Jesse Theisen‐Toupal, MD

In the United States, there are an estimated 744,000 individuals who have engaged in recent injection drug use (IDU) and 6.6 million individuals who have ever injected a drug.[1] The practice of IDU predisposes individuals to serious bacterial and fungal infections that often require long‐term intravenous antibiotics. In individuals without IDU, these serious infections are often treated with outpatient parenteral antibiotic therapy (OPAT). However, a different standard exists for many persons who inject drugs (PWID)the mandated completion of antibiotics in an inpatient setting.

Though mandating inpatient antibiotic therapy for PWID is a widely adopted standard, this practice is not evidence based and may increase overall costs to the healthcare system. In 2012, in a quality‐improvement initiative, UKHealthCare established a protocol for treating appropriate PWID with OPAT.[2] They found very few inpatient providers willing to discharge PWID on OPAT, even with an established protocol.

To better understand the reasons for the low adoption of this protocol, Fanucchi and colleagues developed a survey designed to assess attitudes, practices, and mediating factors impacting the decision making about discharging PWID on OPAT.[2] The results of this survey are reported in this issue of the Journal of Hospital Medicine.

The study found that 95% of inpatient providers use OPAT for patients without IDU, but only 29% would even consider OPAT in PWID. The most common barriers to discharging a patient with IDU on OPAT were socioeconomic factors, willingness of infectious diseases physicians to follow as an outpatient, and concerns for misuse of peripherally inserted central catheters and adherence with antibiotic treatment.

At first glance, these reservations seem very reasonable. The presence of socioeconomic factors such as homelessness or lack of infectious diseases specialist follow‐up would make the risks of discharge on OPAT significant. The concerns for misuse of peripherally inserted central catheters and adherence to antibiotic treatment suggest that inpatient providers have an overall goal of reducing drug misuse and improving treatment outcomes.

Unfortunately, there are no data to suggest that completion of antibiotics in an inpatient setting reduces drug misuse or improves adherence to antibiotic treatments. Studies have found that at least 16% of PWID will misuse drugs during their hospitalization,[3] and 25% to 30% will be discharged against medical advice.[3, 4] This may be in large part due to the fact that inpatient providers are historically poor at addressing substance use disorders, even in patients with serious infections associated with IDU.[5] Yet the provision of methadone during hospitalization has been associated with a significant reduction in discharges against medical advice.[4] Rather than focusing on placing restrictions on individuals with risky behaviors, patients may benefit more from minimizing these risks through prompt recognition and management of substance use disorder.

Although limited, there is also evidence to support the feasibility of safe and effective OPAT in some PWID. A study by Ho et al. used OPAT to treat 29 PWID hospitalized with serious infections.[6] The study population had adequate housing, a reliable guardian, and signed a contract agreeing to abstain from drug misuse. In addition, all patients received substance use counseling and novel tamper‐proof security seals to prevent misuse of peripherally inserted central catheters, and antibiotics were delivered daily at an infusion center. They found no evidence of line tampering, excess readmissions, or excess line infections. Of note, the study population included 2 patients who were discharged against medical advice but successfully completed OPAT without issue. Although we do not believe that all individuals are appropriate for OPAT, this study suggests that OPAT can be considered in select PWID.

The study by Fanucchi et al. also reinforces the importance of making individualized risk assessments of persons with a history of IDU rather than assuming uniformity among the population. Of particular note is the lack of agreed‐upon definition of remote history of IDU (range, 2120 months; median, 12 months). The idea that individuals with a decade of sobriety could be subject to the same restrictions as a patient injecting multiple times a day speaks to providers' discomfort with assessing the individual risk of a person who has suffered from substance use disorder. Further, the fact that so few providers felt substance use disorder treatment was a critical component of a decision to allow OPAT raises concerns that providers are not aware of effective means to treat addiction. In particular, it is crucial for providers to understand that medication‐assisted treatment, such as methadone or buprenorphine for opioid use disorder, has significant evidence to support efficacy in decreasing drug misuse and improving outcomes.

This study suggests more work will need to be done before inpatient providers will be comfortable discharging any PWID with OPAT. This includes improved outpatient services (enhanced case management and home health services, and better access to outpatient physicians including infectious diseases specialists), the development of tamper‐evident devices to deter misuse of peripherally inserted central catheters, and defined legal protection for providers.

In addition, more research needs to be done on this population to objectively stratify risk for PWID and assess outcomes for PWID treated with OPAT versus the current standard of care. This research should have a particular focus on the long‐term financial and societal costs associated with PWID leaving against medical advice or receiving potentially unnecessary inpatient services. Minimizing the length of stay may defray inpatient costs and afford investment into more robust, effective outpatient services. It is essential that we develop a system to provide antibiotics in a way that optimizes outcomes and is cost‐effective.

Regardless of the decision to mandate antibiotic treatment in an inpatient setting or to discharge with OPAT, it is clear that more needs to be done to address addiction in hospitalized patients. All hospitalized PWID should receive safe injection education and a referral to a substance use disorder specialist. In addition, individuals with opioid‐misuse or opioid use disorder should receive opioid overdose education and naloxone distribution. Hospitalizations serve as important opportunities to engage individuals in the treatment of their addiction. It is essential that hospitalists begin utilizing these opportunities.

Disclosures: Nothing to report.

In the United States, there are an estimated 744,000 individuals who have engaged in recent injection drug use (IDU) and 6.6 million individuals who have ever injected a drug.[1] The practice of IDU predisposes individuals to serious bacterial and fungal infections that often require long‐term intravenous antibiotics. In individuals without IDU, these serious infections are often treated with outpatient parenteral antibiotic therapy (OPAT). However, a different standard exists for many persons who inject drugs (PWID)the mandated completion of antibiotics in an inpatient setting.

Though mandating inpatient antibiotic therapy for PWID is a widely adopted standard, this practice is not evidence based and may increase overall costs to the healthcare system. In 2012, in a quality‐improvement initiative, UKHealthCare established a protocol for treating appropriate PWID with OPAT.[2] They found very few inpatient providers willing to discharge PWID on OPAT, even with an established protocol.

To better understand the reasons for the low adoption of this protocol, Fanucchi and colleagues developed a survey designed to assess attitudes, practices, and mediating factors impacting the decision making about discharging PWID on OPAT.[2] The results of this survey are reported in this issue of the Journal of Hospital Medicine.

The study found that 95% of inpatient providers use OPAT for patients without IDU, but only 29% would even consider OPAT in PWID. The most common barriers to discharging a patient with IDU on OPAT were socioeconomic factors, willingness of infectious diseases physicians to follow as an outpatient, and concerns for misuse of peripherally inserted central catheters and adherence with antibiotic treatment.

At first glance, these reservations seem very reasonable. The presence of socioeconomic factors such as homelessness or lack of infectious diseases specialist follow‐up would make the risks of discharge on OPAT significant. The concerns for misuse of peripherally inserted central catheters and adherence to antibiotic treatment suggest that inpatient providers have an overall goal of reducing drug misuse and improving treatment outcomes.

Unfortunately, there are no data to suggest that completion of antibiotics in an inpatient setting reduces drug misuse or improves adherence to antibiotic treatments. Studies have found that at least 16% of PWID will misuse drugs during their hospitalization,[3] and 25% to 30% will be discharged against medical advice.[3, 4] This may be in large part due to the fact that inpatient providers are historically poor at addressing substance use disorders, even in patients with serious infections associated with IDU.[5] Yet the provision of methadone during hospitalization has been associated with a significant reduction in discharges against medical advice.[4] Rather than focusing on placing restrictions on individuals with risky behaviors, patients may benefit more from minimizing these risks through prompt recognition and management of substance use disorder.

Although limited, there is also evidence to support the feasibility of safe and effective OPAT in some PWID. A study by Ho et al. used OPAT to treat 29 PWID hospitalized with serious infections.[6] The study population had adequate housing, a reliable guardian, and signed a contract agreeing to abstain from drug misuse. In addition, all patients received substance use counseling and novel tamper‐proof security seals to prevent misuse of peripherally inserted central catheters, and antibiotics were delivered daily at an infusion center. They found no evidence of line tampering, excess readmissions, or excess line infections. Of note, the study population included 2 patients who were discharged against medical advice but successfully completed OPAT without issue. Although we do not believe that all individuals are appropriate for OPAT, this study suggests that OPAT can be considered in select PWID.

The study by Fanucchi et al. also reinforces the importance of making individualized risk assessments of persons with a history of IDU rather than assuming uniformity among the population. Of particular note is the lack of agreed‐upon definition of remote history of IDU (range, 2120 months; median, 12 months). The idea that individuals with a decade of sobriety could be subject to the same restrictions as a patient injecting multiple times a day speaks to providers' discomfort with assessing the individual risk of a person who has suffered from substance use disorder. Further, the fact that so few providers felt substance use disorder treatment was a critical component of a decision to allow OPAT raises concerns that providers are not aware of effective means to treat addiction. In particular, it is crucial for providers to understand that medication‐assisted treatment, such as methadone or buprenorphine for opioid use disorder, has significant evidence to support efficacy in decreasing drug misuse and improving outcomes.

This study suggests more work will need to be done before inpatient providers will be comfortable discharging any PWID with OPAT. This includes improved outpatient services (enhanced case management and home health services, and better access to outpatient physicians including infectious diseases specialists), the development of tamper‐evident devices to deter misuse of peripherally inserted central catheters, and defined legal protection for providers.

In addition, more research needs to be done on this population to objectively stratify risk for PWID and assess outcomes for PWID treated with OPAT versus the current standard of care. This research should have a particular focus on the long‐term financial and societal costs associated with PWID leaving against medical advice or receiving potentially unnecessary inpatient services. Minimizing the length of stay may defray inpatient costs and afford investment into more robust, effective outpatient services. It is essential that we develop a system to provide antibiotics in a way that optimizes outcomes and is cost‐effective.

Regardless of the decision to mandate antibiotic treatment in an inpatient setting or to discharge with OPAT, it is clear that more needs to be done to address addiction in hospitalized patients. All hospitalized PWID should receive safe injection education and a referral to a substance use disorder specialist. In addition, individuals with opioid‐misuse or opioid use disorder should receive opioid overdose education and naloxone distribution. Hospitalizations serve as important opportunities to engage individuals in the treatment of their addiction. It is essential that hospitalists begin utilizing these opportunities.

Disclosures: Nothing to report.

In the United States, there are an estimated 744,000 individuals who have engaged in recent injection drug use (IDU) and 6.6 million individuals who have ever injected a drug.[1] The practice of IDU predisposes individuals to serious bacterial and fungal infections that often require long‐term intravenous antibiotics. In individuals without IDU, these serious infections are often treated with outpatient parenteral antibiotic therapy (OPAT). However, a different standard exists for many persons who inject drugs (PWID)the mandated completion of antibiotics in an inpatient setting.

Though mandating inpatient antibiotic therapy for PWID is a widely adopted standard, this practice is not evidence based and may increase overall costs to the healthcare system. In 2012, in a quality‐improvement initiative, UKHealthCare established a protocol for treating appropriate PWID with OPAT.[2] They found very few inpatient providers willing to discharge PWID on OPAT, even with an established protocol.

To better understand the reasons for the low adoption of this protocol, Fanucchi and colleagues developed a survey designed to assess attitudes, practices, and mediating factors impacting the decision making about discharging PWID on OPAT.[2] The results of this survey are reported in this issue of the Journal of Hospital Medicine.

