000 military recruits with sickle cell trait, compared with 1.2 per 100,000 without sickle cell trait) [99]. In 2018, the United States Army reported on risk factors for mild heat injury, as well as heat stroke in sickle cell trait-tested African-American soldiers in a setting in which precautions were used for all soldiers to mitigate exercise-induced illness [105]. In this setting, sickle cell trait was not associated with heat injury. Risk factors for heat-associated injury included prescription medications for psychotic illness and overweight or obesity.

Exercise-induced deaths in the military decreased dramatically following implementation of sickle cell trait screening in 1982; a general reduction in training intensity and earlier recognition of heat-related injuries also occurred and may have contributed to the decline in deaths. In athletes with sickle cell trait, the risk of sudden nontraumatic death is intensely debated, and rare deaths continue to be reported [102,106,107]. However, it remains unclear whether there is a causal relationship, and data from large epidemiologic studies are limited. In a report of 160 nontraumatic deaths in high school and college athletic activities between 1983 and 1993, cardiovascular conditions (eg, cardiomyopathies, arrhythmia syndromes) accounted for 74 percent of the deaths [108]. Seven deaths were attributed to rhabdomyolysis and sickle cell trait. A report of 10 college-level football players with sickle cell trait who died during the early 2000s found that half had been performing serial sprints or drills without interval rest periods at the time of sudden death [38].

As discussed below, we favor institution of practices to reduce rhabdomyolysis for all individuals undergoing strenuous physical activity, and rapid intervention should symptoms occur, regardless of sickle cell trait status. (See 'Intensive exercise/physical training' below.)

Symptoms of sickle cell disease — Very rarely, individuals with sickle cell trait show symptoms of sickle cell disease such as anemia or acute chest syndrome. Often these individuals have co-inherited another hemoglobin mutation that decreases hemoglobin solubility (eg, Hb S-Antilles; Hb Quebec-Chori; Hb S-Oman; Hb Jamaica Plain) [109-111]. In one case, a boy who was genetically heterozygous for the sickle mutation had mosaicism for cells in which only the sickle mutation was expressed due to post-zygotic uniparental disomy [40]. (See "Diagnosis of sickle cell disorders" and "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'HPLC'.)

Another rare cause of symptomatic sickle cell trait occurs when sickle cell trait coexists with pyruvate kinase deficiency, which lowers the hemoglobin oxygen affinity, resulting in hemoglobin S polymerization and sickling [112]. (See "Pyruvate kinase deficiency".)

Evaluation for these other inherited conditions is appropriate in individuals who are heterozygous for the sickle mutation yet have symptoms of sickle cell disease, and it may be appropriate to manage these individuals more similarly to those with sickle cell disease, depending on the severity of findings.

In contrast, those who co-inherit another beta globin variant (beta thalassemia, Hb C) are considered to have sickle cell disease rather than sickle cell trait. (See "Overview of compound sickle cell syndromes".)

MANAGEMENT AND PREVENTIVE CARE — In most cases, individuals with sickle cell trait are managed similarly to the general population. However, patients may benefit from information regarding sickle cell trait, and counseling should be offered by a qualified clinician regarding the risk of having a child with sickle cell disease. (See 'Information/counseling to be provided with results' above and 'Reproductive issues' below.)

In addition, the knowledge of sickle cell trait may be helpful in the setting of blood or hematopoietic stem cell donation, and in some individuals planning strenuous exercise or physical activity. (See 'Blood and stem cell donation' below and 'Intensive exercise/physical training' below.)

Reproductive issues

Birth control — Individuals with sickle cell trait should have unrestricted access to birth control of their choice.

African American women have increased risk of thrombosis with hormonal birth control, which should be explained to the individual. A further increased risk for thrombosis due to sickle cell trait in the setting of hormonal birth control has not been well studied. One study found an increased rate of thrombosis in African American women that was not further increased in those who also had in sickle cell trait [113,114]. This potential increased risk does not alter routine management of individuals with sickle cell trait. (See 'Venous thromboembolism' above.)

Preconception screening and prenatal diagnosis — Adequate counseling for families with sickle cell trait is important at various stages of family planning. The ethnicity or race of the parents should not influence family screening and counseling, because beta globin mutations occur in all ethnic groups and sickle cell trait is relatively common in mixed ethnic/racial parents.

Screening of the parents is a priority to offer prenatal diagnosis to at-risk couples, and it is the responsibility of the clinician to ensure that this counseling occurs [115]. (See 'Genetics and epidemiology' above.)