The study found that 95% of inpatient providers use OPAT for patients without IDU, but only 29% would even consider OPAT in PWID. The most common barriers to discharging a patient with IDU on OPAT were socioeconomic factors, willingness of infectious diseases physicians to follow as an outpatient, and concerns for misuse of peripherally inserted central catheters and adherence with antibiotic treatment.

At first glance, these reservations seem very reasonable. The presence of socioeconomic factors such as homelessness or lack of infectious diseases specialist follow‐up would make the risks of discharge on OPAT significant. The concerns for misuse of peripherally inserted central catheters and adherence to antibiotic treatment suggest that inpatient providers have an overall goal of reducing drug misuse and improving treatment outcomes.

Unfortunately, there are no data to suggest that completion of antibiotics in an inpatient setting reduces drug misuse or improves adherence to antibiotic treatments. Studies have found that at least 16% of PWID will misuse drugs during their hospitalization,[3] and 25% to 30% will be discharged against medical advice.[3, 4] This may be in large part due to the fact that inpatient providers are historically poor at addressing substance use disorders, even in patients with serious infections associated with IDU.[5] Yet the provision of methadone during hospitalization has been associated with a significant reduction in discharges against medical advice.[4] Rather than focusing on placing restrictions on individuals with risky behaviors, patients may benefit more from minimizing these risks through prompt recognition and management of substance use disorder.

Although limited, there is also evidence to support the feasibility of safe and effective OPAT in some PWID. A study by Ho et al. used OPAT to treat 29 PWID hospitalized with serious infections.[6] The study population had adequate housing, a reliable guardian, and signed a contract agreeing to abstain from drug misuse. In addition, all patients received substance use counseling and novel tamper‐proof security seals to prevent misuse of peripherally inserted central catheters, and antibiotics were delivered daily at an infusion center. They found no evidence of line tampering, excess readmissions, or excess line infections. Of note, the study population included 2 patients who were discharged against medical advice but successfully completed OPAT without issue. Although we do not believe that all individuals are appropriate for OPAT, this study suggests that OPAT can be considered in select PWID.

The study by Fanucchi et al. also reinforces the importance of making individualized risk assessments of persons with a history of IDU rather than assuming uniformity among the population. Of particular note is the lack of agreed‐upon definition of remote history of IDU (range, 2120 months; median, 12 months). The idea that individuals with a decade of sobriety could be subject to the same restrictions as a patient injecting multiple times a day speaks to providers' discomfort with assessing the individual risk of a person who has suffered from substance use disorder. Further, the fact that so few providers felt substance use disorder treatment was a critical component of a decision to allow OPAT raises concerns that providers are not aware of effective means to treat addiction. In particular, it is crucial for providers to understand that medication‐assisted treatment, such as methadone or buprenorphine for opioid use disorder, has significant evidence to support efficacy in decreasing drug misuse and improving outcomes.

This study suggests more work will need to be done before inpatient providers will be comfortable discharging any PWID with OPAT. This includes improved outpatient services (enhanced case management and home health services, and better access to outpatient physicians including infectious diseases specialists), the development of tamper‐evident devices to deter misuse of peripherally inserted central catheters, and defined legal protection for providers.

In addition, more research needs to be done on this population to objectively stratify risk for PWID and assess outcomes for PWID treated with OPAT versus the current standard of care. This research should have a particular focus on the long‐term financial and societal costs associated with PWID leaving against medical advice or receiving potentially unnecessary inpatient services. Minimizing the length of stay may defray inpatient costs and afford investment into more robust, effective outpatient services. It is essential that we develop a system to provide antibiotics in a way that optimizes outcomes and is cost‐effective.

Regardless of the decision to mandate antibiotic treatment in an inpatient setting or to discharge with OPAT, it is clear that more needs to be done to address addiction in hospitalized patients. All hospitalized PWID should receive safe injection education and a referral to a substance use disorder specialist. In addition, individuals with opioid‐misuse or opioid use disorder should receive opioid overdose education and naloxone distribution. Hospitalizations serve as important opportunities to engage individuals in the treatment of their addiction. It is essential that hospitalists begin utilizing these opportunities.

Disclosures: Nothing to report.

The Things We Do for No Reason (TWDFNR) series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent black and white conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

CASE PRESENTATION

A 65‐year‐old man is admitted with pneumonia. Review of the medical record reveals a persistent macrocytic anemia (hematocrit 29%, hemoglobin 9.3 g/dL, mean corpuscular volume [MCV] 105 fL) with a low reticulocyte count and normal peripheral blood smear. The provider contemplates ordering a serum folate or red blood cell (RBC) folate test to workup the persistent macrocytic anemia.

BACKGROUND

Folate is a water‐soluble B vitamin essential for the synthesis of DNA and for converting homocysteine to methionine. Folate deficiency is causally linked with both neural tube defects and megaloblastic anemia. Low levels of folate are associated with cardiovascular disease, colon cancer, neuropathy, depression, hypercoagulability, and cognitive decline, though there is a paucity of evidence showing causation or risk reduction with folate supplementation.[1] In patients with inadequate folate intake, the earliest sign is a decline in serum folate levels, followed by a fall in RBC folate levels. Only weeks later do macrocytosis, megaloblastic bone marrow, and finally anemia occur.[2] Given that humans are unable to synthesize folate and are therefore dependent on dietary sources, those with inadequate intake or absorption are at risk of folate deficiency.

WHY FOLATE TESTING IS ORDERED

In hospitalized patients, the most common indication for folate testing is anemia, either with or without macrocytosis.[3, 4] Given that at least 10% to 15% of hospitalized patients are anemic,[5, 6] it is unsurprising that folate testing is frequently performed. Despite the link between folate deficiency and megaloblastic anemia, >85% of patients evaluated for folate deficiency have normocytic or microcytic anemia.[3, 4] In addition, a study found that 30% of all folate testing was performed not as part of an anemia workup but in the evaluation of other comorbidities (eg, dementia and altered mental status) that are not causally linked to folate deficiency.[7]

WHY THERE IS NO REASON TO ORDER FOLATE TESTING

There are 2 reasons why testing hospitalized patients for folate deficiency does not contribute value: (1) the poor characteristics of the tests used and (2) the low prevalence of folate deficiency in the postfortification era.

There is no accepted gold standard for the diagnosis of folate deficiency, though biological assays are considered more accurate than the now more commonly used protein binding assays.[8] The lack of a gold standard limits the ability to fully quantify the sensitivity and specificity of either serum or RBC folate testing, though falsely low and high serum folate results can be seen. Falsely low serum levels (false positives) are found with heavy alcohol use and with certain anticonvulsant or antineoplastic drug use.[9] The low levels in these patients indicate low serum folate but do not necessarily reflect tissue stores. Serum folate levels may fall rapidly within a few days of the start of low dietary folate intake, resulting in low serum folate levels that also do not represent true folate deficiency.[10] On the other hand, intake of folatethrough a meal or ingestion of an oral supplementdirectly preceding evaluation of serum folate can lead to falsely elevated levels (false negatives).[10]

Although RBC folate reflects body stores and is largely unaffected by diet, the available tests also lack sensitivity and specificity.[11] Furthermore, serum folate levels and RBC folate levels correlate well.[12] Because RBC folate testing is more expensive than serum folate testing, has results that correlate well with serum folate testing, and is without significantly better test characteristics, there is no added value to using RBC folate testing as compared to serum folate testing.

In addition to the issues with available diagnostic tests, numerous studies now indicate that the rate of folate deficiency in the United States is exceptionally low. This is largely driven by the United States Food and Drug Administration's mandate that all grain products be fortified with 0.14 mg of folic acid per gram of grains.[13] Fortification has been overwhelmingly successful at increasing folic acid intake[14, 15] and reducing the incidence of neural tube defects.[16] Although the serum and RBC folate tests are prone to inaccuracies for an individual patient, population trends postfortification, coupled with the data on intake and rates of neural tube defects, make a strong argument that the prevalence of deficiency has decreased dramatically.

Similar to these population‐based trends, studies of hospital‐based laboratories have shown a marked decrease in the rate of low serum and RBC folate levels, making for a very low pretest probability for folate deficiency (Table 1). Even before fortification had been fully implemented, a study of outpatients and inpatients cared for at 3 hospitals in Denver, Colorado in 1996 found that just 1.9% of patients had low serum folate levels and 4.4% had low RBC folate levels.[17] A retrospective study of 26,662 patients in 1998 showed a rate of serum deficiency (<2.7 ng/mL) of 0.3%.[18] The authors also found that despite a decline in rate of serum deficiency from 1.3% to 0.3% between 1994 and 1998, the total number of serum folate tests performed increased by 84%. A similar study found just 0.4% of 1007 patients with low serum folate levels (<3.0 ng/mL).[7] Parallel results have been seen in other countries after implementation of folate fortification with a cohort of 2154 Canadian patients reporting low serum folate (<6.8 nmol/L) and RBC folate (<417 nmol/L) levels in just 0.5% and 0.7% of patients, respectively.[19]

Few studies have looked exclusively at hospitalized and emergency room patients. In an evaluation of 2093 serum folate tests performed on hospitalized or emergency room patients (98.1% of whom were admitted) in 2011, only 2 (0.1%) deficient levels (<3 ng/mL) were identified, 1 of which was associated with a macrocytic anemia.[3] A similar study of RBC folate levels in 2562 patients at 3 Canadian hospitals found just 4 (0.16%) levels to be low (<254 nmol/L), only 1 of which was associated with macrocytic anemia.[20]

When examining only patients with macrocytic anemia, the rates of folate deficiency are only slightly higher than the general population. As noted above, each of the 2 studies of inpatients uncovered just 1 patient with macrocytic anemia and concomitant low serum or RBC folate levels.[3, 20] Other studies reveal rates of serum folate deficiency in patients with macrocytic anemia and macrocytosis of 2.8%[7] and 1%,[21] respectively, and RBC folate deficiency rates in patients with macrocytosis of 1.8%.[22] Patients with extreme macrocytosis (MCV >130) represent 1 subset of patients with a high pretest probability of low serum folate, with 1 study reporting low levels in 37% of patients.[23]

Despite the relatively inexpensive cost per serum and RBC folate test, expenses per test that result in an abnormally low level are significant. As the pretest probability for folate deficiency is extremely low, tests must be ordered on a large number of patients to find 1 patient with levels suggesting deficiency. For example, a study found that an institution charged $151 per serum folate test, which amounted to $158,000 per deficient result.[3] The institutional cost was <$2.00 per serum folate test and <$2093 per deficient result. Another study reported the institutional cost of RBC folate to be $12.54 per test and $8035 per deficient result.[20] The charges and costs are institution specific and will vary. However, in light of the low pretest probability of testing, any expense associated with these tests represents low value.

WHAT YOU SHOULD DO INSTEAD

The clinician in our case presentation is facing a common scenarioa patient with persistent anemia without a known etiology. The treatment of suspected or confirmed folate deficiency includes improving diet or adding a folic acid supplement, a low‐cost (as little $0.01 per tablet) intervention. Furthermore, other at‐risk patients (eg, those with sickle cell disease, alcoholism, or malabsorption) may be candidates for long‐term supplementation regardless of serum folate and/or RBC folate testing results.

Folate deficiency in patients living in the United States and Canada is exceedingly rare, making the pretest probability of testing low. Furthermore, even patients with typical hematologic characteristics for folate deficiency (anemia and macrocytosis) are unlikely to have folate deficiency. Importantly, there are no nonhematologic indications to test for folate deficiency, and testing those patients, just as in the general population, yields an extremely low rate of folate deficiency. The tests themselves are unreliable and inaccurate, and fortunately, treatment is cheap, easy to administer, and can be done empirically. In other words, testing for folate deficiency is a Thing We Do for No Reason.

RECOMMENDATIONS

In patients suspected of having folate deficiency or who are at high risk of folate deficiency (eg, diet poor in folate‐rich or folic acid fortified foods), treat with a diet containing folate or folic acid fortified foods and/or a supplement containing 400 to 1000 g of folic acid. Approximately 1 to 2 weeks following initiation of treatment, a complete blood count should be performed to evaluate for an appropriate increase in hematocrit/hemoglobin and decrease in MCV.[24] Once a full hematologic response is seen, treatment beyond this time is not required unless the cause (eg, malnutrition) persists.

Serum folate and RBC folate tests should not be routinely ordered. Even in those with macrocytic anemia, the pretest probability of folate deficiency remains low. Although testing may suggest a folate deficiency, it is still more likely there is another cause for the patient's anemia. This places providers at risk for premature closure. For patients such as the one presented in the case presentation, obtaining B12 levels is of greater importance, given the higher prevalence and the risks of untreated deficiency.

For patients in whom the pretest probability of folate deficiency is high (eg, those with an MCV >130), obtain fasting serum folate levels on samples taken before supplementation has begun or a diet administered.

Do you think this is a low‐value practice? Is this truly a Thing We Do for No Reason? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and Liking It on Facebook. We invite you to propose ideas for other Things We Do for No Reason topics by emailing TWDFNR@hospitalmedicine.org.

The Things We Do for No Reason (TWDFNR) series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent black and white conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

CASE PRESENTATION

A 65‐year‐old man is admitted with pneumonia. Review of the medical record reveals a persistent macrocytic anemia (hematocrit 29%, hemoglobin 9.3 g/dL, mean corpuscular volume [MCV] 105 fL) with a low reticulocyte count and normal peripheral blood smear. The provider contemplates ordering a serum folate or red blood cell (RBC) folate test to workup the persistent macrocytic anemia.

BACKGROUND

Folate is a water‐soluble B vitamin essential for the synthesis of DNA and for converting homocysteine to methionine. Folate deficiency is causally linked with both neural tube defects and megaloblastic anemia. Low levels of folate are associated with cardiovascular disease, colon cancer, neuropathy, depression, hypercoagulability, and cognitive decline, though there is a paucity of evidence showing causation or risk reduction with folate supplementation.[1] In patients with inadequate folate intake, the earliest sign is a decline in serum folate levels, followed by a fall in RBC folate levels. Only weeks later do macrocytosis, megaloblastic bone marrow, and finally anemia occur.[2] Given that humans are unable to synthesize folate and are therefore dependent on dietary sources, those with inadequate intake or absorption are at risk of folate deficiency.

WHY FOLATE TESTING IS ORDERED

In hospitalized patients, the most common indication for folate testing is anemia, either with or without macrocytosis.[3, 4] Given that at least 10% to 15% of hospitalized patients are anemic,[5, 6] it is unsurprising that folate testing is frequently performed. Despite the link between folate deficiency and megaloblastic anemia, >85% of patients evaluated for folate deficiency have normocytic or microcytic anemia.[3, 4] In addition, a study found that 30% of all folate testing was performed not as part of an anemia workup but in the evaluation of other comorbidities (eg, dementia and altered mental status) that are not causally linked to folate deficiency.[7]

WHY THERE IS NO REASON TO ORDER FOLATE TESTING

There are 2 reasons why testing hospitalized patients for folate deficiency does not contribute value: (1) the poor characteristics of the tests used and (2) the low prevalence of folate deficiency in the postfortification era.

There is no accepted gold standard for the diagnosis of folate deficiency, though biological assays are considered more accurate than the now more commonly used protein binding assays.[8] The lack of a gold standard limits the ability to fully quantify the sensitivity and specificity of either serum or RBC folate testing, though falsely low and high serum folate results can be seen. Falsely low serum levels (false positives) are found with heavy alcohol use and with certain anticonvulsant or antineoplastic drug use.[9] The low levels in these patients indicate low serum folate but do not necessarily reflect tissue stores. Serum folate levels may fall rapidly within a few days of the start of low dietary folate intake, resulting in low serum folate levels that also do not represent true folate deficiency.[10] On the other hand, intake of folatethrough a meal or ingestion of an oral supplementdirectly preceding evaluation of serum folate can lead to falsely elevated levels (false negatives).[10]

Although RBC folate reflects body stores and is largely unaffected by diet, the available tests also lack sensitivity and specificity.[11] Furthermore, serum folate levels and RBC folate levels correlate well.[12] Because RBC folate testing is more expensive than serum folate testing, has results that correlate well with serum folate testing, and is without significantly better test characteristics, there is no added value to using RBC folate testing as compared to serum folate testing.

In addition to the issues with available diagnostic tests, numerous studies now indicate that the rate of folate deficiency in the United States is exceptionally low. This is largely driven by the United States Food and Drug Administration's mandate that all grain products be fortified with 0.14 mg of folic acid per gram of grains.[13] Fortification has been overwhelmingly successful at increasing folic acid intake[14, 15] and reducing the incidence of neural tube defects.[16] Although the serum and RBC folate tests are prone to inaccuracies for an individual patient, population trends postfortification, coupled with the data on intake and rates of neural tube defects, make a strong argument that the prevalence of deficiency has decreased dramatically.

Similar to these population‐based trends, studies of hospital‐based laboratories have shown a marked decrease in the rate of low serum and RBC folate levels, making for a very low pretest probability for folate deficiency (Table 1). Even before fortification had been fully implemented, a study of outpatients and inpatients cared for at 3 hospitals in Denver, Colorado in 1996 found that just 1.9% of patients had low serum folate levels and 4.4% had low RBC folate levels.[17] A retrospective study of 26,662 patients in 1998 showed a rate of serum deficiency (<2.7 ng/mL) of 0.3%.[18] The authors also found that despite a decline in rate of serum deficiency from 1.3% to 0.3% between 1994 and 1998, the total number of serum folate tests performed increased by 84%. A similar study found just 0.4% of 1007 patients with low serum folate levels (<3.0 ng/mL).[7] Parallel results have been seen in other countries after implementation of folate fortification with a cohort of 2154 Canadian patients reporting low serum folate (<6.8 nmol/L) and RBC folate (<417 nmol/L) levels in just 0.5% and 0.7% of patients, respectively.[19]

Few studies have looked exclusively at hospitalized and emergency room patients. In an evaluation of 2093 serum folate tests performed on hospitalized or emergency room patients (98.1% of whom were admitted) in 2011, only 2 (0.1%) deficient levels (<3 ng/mL) were identified, 1 of which was associated with a macrocytic anemia.[3] A similar study of RBC folate levels in 2562 patients at 3 Canadian hospitals found just 4 (0.16%) levels to be low (<254 nmol/L), only 1 of which was associated with macrocytic anemia.[20]

When examining only patients with macrocytic anemia, the rates of folate deficiency are only slightly higher than the general population. As noted above, each of the 2 studies of inpatients uncovered just 1 patient with macrocytic anemia and concomitant low serum or RBC folate levels.[3, 20] Other studies reveal rates of serum folate deficiency in patients with macrocytic anemia and macrocytosis of 2.8%[7] and 1%,[21] respectively, and RBC folate deficiency rates in patients with macrocytosis of 1.8%.[22] Patients with extreme macrocytosis (MCV >130) represent 1 subset of patients with a high pretest probability of low serum folate, with 1 study reporting low levels in 37% of patients.[23]

Despite the relatively inexpensive cost per serum and RBC folate test, expenses per test that result in an abnormally low level are significant. As the pretest probability for folate deficiency is extremely low, tests must be ordered on a large number of patients to find 1 patient with levels suggesting deficiency. For example, a study found that an institution charged $151 per serum folate test, which amounted to $158,000 per deficient result.[3] The institutional cost was <$2.00 per serum folate test and <$2093 per deficient result. Another study reported the institutional cost of RBC folate to be $12.54 per test and $8035 per deficient result.[20] The charges and costs are institution specific and will vary. However, in light of the low pretest probability of testing, any expense associated with these tests represents low value.

WHAT YOU SHOULD DO INSTEAD

The clinician in our case presentation is facing a common scenarioa patient with persistent anemia without a known etiology. The treatment of suspected or confirmed folate deficiency includes improving diet or adding a folic acid supplement, a low‐cost (as little $0.01 per tablet) intervention. Furthermore, other at‐risk patients (eg, those with sickle cell disease, alcoholism, or malabsorption) may be candidates for long‐term supplementation regardless of serum folate and/or RBC folate testing results.

Folate deficiency in patients living in the United States and Canada is exceedingly rare, making the pretest probability of testing low. Furthermore, even patients with typical hematologic characteristics for folate deficiency (anemia and macrocytosis) are unlikely to have folate deficiency. Importantly, there are no nonhematologic indications to test for folate deficiency, and testing those patients, just as in the general population, yields an extremely low rate of folate deficiency. The tests themselves are unreliable and inaccurate, and fortunately, treatment is cheap, easy to administer, and can be done empirically. In other words, testing for folate deficiency is a Thing We Do for No Reason.

RECOMMENDATIONS

In patients suspected of having folate deficiency or who are at high risk of folate deficiency (eg, diet poor in folate‐rich or folic acid fortified foods), treat with a diet containing folate or folic acid fortified foods and/or a supplement containing 400 to 1000 g of folic acid. Approximately 1 to 2 weeks following initiation of treatment, a complete blood count should be performed to evaluate for an appropriate increase in hematocrit/hemoglobin and decrease in MCV.[24] Once a full hematologic response is seen, treatment beyond this time is not required unless the cause (eg, malnutrition) persists.

Serum folate and RBC folate tests should not be routinely ordered. Even in those with macrocytic anemia, the pretest probability of folate deficiency remains low. Although testing may suggest a folate deficiency, it is still more likely there is another cause for the patient's anemia. This places providers at risk for premature closure. For patients such as the one presented in the case presentation, obtaining B12 levels is of greater importance, given the higher prevalence and the risks of untreated deficiency.

For patients in whom the pretest probability of folate deficiency is high (eg, those with an MCV >130), obtain fasting serum folate levels on samples taken before supplementation has begun or a diet administered.

Do you think this is a low‐value practice? Is this truly a Thing We Do for No Reason? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and Liking It on Facebook. We invite you to propose ideas for other Things We Do for No Reason topics by emailing TWDFNR@hospitalmedicine.org.

The Things We Do for No Reason (TWDFNR) series reviews practices which have become common parts of hospital care but which may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent black and white conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion. https://www.choosingwisely.org/

CASE PRESENTATION

A 65‐year‐old man is admitted with pneumonia. Review of the medical record reveals a persistent macrocytic anemia (hematocrit 29%, hemoglobin 9.3 g/dL, mean corpuscular volume [MCV] 105 fL) with a low reticulocyte count and normal peripheral blood smear. The provider contemplates ordering a serum folate or red blood cell (RBC) folate test to workup the persistent macrocytic anemia.