Individuals who learn that they have sickle cell trait during preconception or perinatal testing should be informed that they are carriers of the sickle cell mutation, and they should receive appropriate counseling regarding their own health (see 'Information/counseling to be provided with results' above). The other parent also needs to be tested, to allow determination of the likelihood of having a child with sickle cell disease.

Sickle cell disease has autosomal recessive inheritance (figure 2). A child born to one parent with sickle cell trait has a 50 percent chance of inheriting sickle cell trait. A child born to two parents with sickle cell trait (or one parent with sickle cell trait and one parent with another beta globin variant such as Hb C, Hb D, Hb O-Arab, or any beta thalassemia) has an approximately 50 percent chance of having sickle cell trait, and approximately a 25 percent chance of having sickle cell disease. (See "Hemoglobin variants including Hb C, Hb D, and Hb E".)

Options for preimplantation genetic diagnosis and/or prenatal testing if both parents carry a beta globin variant are discussed separately. (See "Prenatal screening and testing for hemoglobinopathy", section on 'Prenatal (fetal) diagnosis'.)

Pregnancy — Data on the risk of pregnancy complications in women with sickle cell trait are conflicting; it is unclear if the risk of pregnancy complications is increased [47,89,116-118].

Overall, most published studies evaluating sickle cell trait and pregnancy complications have methodologic problems and do not demonstrate a strong relationship between sickle cell trait and complication risk.

A 2020 retrospective analysis of a cohort of 25,000 women in the military, 5000 of whom had sickle cell trait, found that sickle cell trait was associated with an increased rate of pregnancy-related hypertensive disorders (PRHD) including gestational hypertension, preeclampsia, and eclampsia (incidence rate ratio [IRR] 1.46; 95% CI 1.32-1.62) [119]. Women with sickle cell trait also had increased health care utilization for PRHD (IRR 2.03; 95% CI 1.97-2.10). However, the dataset was limited and did not analyze several confounding variables.

A 2019 retrospective cohort study initially found an association of sickle cell trait with adverse pregnancy outcomes including hypertension, small for gestational age, diabetes, and preterm delivery [120]. However, after multivariable analysis, sickle cell trait no longer predicted these outcomes.

Blood and stem cell donation

Donating blood — Individuals with sickle cell trait can donate blood for the general blood supply, and we encourage efforts to diversify the pool of available blood for transfusion.

In contrast, blood from donors with sickle cell trait is generally not given to individuals with sickle cell disease because it will be more difficult to reach the appropriate target hemoglobin S percentage. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Transfusion techniques'.)

Leukoreduction — It may be difficult to leukoreduce blood from donors with sickle cell trait, due to blockage of the leukoreduction filters. Studies with high-performance filters for leukoreduction of packed red blood cells (pRBCs) from individuals with sickle cell trait have found increased residual white blood cells (WBCs) and increased hemolysis in the pRBC units after leukoreduction [121]. Overall, approximately 50 percent of sickle cell positive pRBC units initially pass through the filter, and eventually, after further testing, only one in four will meet transfusable leukoreduction requirements [122].

Blood centers that are 100 percent leukoreduced will generally contact and defer donors whose blood is difficult to filter after the second failed attempt. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Pre-storage leukoreduction'.)

Hematopoietic stem cell donation — Individuals with sickle cell trait can serve as donors for hematopoietic stem cell transplantation. If donation is used for a sibling with sickle cell disease, this would transform the sibling from symptomatic disease to an asymptomatic carrier state. (See "Hematopoietic stem cell transplantation in sickle cell disease", section on 'Optimal donor'.)

Individuals with sickle cell trait can receive granulocyte colony-stimulating factor (G-CSF) for hematopoietic stem cell mobilization, unlike those with sickle cell disease, in whom G-CSF should not be used [123].

Intensive exercise/physical training — As noted above, concerns have been raised regarding increased risks of rhabdomyolysis and possibly increased mortality in the setting of intensive physical training in individuals with sickle cell trait compared with the general population, although there is a lack of high quality evidence that screening improves clinical outcomes. (See 'Rhabdomyolysis and sudden death during strenuous physical activity' above.)