BACKGROUND

Folate is a water‐soluble B vitamin essential for the synthesis of DNA and for converting homocysteine to methionine. Folate deficiency is causally linked with both neural tube defects and megaloblastic anemia. Low levels of folate are associated with cardiovascular disease, colon cancer, neuropathy, depression, hypercoagulability, and cognitive decline, though there is a paucity of evidence showing causation or risk reduction with folate supplementation.[1] In patients with inadequate folate intake, the earliest sign is a decline in serum folate levels, followed by a fall in RBC folate levels. Only weeks later do macrocytosis, megaloblastic bone marrow, and finally anemia occur.[2] Given that humans are unable to synthesize folate and are therefore dependent on dietary sources, those with inadequate intake or absorption are at risk of folate deficiency.

WHY FOLATE TESTING IS ORDERED

In hospitalized patients, the most common indication for folate testing is anemia, either with or without macrocytosis.[3, 4] Given that at least 10% to 15% of hospitalized patients are anemic,[5, 6] it is unsurprising that folate testing is frequently performed. Despite the link between folate deficiency and megaloblastic anemia, >85% of patients evaluated for folate deficiency have normocytic or microcytic anemia.[3, 4] In addition, a study found that 30% of all folate testing was performed not as part of an anemia workup but in the evaluation of other comorbidities (eg, dementia and altered mental status) that are not causally linked to folate deficiency.[7]

WHY THERE IS NO REASON TO ORDER FOLATE TESTING

There are 2 reasons why testing hospitalized patients for folate deficiency does not contribute value: (1) the poor characteristics of the tests used and (2) the low prevalence of folate deficiency in the postfortification era.

There is no accepted gold standard for the diagnosis of folate deficiency, though biological assays are considered more accurate than the now more commonly used protein binding assays.[8] The lack of a gold standard limits the ability to fully quantify the sensitivity and specificity of either serum or RBC folate testing, though falsely low and high serum folate results can be seen. Falsely low serum levels (false positives) are found with heavy alcohol use and with certain anticonvulsant or antineoplastic drug use.[9] The low levels in these patients indicate low serum folate but do not necessarily reflect tissue stores. Serum folate levels may fall rapidly within a few days of the start of low dietary folate intake, resulting in low serum folate levels that also do not represent true folate deficiency.[10] On the other hand, intake of folatethrough a meal or ingestion of an oral supplementdirectly preceding evaluation of serum folate can lead to falsely elevated levels (false negatives).[10]

Although RBC folate reflects body stores and is largely unaffected by diet, the available tests also lack sensitivity and specificity.[11] Furthermore, serum folate levels and RBC folate levels correlate well.[12] Because RBC folate testing is more expensive than serum folate testing, has results that correlate well with serum folate testing, and is without significantly better test characteristics, there is no added value to using RBC folate testing as compared to serum folate testing.

In addition to the issues with available diagnostic tests, numerous studies now indicate that the rate of folate deficiency in the United States is exceptionally low. This is largely driven by the United States Food and Drug Administration's mandate that all grain products be fortified with 0.14 mg of folic acid per gram of grains.[13] Fortification has been overwhelmingly successful at increasing folic acid intake[14, 15] and reducing the incidence of neural tube defects.[16] Although the serum and RBC folate tests are prone to inaccuracies for an individual patient, population trends postfortification, coupled with the data on intake and rates of neural tube defects, make a strong argument that the prevalence of deficiency has decreased dramatically.

Similar to these population‐based trends, studies of hospital‐based laboratories have shown a marked decrease in the rate of low serum and RBC folate levels, making for a very low pretest probability for folate deficiency (Table 1). Even before fortification had been fully implemented, a study of outpatients and inpatients cared for at 3 hospitals in Denver, Colorado in 1996 found that just 1.9% of patients had low serum folate levels and 4.4% had low RBC folate levels.[17] A retrospective study of 26,662 patients in 1998 showed a rate of serum deficiency (<2.7 ng/mL) of 0.3%.[18] The authors also found that despite a decline in rate of serum deficiency from 1.3% to 0.3% between 1994 and 1998, the total number of serum folate tests performed increased by 84%. A similar study found just 0.4% of 1007 patients with low serum folate levels (<3.0 ng/mL).[7] Parallel results have been seen in other countries after implementation of folate fortification with a cohort of 2154 Canadian patients reporting low serum folate (<6.8 nmol/L) and RBC folate (<417 nmol/L) levels in just 0.5% and 0.7% of patients, respectively.[19]

Few studies have looked exclusively at hospitalized and emergency room patients. In an evaluation of 2093 serum folate tests performed on hospitalized or emergency room patients (98.1% of whom were admitted) in 2011, only 2 (0.1%) deficient levels (<3 ng/mL) were identified, 1 of which was associated with a macrocytic anemia.[3] A similar study of RBC folate levels in 2562 patients at 3 Canadian hospitals found just 4 (0.16%) levels to be low (<254 nmol/L), only 1 of which was associated with macrocytic anemia.[20]

When examining only patients with macrocytic anemia, the rates of folate deficiency are only slightly higher than the general population. As noted above, each of the 2 studies of inpatients uncovered just 1 patient with macrocytic anemia and concomitant low serum or RBC folate levels.[3, 20] Other studies reveal rates of serum folate deficiency in patients with macrocytic anemia and macrocytosis of 2.8%[7] and 1%,[21] respectively, and RBC folate deficiency rates in patients with macrocytosis of 1.8%.[22] Patients with extreme macrocytosis (MCV >130) represent 1 subset of patients with a high pretest probability of low serum folate, with 1 study reporting low levels in 37% of patients.[23]

Despite the relatively inexpensive cost per serum and RBC folate test, expenses per test that result in an abnormally low level are significant. As the pretest probability for folate deficiency is extremely low, tests must be ordered on a large number of patients to find 1 patient with levels suggesting deficiency. For example, a study found that an institution charged $151 per serum folate test, which amounted to $158,000 per deficient result.[3] The institutional cost was <$2.00 per serum folate test and <$2093 per deficient result. Another study reported the institutional cost of RBC folate to be $12.54 per test and $8035 per deficient result.[20] The charges and costs are institution specific and will vary. However, in light of the low pretest probability of testing, any expense associated with these tests represents low value.

WHAT YOU SHOULD DO INSTEAD

The clinician in our case presentation is facing a common scenarioa patient with persistent anemia without a known etiology. The treatment of suspected or confirmed folate deficiency includes improving diet or adding a folic acid supplement, a low‐cost (as little $0.01 per tablet) intervention. Furthermore, other at‐risk patients (eg, those with sickle cell disease, alcoholism, or malabsorption) may be candidates for long‐term supplementation regardless of serum folate and/or RBC folate testing results.

Folate deficiency in patients living in the United States and Canada is exceedingly rare, making the pretest probability of testing low. Furthermore, even patients with typical hematologic characteristics for folate deficiency (anemia and macrocytosis) are unlikely to have folate deficiency. Importantly, there are no nonhematologic indications to test for folate deficiency, and testing those patients, just as in the general population, yields an extremely low rate of folate deficiency. The tests themselves are unreliable and inaccurate, and fortunately, treatment is cheap, easy to administer, and can be done empirically. In other words, testing for folate deficiency is a Thing We Do for No Reason.

RECOMMENDATIONS

In patients suspected of having folate deficiency or who are at high risk of folate deficiency (eg, diet poor in folate‐rich or folic acid fortified foods), treat with a diet containing folate or folic acid fortified foods and/or a supplement containing 400 to 1000 g of folic acid. Approximately 1 to 2 weeks following initiation of treatment, a complete blood count should be performed to evaluate for an appropriate increase in hematocrit/hemoglobin and decrease in MCV.[24] Once a full hematologic response is seen, treatment beyond this time is not required unless the cause (eg, malnutrition) persists.

Serum folate and RBC folate tests should not be routinely ordered. Even in those with macrocytic anemia, the pretest probability of folate deficiency remains low. Although testing may suggest a folate deficiency, it is still more likely there is another cause for the patient's anemia. This places providers at risk for premature closure. For patients such as the one presented in the case presentation, obtaining B12 levels is of greater importance, given the higher prevalence and the risks of untreated deficiency.

For patients in whom the pretest probability of folate deficiency is high (eg, those with an MCV >130), obtain fasting serum folate levels on samples taken before supplementation has begun or a diet administered.

Do you think this is a low‐value practice? Is this truly a Thing We Do for No Reason? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and Liking It on Facebook. We invite you to propose ideas for other Things We Do for No Reason topics by emailing TWDFNR@hospitalmedicine.org.

Delirium is a common and costly problem in hospitalized medical patients. It is present on admission in 10% to 31% of cases and develops in up to 56% of patients during hospitalization.[1, 2] Prompt identification and treatment of the cause of delirium is important, because delirium is associated with increased morbidity and mortality, long‐term cognitive impairment, higher cost of care, increased length of stay, and more frequent discharge to an extended care facility.[3, 4, 5, 6]

Delirium can be caused or worsened by a variety of factors including adverse drug events, metabolic abnormalities, infections, immobilization, the use of tethers (eg, physical restraints, bladder catheters, telemetry), and disruption of sleepwake cycle.[7] An appropriate history, medication review, physical examination, and tailored laboratory evaluation is sufficient workup in the majority of cases.[8] However, neurologic processes, such as intracranial mass, intracranial hemorrhage, or stroke, can also present as delirium and require head imaging for diagnosis.

Because head imaging is a costly limited resource, a number of studies have aimed to determine which patients with delirium require this evaluation. The majority of research has focused on head computed tomography (CT) in patients presenting for evaluation to the emergency department (ED). In ED patients presenting with delirium, acute confusion, or altered mental status, head imaging identifies acute intracranial pathologic findings in 14% to 39% of cases.[9, 10, 11, 12, 13, 14] Only 2 studies have evaluated patients with delirium who have already been admitted to the hospital. One study involved patients admitted to a neurology unit with acute confusion and found that the yield of head imaging (head CT and magnetic resonance imaging) was 14% for acute intracranial pathology.[15] Another study reviewed patients admitted to an acute delirium unit and found a similar rate of positive findings on head CT (14.5%).[16] Neither study specified whether the head imaging occurred during initial presentation or later in the hospitalization.

Factors that increase the likelihood that delirium is caused by acute intracranial pathology include acute neurologic deficit, recent history of fall or head trauma, and significantly impaired consciousness.[9, 10, 11, 12, 13, 14, 15, 16, 17] Based on these findings, current guidelines and expert clinical statements recommend head imaging for patients with acute neurologic deficit, recent head trauma, or recent fall.[18, 19, 20]

Expert clinical statements also recommend imaging in cases where the cause is unidentified after appropriate medical testing or where delirium continues despite treatment.[8, 21] Yet the utility of head CT performed for nonresolving delirium or delirium that develops during hospitalization in the absence of recent fall, head trauma, or new neurologic deficits is not known. Our study aimed to determine the diagnostic yield of performing a head CT in this patient population. We hypothesized that the diagnostic yield of head CT in this population would be low.

METHODS

RESULTS

Of 1714 head CT studies performed on hospitalized medical patients from January 1, 2010 to November 30, 2012, 398 studies were performed for an indication of delirium, altered mental status, confusion, encephalopathy, somnolence, or unresponsiveness in patients who were admitted for >24 hours. One hundred seventy‐eight studies were excluded (137 for admitting diagnosis of intracranial process, recent fall, or head trauma, and 41 for new neurologic deficit). There were 220 scans included in the study performed on 210 patients.