The American Society of Hematology (ASH) has urged athletics programs to adopt universal interventions to reduce exertion-related injuries and deaths, since this approach can be effective for all athletes regardless of their sickle cell status [124,125]. Similar policies have been developed by other professional organizations, including the American Society of Pediatric Hematology/Oncology (www.aspho.org), which opposes mandatory sickle cell trait screening for sports. The Sickle Cell Disease Association of America (www.sicklecelldisease.org), the major advocacy organization for sickle cell disease, also supports a voluntary policy.

Each branch of the US military has its own policies on physical activity [38].

If screening has been done, the sports counseling component by the clinician and trainer should be detailed [35,36]. The recommendations and protocols by the National Athletic Trainers' Association (NATA), the American College of Sports Medicine, and NCAA provide detailed and useful guidelines for counseling [126,127].

Regardless of screening policies, anticipatory interventions to prevent dehydration and hyperthermia during intensive exercise or physical training need to be enforced and expanded for all athletes, including those with sickle cell trait, particularly at the onset of conditioning training. The following guidelines for athletic participation and physical training may be useful; these apply to individuals with sickle cell trait as well as to the general population:

If any athlete with sickle cell trait begins to struggle in any drill, the drill should be stopped and medical attention should be prompt. The athlete should lie down, vital signs should be checked, supplemental oxygen given by face mask, and the athlete cooled if necessary. Failing immediate improvement, emergency personnel should be alerted (in the United States, 911 should be called), an automated external defibrillator placed, and an intravenous line with normal saline started. The athlete should be moved to a hospital urgently, and the emergency department told to expect fulminant rhabdomyolysis and its grave metabolic complications. (See "Exertional heat illness in adolescents and adults: Management and prevention" and "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)" and "Rhabdomyolysis: Clinical manifestations and diagnosis", section on 'Management'.)

Some sports and medical experts recommend a modified exercise program be instituted for all individuals with sickle cell trait. However, these recommendations should be provided to all individuals participating in sports, in particular those with specific risk factors such as reduced conditioning, excess weight, medication use, asthma, or other comorbid medical conditions [128]. The athlete with sickle cell trait should build up slowly in training, tempo of drills should be slowed, and longer periods of rest given. The athlete should run no timed serial sprints or miles and should avoid lengthy, sustained sprints or any all-out exertion beyond two to three minutes without a rest. Work/rest cycles should be adjusted for heat and altitude. The athlete should stay vigorously hydrated, and any asthma must be controlled.

Dietary stimulants, use of which may not be disclosed, can exacerbate hyperthermia and dehydration; these should be discouraged. (See "Prohibited non-hormonal performance-enhancing drugs in sport", section on 'Stimulants (banned)'.)

Compared with individuals without sickle cell trait, those with sickle cell trait may be slower to acclimate to high altitudes [38]. (See "High-altitude illness: Physiology, risk factors, and general prevention", section on 'Acclimatization'.)

LIFE EXPECTANCY — Sickle cell trait is not a disease, and life expectancy is not reduced by heterozygosity for the sickle mutation [129,130]. However, individuals with sickle cell trait may be at risk for certain conditions under certain circumstances, as discussed above. (See 'Urologic and kidney disease' above and 'Rhabdomyolysis and sudden death during strenuous physical activity' above.)

In areas in which Plasmodium falciparum malaria is endemic, sickle cell trait decreases the risk of severe malaria and hospitalization [5]. However, sickle cell trait does not eliminate this risk, and malaria prophylaxis in individuals with sickle cell trait should be the same as the general population. Sickle cell trait does not provide protection from P. vivax, P. ovale, or P. malariae. (See "Protection against malaria in the hemoglobinopathies" and "Prevention of malaria infection in travelers".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias" and "Society guideline links: Exertional heat illness".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Sickle cell trait (The Basics)")

SUMMARY AND RECOMMENDATIONS

Genetics and prevalence – Sickle cell trait is a benign carrier condition (heterozygous state) for the sickle hemoglobin variant. It is found in over 300 million people worldwide, and 2.5 million people in the United States. The frequency is higher in sub-Saharan Africa, Mediterranean countries (especially Greece), the Middle East, and parts of India. (See 'Genetics and epidemiology' above.)

Screening indications – In many parts of the world, newborns are routinely screened for sickle cell trait; however, reporting of results to the family is highly variable. Screening of asymptomatic individuals who are unaware of their status is generally deferred until late adolescence/early adulthood. We generally offer screening to appropriate individuals as part of preconception counseling and prior to athletic participation. (See 'Newborn screening' above and 'Adolescents and adults' above.)