Table 1 displays characteristics of the 210 patients who underwent CT head imaging. Of the 42 patients on anticoagulation, 15 were potentially supratherapeutic; 10 were on warfarin (INR range, 3.37.7) and 5 were on intravenous heparin infusion (PTT range, 101>150 seconds). None of these individuals had positive or equivocal findings on head CT.

The main outcomes of the 220 included head CT scans and a separate analysis of the 60 head CT scans performed for indications of somnolence or unresponsiveness are shown in Table 2. The 6 (2.7%) positive and 4 (1.8%) equivocal head CT findings are listed in Table 3. Of the 3 positive results in patients on anticoagulation, 2 were on warfarin with an INR of 2.1 and 2.4, respectively, and another was on warfarin and therapeutic enoxaparin (dosed 1 mg/kg twice daily) with an INR of 1.6. The median time from admission to positive head CT was 8 days, with a range of 2 to 28 days. All of the positive head CT studies resulted in change of management. All equivocal head CT studies resulted in repeat imaging. None of these repeat head imaging studies diagnosed acute intracranial pathology. Chronic findings identified included 111 (50.5%) involution or atrophy, 95 (43.2%) small vessel ischemic disease, 31 (14.1%) prior stroke, and 18 (8.2%) other chronic abnormalities (eg, cyst or meningioma).

DISCUSSION

In this retrospective review, we determined that there is a low diagnostic yield of head CT imaging for identifying the cause of nonresolving or new‐onset delirium in hospitalized medical patients. Only 2.7% of head CT scans resulted in identifying an acute intracranial process. Because of the low number of positive results, no risk factor associations could be made from our study.

The low diagnostic yield of head imaging in hospitalized patients with delirium is particularly important for clinicians who care for hospitalized medical patients. Prior to this study, the yield of head CT scans in hospitalized medical patients with nonresolving or new‐onset delirium was unknown. In cases with known risk factors, such as recent fall, head trauma, or acute neurologic deficit, the guidelines recommend head CT imaging.[18, 19, 20] However, in the absence of these findings, the guidelines do not make any recommendation regarding when and in whom to perform head imaging. Expert statements recommend considering head CT imaging when the cause is not identified after appropriate testing or delirium continues despite treatment.[8, 21] Given these recommendations and lack of data, there is no clear standard of care for ordering head CT imaging when hospitalized patients experience delirium in the absence of known risk factors. The low diagnostic yield in this study suggests that head CT imaging is unlikely to diagnose the cause of delirium in hospitalized patients with nonresolving or new‐onset delirium.

The diagnostic yield of head CT for diagnosis of acute intracranial process in delirium was lower in our study than prior studies, which found between 14.0 and 39.1%.[9, 10, 11, 12, 13, 14, 15, 16] This was expected, as our study excluded patients with new neurologic deficits, recent fall or trauma, or an admitting diagnosis of an intracranial process. Even with these exclusions, we still allowed for a number of findings that prior studies considered to be high risk for intracranial pathology, such as age over 73 years, use of anticoagulation, and deterioration in consciousness level or Glasgow coma score under 14.[10, 11, 16] The inclusion and exclusion criteria were designed to create a generalizable study population without a clear standard of care based on current guidelines and expert statements.

Though the rate of positive findings found in our study is low, it likely overestimates the overall yield of head CT in hospitalized patients with delirium. This is because most hospitalized patients with delirium never receive head imaging. Presumably, ordering clinicians have deemed these patients to be at higher risk for intracranial processes than the average hospitalized patient with delirium who does not receive a head CT. Thus, the true rate of positive findings in head CT imaging in delirious hospitalized medical patients is likely lower than what we identified.

Although head CT had a low diagnostic yield, the positive and equivocal studies had a high impact on clinical care. All of the positive and equivocal head CT results produced a change in management. The equivocal findings led to repeat head imaging; however, none of the repeat images identified the cause of delirium. The positive results produced a more significant change in management, ranging from a higher platelet transfusion target, reversal of anticoagulation, repeat advanced head imaging, neurosurgery consultation, and a change in goals of care to a focus on comfort. No patients in our study underwent neurosurgical intervention.

The challenge for inpatient clinicians is to weigh the low diagnostic yield of head CT with the consequences of a missed or delayed diagnosis of an acute intracranial process. The low diagnostic yield leads to unnecessary cost, resource utilization, radiation exposure, and downstream evaluation of insignificant or indeterminate results when head CT is performed. Alternatively, a missed or delayed diagnosis can lead to potentially reversible morbidity and mortality. Given this, we feel that the routine use of head CT in the evaluation of delirium in hospitalized patients is unnecessary. However, there may be a subset of patients with delirium with an increased risk of acute intracranial processes that would benefit from head imaging. Further research is needed to identify this high‐risk population.

There are a number of limitations to our study. It is a retrospective chart review, which introduces a possibility of bias and relies on proper and thorough documentation. In addition, the diagnosis of delirium was made by individual clinicians without the use of a standardized delirium assessment tool. Furthermore, it is possible there may have been CT scans that were not identified due to mischaracterization of indication, or studies may have been included in individuals with new neurologic deficit or recent fall or trauma that were not documented or clinically appreciated. Finally, the study was conducted on medicine and medical subspecialty patients at a single academic tertiary care institution, potentially limiting the generalizability to patients in other settings.

In conclusion, our study suggests that the diagnostic yield of head CT to evaluate delirium in hospitalized patients in the absence of recent fall, head trauma, or new neurologic deficit is low. The routine use of head CT in evaluation of these individuals is unnecessary. However, there may be a subset of high‐risk individuals in which head CT imaging would be indicated. Further research is needed to identify these high‐risk individuals.

Delirium is a common and costly problem in hospitalized medical patients. It is present on admission in 10% to 31% of cases and develops in up to 56% of patients during hospitalization.[1, 2] Prompt identification and treatment of the cause of delirium is important, because delirium is associated with increased morbidity and mortality, long‐term cognitive impairment, higher cost of care, increased length of stay, and more frequent discharge to an extended care facility.[3, 4, 5, 6]

Delirium can be caused or worsened by a variety of factors including adverse drug events, metabolic abnormalities, infections, immobilization, the use of tethers (eg, physical restraints, bladder catheters, telemetry), and disruption of sleepwake cycle.[7] An appropriate history, medication review, physical examination, and tailored laboratory evaluation is sufficient workup in the majority of cases.[8] However, neurologic processes, such as intracranial mass, intracranial hemorrhage, or stroke, can also present as delirium and require head imaging for diagnosis.

Because head imaging is a costly limited resource, a number of studies have aimed to determine which patients with delirium require this evaluation. The majority of research has focused on head computed tomography (CT) in patients presenting for evaluation to the emergency department (ED). In ED patients presenting with delirium, acute confusion, or altered mental status, head imaging identifies acute intracranial pathologic findings in 14% to 39% of cases.[9, 10, 11, 12, 13, 14] Only 2 studies have evaluated patients with delirium who have already been admitted to the hospital. One study involved patients admitted to a neurology unit with acute confusion and found that the yield of head imaging (head CT and magnetic resonance imaging) was 14% for acute intracranial pathology.[15] Another study reviewed patients admitted to an acute delirium unit and found a similar rate of positive findings on head CT (14.5%).[16] Neither study specified whether the head imaging occurred during initial presentation or later in the hospitalization.

Factors that increase the likelihood that delirium is caused by acute intracranial pathology include acute neurologic deficit, recent history of fall or head trauma, and significantly impaired consciousness.[9, 10, 11, 12, 13, 14, 15, 16, 17] Based on these findings, current guidelines and expert clinical statements recommend head imaging for patients with acute neurologic deficit, recent head trauma, or recent fall.[18, 19, 20]

Expert clinical statements also recommend imaging in cases where the cause is unidentified after appropriate medical testing or where delirium continues despite treatment.[8, 21] Yet the utility of head CT performed for nonresolving delirium or delirium that develops during hospitalization in the absence of recent fall, head trauma, or new neurologic deficits is not known. Our study aimed to determine the diagnostic yield of performing a head CT in this patient population. We hypothesized that the diagnostic yield of head CT in this population would be low.

METHODS

RESULTS

Of 1714 head CT studies performed on hospitalized medical patients from January 1, 2010 to November 30, 2012, 398 studies were performed for an indication of delirium, altered mental status, confusion, encephalopathy, somnolence, or unresponsiveness in patients who were admitted for >24 hours. One hundred seventy‐eight studies were excluded (137 for admitting diagnosis of intracranial process, recent fall, or head trauma, and 41 for new neurologic deficit). There were 220 scans included in the study performed on 210 patients.

Table 1 displays characteristics of the 210 patients who underwent CT head imaging. Of the 42 patients on anticoagulation, 15 were potentially supratherapeutic; 10 were on warfarin (INR range, 3.37.7) and 5 were on intravenous heparin infusion (PTT range, 101>150 seconds). None of these individuals had positive or equivocal findings on head CT.

The main outcomes of the 220 included head CT scans and a separate analysis of the 60 head CT scans performed for indications of somnolence or unresponsiveness are shown in Table 2. The 6 (2.7%) positive and 4 (1.8%) equivocal head CT findings are listed in Table 3. Of the 3 positive results in patients on anticoagulation, 2 were on warfarin with an INR of 2.1 and 2.4, respectively, and another was on warfarin and therapeutic enoxaparin (dosed 1 mg/kg twice daily) with an INR of 1.6. The median time from admission to positive head CT was 8 days, with a range of 2 to 28 days. All of the positive head CT studies resulted in change of management. All equivocal head CT studies resulted in repeat imaging. None of these repeat head imaging studies diagnosed acute intracranial pathology. Chronic findings identified included 111 (50.5%) involution or atrophy, 95 (43.2%) small vessel ischemic disease, 31 (14.1%) prior stroke, and 18 (8.2%) other chronic abnormalities (eg, cyst or meningioma).

DISCUSSION

In this retrospective review, we determined that there is a low diagnostic yield of head CT imaging for identifying the cause of nonresolving or new‐onset delirium in hospitalized medical patients. Only 2.7% of head CT scans resulted in identifying an acute intracranial process. Because of the low number of positive results, no risk factor associations could be made from our study.

The low diagnostic yield of head imaging in hospitalized patients with delirium is particularly important for clinicians who care for hospitalized medical patients. Prior to this study, the yield of head CT scans in hospitalized medical patients with nonresolving or new‐onset delirium was unknown. In cases with known risk factors, such as recent fall, head trauma, or acute neurologic deficit, the guidelines recommend head CT imaging.[18, 19, 20] However, in the absence of these findings, the guidelines do not make any recommendation regarding when and in whom to perform head imaging. Expert statements recommend considering head CT imaging when the cause is not identified after appropriate testing or delirium continues despite treatment.[8, 21] Given these recommendations and lack of data, there is no clear standard of care for ordering head CT imaging when hospitalized patients experience delirium in the absence of known risk factors. The low diagnostic yield in this study suggests that head CT imaging is unlikely to diagnose the cause of delirium in hospitalized patients with nonresolving or new‐onset delirium.

The diagnostic yield of head CT for diagnosis of acute intracranial process in delirium was lower in our study than prior studies, which found between 14.0 and 39.1%.[9, 10, 11, 12, 13, 14, 15, 16] This was expected, as our study excluded patients with new neurologic deficits, recent fall or trauma, or an admitting diagnosis of an intracranial process. Even with these exclusions, we still allowed for a number of findings that prior studies considered to be high risk for intracranial pathology, such as age over 73 years, use of anticoagulation, and deterioration in consciousness level or Glasgow coma score under 14.[10, 11, 16] The inclusion and exclusion criteria were designed to create a generalizable study population without a clear standard of care based on current guidelines and expert statements.

Though the rate of positive findings found in our study is low, it likely overestimates the overall yield of head CT in hospitalized patients with delirium. This is because most hospitalized patients with delirium never receive head imaging. Presumably, ordering clinicians have deemed these patients to be at higher risk for intracranial processes than the average hospitalized patient with delirium who does not receive a head CT. Thus, the true rate of positive findings in head CT imaging in delirious hospitalized medical patients is likely lower than what we identified.

Although head CT had a low diagnostic yield, the positive and equivocal studies had a high impact on clinical care. All of the positive and equivocal head CT results produced a change in management. The equivocal findings led to repeat head imaging; however, none of the repeat images identified the cause of delirium. The positive results produced a more significant change in management, ranging from a higher platelet transfusion target, reversal of anticoagulation, repeat advanced head imaging, neurosurgery consultation, and a change in goals of care to a focus on comfort. No patients in our study underwent neurosurgical intervention.

The challenge for inpatient clinicians is to weigh the low diagnostic yield of head CT with the consequences of a missed or delayed diagnosis of an acute intracranial process. The low diagnostic yield leads to unnecessary cost, resource utilization, radiation exposure, and downstream evaluation of insignificant or indeterminate results when head CT is performed. Alternatively, a missed or delayed diagnosis can lead to potentially reversible morbidity and mortality. Given this, we feel that the routine use of head CT in the evaluation of delirium in hospitalized patients is unnecessary. However, there may be a subset of patients with delirium with an increased risk of acute intracranial processes that would benefit from head imaging. Further research is needed to identify this high‐risk population.

There are a number of limitations to our study. It is a retrospective chart review, which introduces a possibility of bias and relies on proper and thorough documentation. In addition, the diagnosis of delirium was made by individual clinicians without the use of a standardized delirium assessment tool. Furthermore, it is possible there may have been CT scans that were not identified due to mischaracterization of indication, or studies may have been included in individuals with new neurologic deficit or recent fall or trauma that were not documented or clinically appreciated. Finally, the study was conducted on medicine and medical subspecialty patients at a single academic tertiary care institution, potentially limiting the generalizability to patients in other settings.

In conclusion, our study suggests that the diagnostic yield of head CT to evaluate delirium in hospitalized patients in the absence of recent fall, head trauma, or new neurologic deficit is low. The routine use of head CT in evaluation of these individuals is unnecessary. However, there may be a subset of high‐risk individuals in which head CT imaging would be indicated. Further research is needed to identify these high‐risk individuals.

Delirium is a common and costly problem in hospitalized medical patients. It is present on admission in 10% to 31% of cases and develops in up to 56% of patients during hospitalization.[1, 2] Prompt identification and treatment of the cause of delirium is important, because delirium is associated with increased morbidity and mortality, long‐term cognitive impairment, higher cost of care, increased length of stay, and more frequent discharge to an extended care facility.[3, 4, 5, 6]

Delirium can be caused or worsened by a variety of factors including adverse drug events, metabolic abnormalities, infections, immobilization, the use of tethers (eg, physical restraints, bladder catheters, telemetry), and disruption of sleepwake cycle.[7] An appropriate history, medication review, physical examination, and tailored laboratory evaluation is sufficient workup in the majority of cases.[8] However, neurologic processes, such as intracranial mass, intracranial hemorrhage, or stroke, can also present as delirium and require head imaging for diagnosis.

Because head imaging is a costly limited resource, a number of studies have aimed to determine which patients with delirium require this evaluation. The majority of research has focused on head computed tomography (CT) in patients presenting for evaluation to the emergency department (ED). In ED patients presenting with delirium, acute confusion, or altered mental status, head imaging identifies acute intracranial pathologic findings in 14% to 39% of cases.[9, 10, 11, 12, 13, 14] Only 2 studies have evaluated patients with delirium who have already been admitted to the hospital. One study involved patients admitted to a neurology unit with acute confusion and found that the yield of head imaging (head CT and magnetic resonance imaging) was 14% for acute intracranial pathology.[15] Another study reviewed patients admitted to an acute delirium unit and found a similar rate of positive findings on head CT (14.5%).[16] Neither study specified whether the head imaging occurred during initial presentation or later in the hospitalization.

Factors that increase the likelihood that delirium is caused by acute intracranial pathology include acute neurologic deficit, recent history of fall or head trauma, and significantly impaired consciousness.[9, 10, 11, 12, 13, 14, 15, 16, 17] Based on these findings, current guidelines and expert clinical statements recommend head imaging for patients with acute neurologic deficit, recent head trauma, or recent fall.[18, 19, 20]

Expert clinical statements also recommend imaging in cases where the cause is unidentified after appropriate medical testing or where delirium continues despite treatment.[8, 21] Yet the utility of head CT performed for nonresolving delirium or delirium that develops during hospitalization in the absence of recent fall, head trauma, or new neurologic deficits is not known. Our study aimed to determine the diagnostic yield of performing a head CT in this patient population. We hypothesized that the diagnostic yield of head CT in this population would be low.

METHODS

RESULTS

Of 1714 head CT studies performed on hospitalized medical patients from January 1, 2010 to November 30, 2012, 398 studies were performed for an indication of delirium, altered mental status, confusion, encephalopathy, somnolence, or unresponsiveness in patients who were admitted for >24 hours. One hundred seventy‐eight studies were excluded (137 for admitting diagnosis of intracranial process, recent fall, or head trauma, and 41 for new neurologic deficit). There were 220 scans included in the study performed on 210 patients.

Table 1 displays characteristics of the 210 patients who underwent CT head imaging. Of the 42 patients on anticoagulation, 15 were potentially supratherapeutic; 10 were on warfarin (INR range, 3.37.7) and 5 were on intravenous heparin infusion (PTT range, 101>150 seconds). None of these individuals had positive or equivocal findings on head CT.

The main outcomes of the 220 included head CT scans and a separate analysis of the 60 head CT scans performed for indications of somnolence or unresponsiveness are shown in Table 2. The 6 (2.7%) positive and 4 (1.8%) equivocal head CT findings are listed in Table 3. Of the 3 positive results in patients on anticoagulation, 2 were on warfarin with an INR of 2.1 and 2.4, respectively, and another was on warfarin and therapeutic enoxaparin (dosed 1 mg/kg twice daily) with an INR of 1.6. The median time from admission to positive head CT was 8 days, with a range of 2 to 28 days. All of the positive head CT studies resulted in change of management. All equivocal head CT studies resulted in repeat imaging. None of these repeat head imaging studies diagnosed acute intracranial pathology. Chronic findings identified included 111 (50.5%) involution or atrophy, 95 (43.2%) small vessel ischemic disease, 31 (14.1%) prior stroke, and 18 (8.2%) other chronic abnormalities (eg, cyst or meningioma).

DISCUSSION

In this retrospective review, we determined that there is a low diagnostic yield of head CT imaging for identifying the cause of nonresolving or new‐onset delirium in hospitalized medical patients. Only 2.7% of head CT scans resulted in identifying an acute intracranial process. Because of the low number of positive results, no risk factor associations could be made from our study.

The low diagnostic yield of head imaging in hospitalized patients with delirium is particularly important for clinicians who care for hospitalized medical patients. Prior to this study, the yield of head CT scans in hospitalized medical patients with nonresolving or new‐onset delirium was unknown. In cases with known risk factors, such as recent fall, head trauma, or acute neurologic deficit, the guidelines recommend head CT imaging.[18, 19, 20] However, in the absence of these findings, the guidelines do not make any recommendation regarding when and in whom to perform head imaging. Expert statements recommend considering head CT imaging when the cause is not identified after appropriate testing or delirium continues despite treatment.[8, 21] Given these recommendations and lack of data, there is no clear standard of care for ordering head CT imaging when hospitalized patients experience delirium in the absence of known risk factors. The low diagnostic yield in this study suggests that head CT imaging is unlikely to diagnose the cause of delirium in hospitalized patients with nonresolving or new‐onset delirium.

The diagnostic yield of head CT for diagnosis of acute intracranial process in delirium was lower in our study than prior studies, which found between 14.0 and 39.1%.[9, 10, 11, 12, 13, 14, 15, 16] This was expected, as our study excluded patients with new neurologic deficits, recent fall or trauma, or an admitting diagnosis of an intracranial process. Even with these exclusions, we still allowed for a number of findings that prior studies considered to be high risk for intracranial pathology, such as age over 73 years, use of anticoagulation, and deterioration in consciousness level or Glasgow coma score under 14.[10, 11, 16] The inclusion and exclusion criteria were designed to create a generalizable study population without a clear standard of care based on current guidelines and expert statements.

Though the rate of positive findings found in our study is low, it likely overestimates the overall yield of head CT in hospitalized patients with delirium. This is because most hospitalized patients with delirium never receive head imaging. Presumably, ordering clinicians have deemed these patients to be at higher risk for intracranial processes than the average hospitalized patient with delirium who does not receive a head CT. Thus, the true rate of positive findings in head CT imaging in delirious hospitalized medical patients is likely lower than what we identified.

Although head CT had a low diagnostic yield, the positive and equivocal studies had a high impact on clinical care. All of the positive and equivocal head CT results produced a change in management. The equivocal findings led to repeat head imaging; however, none of the repeat images identified the cause of delirium. The positive results produced a more significant change in management, ranging from a higher platelet transfusion target, reversal of anticoagulation, repeat advanced head imaging, neurosurgery consultation, and a change in goals of care to a focus on comfort. No patients in our study underwent neurosurgical intervention.

The challenge for inpatient clinicians is to weigh the low diagnostic yield of head CT with the consequences of a missed or delayed diagnosis of an acute intracranial process. The low diagnostic yield leads to unnecessary cost, resource utilization, radiation exposure, and downstream evaluation of insignificant or indeterminate results when head CT is performed. Alternatively, a missed or delayed diagnosis can lead to potentially reversible morbidity and mortality. Given this, we feel that the routine use of head CT in the evaluation of delirium in hospitalized patients is unnecessary. However, there may be a subset of patients with delirium with an increased risk of acute intracranial processes that would benefit from head imaging. Further research is needed to identify this high‐risk population.

There are a number of limitations to our study. It is a retrospective chart review, which introduces a possibility of bias and relies on proper and thorough documentation. In addition, the diagnosis of delirium was made by individual clinicians without the use of a standardized delirium assessment tool. Furthermore, it is possible there may have been CT scans that were not identified due to mischaracterization of indication, or studies may have been included in individuals with new neurologic deficit or recent fall or trauma that were not documented or clinically appreciated. Finally, the study was conducted on medicine and medical subspecialty patients at a single academic tertiary care institution, potentially limiting the generalizability to patients in other settings.

In conclusion, our study suggests that the diagnostic yield of head CT to evaluate delirium in hospitalized patients in the absence of recent fall, head trauma, or new neurologic deficit is low. The routine use of head CT in evaluation of these individuals is unnecessary. However, there may be a subset of high‐risk individuals in which head CT imaging would be indicated. Further research is needed to identify these high‐risk individuals.