Screening methods – Screening for sickle cell trait is done with hemoglobin electrophoresis (figure 1) or high performance liquid chromatography (HPLC). Sickle cell trait is established by the presence of both hemoglobin A (Hb A) and hemoglobin S (Hb S), with the amount of Hb A greater than Hb S (the FAS pattern) (figure 1 and table 3). The sickle prep test and sickle solubility test are generally avoided. Unlike sickle cell disease, individuals with sickle cell trait have a normal hemoglobin level, hematocrit, reticulocyte count, red blood cell indices, and peripheral blood smear. (See 'Appropriate laboratory testing' above.)

Counseling – Communication of a screening result consistent with sickle cell trait should always be accompanied by appropriate counseling about the implications (table 4), provided by an individual with adequate training and understanding of the information. (See 'Information/counseling to be provided with results' above.)

Clinical findings – Individuals with sickle cell trait do not have an increased mortality rate compared with the general population. (See 'General health' above and 'Life expectancy' above.)

Sickle cell trait is a small but significant risk factor for exertional rhabdomyolysis, which is one of the factors in sudden death associated with prolonged exercise and physical training. The universal use of preventative precautions largely mitigates the risk and severity of rhabdomyolysis. (See 'Rhabdomyolysis and sudden death during strenuous physical activity' above.)

Sickle cell trait is likely a risk factor for hyposthenuria, which can lead to dehydration, as well as chronic kidney disease (CKD) and end-stage kidney disease (ESKD), as well as proteinuria, hematuria, renal medullary carcinoma (extremely rare). (See 'Urologic and kidney disease' above.)

There may be a small but significant increased risk of pulmonary embolism and possible deep vein thrombosis. (See 'Venous thromboembolism' above.)

Data are conflicting regarding increased risks of hypertension and diabetes. Coronary heart disease, myocardial infarction, and heart failure are no different from controls. (See 'Inadequate evidence or conflicting results on the risk of hypertension, diabetes, heart disease, or stroke' above.)

Other potential complications include splenic infarction at high altitude, complications of traumatic hyphema, and possibly retinal disease. (See 'Vaso-occlusive phenomena' above.)

Pregnancy is well-tolerated in individuals with sickle cell trait, and sickle cell trait does not appear to be a risk factor for large or small gestational age infants. (See 'Pregnancy' above.)

We generally offer testing for sickle cell trait in appropriate individuals with these findings, and in some cases management differs if sickle cell trait is identified. Sickle cell trait can lead to lower glycosylated hemoglobin (HbA1c) values, which may have implications for diabetes testing and monitoring.

Medical care – In most cases, individuals with sickle cell trait are managed similarly to the general population. However, counseling should be offered by a qualified individual regarding the risk of having a child with sickle cell disease. Individuals with sickle cell trait who are planning to become pregnant or already pregnant should obtain testing for the other parent to allow determination of the likelihood of having a child with sickle cell disease. Individuals with sickle cell trait should receive unrestricted access to birth control and should be informed of a possible increased risk of thrombosis with hormonal birth control methods. Like all individuals engaging in intensive exercise and training, appropriate preventative measures for dehydration and heat related injury should be instituted. While the risk of kidney disease may be increased, there is no evidence to support more aggressive screening and subsequent treatment compared to general population monitoring. The potential risk of thrombosis should be mitigated by improved adherence to standard thromboprophylaxis for hospitalized ambulatory patients. (See 'Management and preventive care' above.)

Blood and stem cell donation – Individuals with sickle cell trait can donate blood or hematopoietic stem cells (HSCs) and can received granulocyte-colony stimulating factor (G-CSF) for HSC mobilization. Blood from a donor with sickle cell trait generally is not transfused to an individual with sickle cell disease because it will be more difficult to decrease the Hb S percentage. (See 'Blood and stem cell donation' above.)

Intensive exercise – There are ongoing discussions regarding routine screening of athletes for sickle cell trait. Anticipatory interventions to prevent dehydration and hyperthermia during intensive physical training need to be enforced and expanded for all athletes. If any athlete with sickle cell trait begins to struggle in a drill, the drill should be stopped and medical attention should be prompt. Failing immediate improvement, emergency personnel should be alerted; an automated external defibrillator placed; an intravenous line with normal saline started; and the athlete moved to a hospital that is prepared to treat fulminant rhabdomyolysis. (See 'Intensive exercise/physical training' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review.

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Topic 7145 Version 65.0

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