Folate deficiency has been associated with a number of medical conditions. It is well established that folate deficiency leads to macrocytic anemia,[1, 2] and that supplementation of folic acid during pregnancy leads to decreased rates of neural tube defects.[3] Folate deficiency has also been hypothesized to affect other conditions including dementia, delirium, peripheral neuropathy, depression, cancer, and cardiovascular disease.[4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18] Most of these latter assertions are based on case reports or observational studies, with randomized controlled trials failing to demonstrate benefit of folic acid supplementation.[19, 20, 21]

Prior to mandatory folic acid fortification in the United States, the prevalence of folate deficiency was estimated to be between 3% and 16%.[16, 22, 23] In a study conducted prior to fortification, serum folate levels were evaluated in patients presenting with macrocytosis and anemia.[24] The study found that 2.3% of patients were serum folate deficient, with a change in management occurring in 24% of the deficient patients. The study also found that patients were charged $9979 per result that changed physician management.

In 1998, mandatory folic acid fortification began in the United States, and the prevalence of folate deficiency in the general population decreased to an estimated 0.5%.[23, 25] In a postfortification study, serum folate levels were evaluated in patients with anemia, dementia, or altered mental status.[26] The overall rate of serum folate deficiency was 0.4%, with the authors concluding that there was a lack of utility in serum folate testing. Despite this, algorithms addressing the evaluation of anemia continue to include serum folate levels.[2, 27, 28]

To our knowledge, the use of serum folate testing in the inpatient and emergency department population has never been independently evaluated. In our study, we aimed to characterize the indications, rate of deficiency, charge and cost per deficient result, and change in management per deficient result in inpatient and emergency department serum folate testing. We hypothesized that serum folate testing in these populations would have poor utility and would not be cost‐effective for any indication.

METHODS

We conducted a retrospective review of all serum folate tests ordered in inpatient units and the emergency department at a large academic medical center in Boston, Massachusetts from January 1, 2011 through December 31, 2011. The test was considered to be an inpatient or emergency department test based on the location of the blood draw on which the test was performed. Serum folate values were determined using a chemiluminescent competitive binding protein assay on an E170 analyzer as prescribed by the manufacturer (Roche Diagnostics, Indianapolis, IN). We defined serum folate levels as deficient (3.0 ng/mL), low‐normal (3.0 ng/mL3.9 ng/mL),[26] normal (4.0 ng/mL20.0 ng/mL), and high (>20.0 ng/mL). Erythrocyte folate levels are not routinely ordered at our institution and were not measured in our study.[29] Macrocytosis was defined as mean corpuscular volume of >99 fL. Vitamin B12 deficiency was defined as vitamin B12 level of under 200 pg/mL or vitamin B12 level of 200 to 300 pg/mL, with a methylmalonic acid >270 nmol/L and a normal homocysteine level (514 mol/L).[30, 31]

We evaluated 250 randomly selected serum folate levels and all deficient or low‐normal serum folate levels and recorded indication, comorbidities, age, sex, race or ethnicity, hemoglobin, hematocrit, mean corpuscular volume, vitamin B12 level, folic acid supplement on presentation, and folic acid supplement on discharge. Indications were determined by chart review. If serum folate was checked at the same time as iron studies, it was assumed that the indication was anemia without macrocytosis or anemia with macrocytosis unless otherwise documented. Comorbidities were selected based on historical risk factors and included depression, peripheral neuropathy, intestinal surgery, gastric bypass, cirrhosis, inflammatory bowel disease, celiac disease, delirium, dementia, alcohol abuse, malnutrition, anemia, end‐stage renal disease, vitamin B12 deficiency, or current use of phenytoin, valproic acid, or methotrexate.[32]

A charge analysis was performed using the same methodology as Robinson and Mladenovic.[24] We defined the charge of serum folate testing as our institution's charge to the patient or payer, which was $151.00 per test. Because hospital charges are variable, we also made a second calculation based on the charge per patient or payer from the Robinson and Mladenovic study,[24] which was $71.00. The analytical cost to our hospital of performing each serum folate test was <$2.00. We determined the total charge and cost for all serum folate tests and the charge and cost per deficient result.

The study was reviewed by the institutional review board and determined to be exempt.

RESULTS

In 2011, a total of 2093 serum folate levels were obtained on 1944 inpatients and emergency department patients. Of the total patients, 79.9% were inpatients and 20.1% were emergency department patients. Of the patients with tests performed in the emergency department, 98.1% were admitted to an inpatient unit.

Of the 250 random chart reviews, all had normal or high serum folate levels. The demographics, indications, and comorbidities are listed in Table 1. The most common indications were anemia without macrocytosis (43.2%), anemia with macrocytosis (13.2%; mean corpuscular volume [MCV], 106.8 fL), delirium (12.0%), malnutrition (6.4%), and peripheral neuropathy (6.0%). The other indications included thrombocytopenia, macrocytosis (without anemia), methotrexate use, alcohol abuse, frequent falls, syncope, headache, lethargy, optic nerve neuropathy, paranoia, psychosis, leukopenia, anxiety, and suicidal ideation. All of these individual indications were 2% of total reviewed indications. There were 16 cases (6.4%) without a documented indication.

Of the 2093 serum folate levels, there were 2 deficient (0.1%), 7 low‐normal (0.3%), 1487 normal (71.1%), and 597 high (28.5%) levels (Table 2). There were 128 patients (6.6%) who had more than 1 serum folate level checked within the prior 12 months, with 1 patient having 5 levels obtained during that time period. All of the deficient and low‐normal serum folate results are listed in Table 3. Of the 9 deficient or low‐normal serum folate levels, 8 had comorbid risk factors for folate deficiency. One of the deficient cases was on folic acid and multivitamin supplementation on presentation, although nonadherence with these supplements was documented in the medical record. The other deficient case was not on folic acid supplementation and did not receive folic acid supplementation for the deficient result. Vitamin B12 levels were checked simultaneously to serum folate levels in 85.2% of cases and within 6 months in 99.2% of cases. Of these patients, 2.0% were found to have vitamin B12 deficiency.

Based on our institution's charge for serum folate, a total of $316,043 was charged for the 2093 serum folate tests. The amount charged per deficient result was $158,022. Substituting the charge from the Robinson and Mladenovic study,[24] we calculated the corresponding total charge and charge per deficient result as $149,545 and $74,772, respectively. The actual total cost to our hospital was <$4186, with a cost per deficient test of <$2093.

DISCUSSION

Serum folate levels are often obtained when evaluating anemia without macrocytosis and anemia with macrocytosis.[2] They are also frequently obtained in the evaluation of delirium and dementia. A prior study evaluated both inpatient and outpatient serum folate levels in anemia, dementia, and altered mental status and found only 0.4% of serum folate results to be deficient.[26] In their study, the indications for serum folate tests were anemia or macrocytic anemia (60%) and dementia or altered mental status (30%).

We found the indications for serum folate testing in inpatients and emergency department patients to be different than prior studies. The majority of tests were done to evaluate anemia without macrocytosis (43.2%) or anemia with macrocytosis (13.2%). Lower percentages were done for the evaluation of delirium (12.0%) or dementia (3.2%). In addition, there were multiple indications that have not been noted in previous studies, including depression, peripheral neuropathy, malnutrition, pancytopenia, and others. These accounted for 28.0% of all indications. The reason for the difference in indications compared to prior studies is unknown but may be related to our cohort of exclusively inpatients and emergency department patients. Also, we observed a high concurrence of serum folate and vitamin B12 testing, with 85.2% of serum folate levels ordered at the same time as vitamin B12 levels. It appears that the tests are often ordered together even when the indication suggests that vitamin B12 alone may be more appropriate, such as peripheral neuropathy.

We found that serum folate deficiency was rare, occurring in only 2 of 2093 results. Furthermore, the deficient serum folate results may have been checked for inappropriate indications. The first deficient result was noted as part of a stroke workup in a patient not taking folic acid supplementation. Current guidelines do not recommend serum folate testing in patients with new stroke.[33] In the second deficient case, serum folate testing was performed for evaluation of macrocytic anemia with an MCV of 119 fL. Although reasonable, this was an alcoholic patient presenting with acute gastrointestinal bleeding already on folic acid and multivitamin supplementation and known nonadherence with these supplements. In neither case was there a change in management based on the deficient result.

Given the low rate of serum folate deficiency and the lack of change in management based on deficient results, we conclude that there is a low utility of serum folate testing for any indication in inpatients and emergency department patients in folic acid‐fortified countries. Based on prior studies, and supported by our results, there is no evidence for checking serum folate levels in delirium, dementia, peripheral neuropathy, malnutrition, or any of the other indications. In addition, our results demonstrate a low utility even in patients with anemia or macrocytic anemia.

The rate of serum folate deficiency in our study was significantly lower than prior studies.[24, 26] There may have been geographical factors that led to a lower prevalence of folate deficiency in our study population. Our cohort included inpatients and emergency department patients, whereas previous studies had a majority of outpatients. It is known that serum folate levels can rapidly fluctuate with proper nutrition.[34] It may be that our patients received nutrition in the hospital that corrected serum folate levels prior to laboratory testing.

In addition to the low utility of serum folate testing, the charge per deficient result in our study ($158,022) was more than 100‐fold higher than that in the Robinson and Mladenovic study ($1321).[24] Even when correcting for variability in hospital charges by using the charge from the latter study, the charge per deficient serum folate test remained 50‐fold higher ($74,772). This implies that the increase in charge per deficient result was driven in part by a decreased rate of deficient tests. Folic acid fortification is likely responsible for some of the decrease. However, we believe another source is the excessive ordering of serum folate tests in patients without previously accepted indications. Because no change in management was made for the deficient patients in our study, the charge per serum folate deficient result that changed management approached infinity. This compares to $9979 in the Robinson and Mladenovic analysis.[24]

The cost to the hospital of a serum folate test was much lower than the charge, and estimated to be <$2093 per deficient result. Because serum folate tests are performed on a highly automated, random access analyzer that performs thousands of other measurements daily, the capital and labor costs for each test was well below $0.50 combined. With the addition of reagent costs, our total cost for each serum folate measurement was <$2.00. It is somewhat difficult to extrapolate these values to other hospitals, as exact costs and charges are variable. Nonetheless, the exceptionally low utility of serum folate testing makes the costs associated with these tests excessive.

Our study has several limitations. We conducted our study at a single institution in a country with mandatory folic acid fortification. Our results may not be generalizable to other institutions or patient populations, such as those in countries without mandatory folic acid fortification. Only 259 (12.4%) charts were reviewed, and indications were determined in 93.6% of charts, which may have caused our frequency to vary from the true frequency. Additionally, the low rate of deficient serum folate results limited our ability to identify associations with deficiency. Further evaluation for geographic variations of serum folate deficiency may reveal variable rates.

We conclude that in folic acid fortified countries, the rate of serum folate deficiency is increasingly rare, and the charge to patients and payers per deficient result is exceptionally high. In addition, testing in our study did not change clinical management, which makes the costs associated with these test wasteful. Further evaluation of serum folate testing of inpatients and emergency department patients in folic acid fortified countries is warranted; however, based on our results the utility appears poor for all indications.

Folate deficiency has been associated with a number of medical conditions. It is well established that folate deficiency leads to macrocytic anemia,[1, 2] and that supplementation of folic acid during pregnancy leads to decreased rates of neural tube defects.[3] Folate deficiency has also been hypothesized to affect other conditions including dementia, delirium, peripheral neuropathy, depression, cancer, and cardiovascular disease.[4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18] Most of these latter assertions are based on case reports or observational studies, with randomized controlled trials failing to demonstrate benefit of folic acid supplementation.[19, 20, 21]

Prior to mandatory folic acid fortification in the United States, the prevalence of folate deficiency was estimated to be between 3% and 16%.[16, 22, 23] In a study conducted prior to fortification, serum folate levels were evaluated in patients presenting with macrocytosis and anemia.[24] The study found that 2.3% of patients were serum folate deficient, with a change in management occurring in 24% of the deficient patients. The study also found that patients were charged $9979 per result that changed physician management.

In 1998, mandatory folic acid fortification began in the United States, and the prevalence of folate deficiency in the general population decreased to an estimated 0.5%.[23, 25] In a postfortification study, serum folate levels were evaluated in patients with anemia, dementia, or altered mental status.[26] The overall rate of serum folate deficiency was 0.4%, with the authors concluding that there was a lack of utility in serum folate testing. Despite this, algorithms addressing the evaluation of anemia continue to include serum folate levels.[2, 27, 28]

To our knowledge, the use of serum folate testing in the inpatient and emergency department population has never been independently evaluated. In our study, we aimed to characterize the indications, rate of deficiency, charge and cost per deficient result, and change in management per deficient result in inpatient and emergency department serum folate testing. We hypothesized that serum folate testing in these populations would have poor utility and would not be cost‐effective for any indication.

METHODS

We conducted a retrospective review of all serum folate tests ordered in inpatient units and the emergency department at a large academic medical center in Boston, Massachusetts from January 1, 2011 through December 31, 2011. The test was considered to be an inpatient or emergency department test based on the location of the blood draw on which the test was performed. Serum folate values were determined using a chemiluminescent competitive binding protein assay on an E170 analyzer as prescribed by the manufacturer (Roche Diagnostics, Indianapolis, IN). We defined serum folate levels as deficient (3.0 ng/mL), low‐normal (3.0 ng/mL3.9 ng/mL),[26] normal (4.0 ng/mL20.0 ng/mL), and high (>20.0 ng/mL). Erythrocyte folate levels are not routinely ordered at our institution and were not measured in our study.[29] Macrocytosis was defined as mean corpuscular volume of >99 fL. Vitamin B12 deficiency was defined as vitamin B12 level of under 200 pg/mL or vitamin B12 level of 200 to 300 pg/mL, with a methylmalonic acid >270 nmol/L and a normal homocysteine level (514 mol/L).[30, 31]

We evaluated 250 randomly selected serum folate levels and all deficient or low‐normal serum folate levels and recorded indication, comorbidities, age, sex, race or ethnicity, hemoglobin, hematocrit, mean corpuscular volume, vitamin B12 level, folic acid supplement on presentation, and folic acid supplement on discharge. Indications were determined by chart review. If serum folate was checked at the same time as iron studies, it was assumed that the indication was anemia without macrocytosis or anemia with macrocytosis unless otherwise documented. Comorbidities were selected based on historical risk factors and included depression, peripheral neuropathy, intestinal surgery, gastric bypass, cirrhosis, inflammatory bowel disease, celiac disease, delirium, dementia, alcohol abuse, malnutrition, anemia, end‐stage renal disease, vitamin B12 deficiency, or current use of phenytoin, valproic acid, or methotrexate.[32]

A charge analysis was performed using the same methodology as Robinson and Mladenovic.[24] We defined the charge of serum folate testing as our institution's charge to the patient or payer, which was $151.00 per test. Because hospital charges are variable, we also made a second calculation based on the charge per patient or payer from the Robinson and Mladenovic study,[24] which was $71.00. The analytical cost to our hospital of performing each serum folate test was <$2.00. We determined the total charge and cost for all serum folate tests and the charge and cost per deficient result.

The study was reviewed by the institutional review board and determined to be exempt.

RESULTS

In 2011, a total of 2093 serum folate levels were obtained on 1944 inpatients and emergency department patients. Of the total patients, 79.9% were inpatients and 20.1% were emergency department patients. Of the patients with tests performed in the emergency department, 98.1% were admitted to an inpatient unit.

Of the 250 random chart reviews, all had normal or high serum folate levels. The demographics, indications, and comorbidities are listed in Table 1. The most common indications were anemia without macrocytosis (43.2%), anemia with macrocytosis (13.2%; mean corpuscular volume [MCV], 106.8 fL), delirium (12.0%), malnutrition (6.4%), and peripheral neuropathy (6.0%). The other indications included thrombocytopenia, macrocytosis (without anemia), methotrexate use, alcohol abuse, frequent falls, syncope, headache, lethargy, optic nerve neuropathy, paranoia, psychosis, leukopenia, anxiety, and suicidal ideation. All of these individual indications were 2% of total reviewed indications. There were 16 cases (6.4%) without a documented indication.

Of the 2093 serum folate levels, there were 2 deficient (0.1%), 7 low‐normal (0.3%), 1487 normal (71.1%), and 597 high (28.5%) levels (Table 2). There were 128 patients (6.6%) who had more than 1 serum folate level checked within the prior 12 months, with 1 patient having 5 levels obtained during that time period. All of the deficient and low‐normal serum folate results are listed in Table 3. Of the 9 deficient or low‐normal serum folate levels, 8 had comorbid risk factors for folate deficiency. One of the deficient cases was on folic acid and multivitamin supplementation on presentation, although nonadherence with these supplements was documented in the medical record. The other deficient case was not on folic acid supplementation and did not receive folic acid supplementation for the deficient result. Vitamin B12 levels were checked simultaneously to serum folate levels in 85.2% of cases and within 6 months in 99.2% of cases. Of these patients, 2.0% were found to have vitamin B12 deficiency.

Based on our institution's charge for serum folate, a total of $316,043 was charged for the 2093 serum folate tests. The amount charged per deficient result was $158,022. Substituting the charge from the Robinson and Mladenovic study,[24] we calculated the corresponding total charge and charge per deficient result as $149,545 and $74,772, respectively. The actual total cost to our hospital was <$4186, with a cost per deficient test of <$2093.

DISCUSSION

Serum folate levels are often obtained when evaluating anemia without macrocytosis and anemia with macrocytosis.[2] They are also frequently obtained in the evaluation of delirium and dementia. A prior study evaluated both inpatient and outpatient serum folate levels in anemia, dementia, and altered mental status and found only 0.4% of serum folate results to be deficient.[26] In their study, the indications for serum folate tests were anemia or macrocytic anemia (60%) and dementia or altered mental status (30%).

We found the indications for serum folate testing in inpatients and emergency department patients to be different than prior studies. The majority of tests were done to evaluate anemia without macrocytosis (43.2%) or anemia with macrocytosis (13.2%). Lower percentages were done for the evaluation of delirium (12.0%) or dementia (3.2%). In addition, there were multiple indications that have not been noted in previous studies, including depression, peripheral neuropathy, malnutrition, pancytopenia, and others. These accounted for 28.0% of all indications. The reason for the difference in indications compared to prior studies is unknown but may be related to our cohort of exclusively inpatients and emergency department patients. Also, we observed a high concurrence of serum folate and vitamin B12 testing, with 85.2% of serum folate levels ordered at the same time as vitamin B12 levels. It appears that the tests are often ordered together even when the indication suggests that vitamin B12 alone may be more appropriate, such as peripheral neuropathy.

We found that serum folate deficiency was rare, occurring in only 2 of 2093 results. Furthermore, the deficient serum folate results may have been checked for inappropriate indications. The first deficient result was noted as part of a stroke workup in a patient not taking folic acid supplementation. Current guidelines do not recommend serum folate testing in patients with new stroke.[33] In the second deficient case, serum folate testing was performed for evaluation of macrocytic anemia with an MCV of 119 fL. Although reasonable, this was an alcoholic patient presenting with acute gastrointestinal bleeding already on folic acid and multivitamin supplementation and known nonadherence with these supplements. In neither case was there a change in management based on the deficient result.

Given the low rate of serum folate deficiency and the lack of change in management based on deficient results, we conclude that there is a low utility of serum folate testing for any indication in inpatients and emergency department patients in folic acid‐fortified countries. Based on prior studies, and supported by our results, there is no evidence for checking serum folate levels in delirium, dementia, peripheral neuropathy, malnutrition, or any of the other indications. In addition, our results demonstrate a low utility even in patients with anemia or macrocytic anemia.

The rate of serum folate deficiency in our study was significantly lower than prior studies.[24, 26] There may have been geographical factors that led to a lower prevalence of folate deficiency in our study population. Our cohort included inpatients and emergency department patients, whereas previous studies had a majority of outpatients. It is known that serum folate levels can rapidly fluctuate with proper nutrition.[34] It may be that our patients received nutrition in the hospital that corrected serum folate levels prior to laboratory testing.

In addition to the low utility of serum folate testing, the charge per deficient result in our study ($158,022) was more than 100‐fold higher than that in the Robinson and Mladenovic study ($1321).[24] Even when correcting for variability in hospital charges by using the charge from the latter study, the charge per deficient serum folate test remained 50‐fold higher ($74,772). This implies that the increase in charge per deficient result was driven in part by a decreased rate of deficient tests. Folic acid fortification is likely responsible for some of the decrease. However, we believe another source is the excessive ordering of serum folate tests in patients without previously accepted indications. Because no change in management was made for the deficient patients in our study, the charge per serum folate deficient result that changed management approached infinity. This compares to $9979 in the Robinson and Mladenovic analysis.[24]

The cost to the hospital of a serum folate test was much lower than the charge, and estimated to be <$2093 per deficient result. Because serum folate tests are performed on a highly automated, random access analyzer that performs thousands of other measurements daily, the capital and labor costs for each test was well below $0.50 combined. With the addition of reagent costs, our total cost for each serum folate measurement was <$2.00. It is somewhat difficult to extrapolate these values to other hospitals, as exact costs and charges are variable. Nonetheless, the exceptionally low utility of serum folate testing makes the costs associated with these tests excessive.

Our study has several limitations. We conducted our study at a single institution in a country with mandatory folic acid fortification. Our results may not be generalizable to other institutions or patient populations, such as those in countries without mandatory folic acid fortification. Only 259 (12.4%) charts were reviewed, and indications were determined in 93.6% of charts, which may have caused our frequency to vary from the true frequency. Additionally, the low rate of deficient serum folate results limited our ability to identify associations with deficiency. Further evaluation for geographic variations of serum folate deficiency may reveal variable rates.

We conclude that in folic acid fortified countries, the rate of serum folate deficiency is increasingly rare, and the charge to patients and payers per deficient result is exceptionally high. In addition, testing in our study did not change clinical management, which makes the costs associated with these test wasteful. Further evaluation of serum folate testing of inpatients and emergency department patients in folic acid fortified countries is warranted; however, based on our results the utility appears poor for all indications.

Folate deficiency has been associated with a number of medical conditions. It is well established that folate deficiency leads to macrocytic anemia,[1, 2] and that supplementation of folic acid during pregnancy leads to decreased rates of neural tube defects.[3] Folate deficiency has also been hypothesized to affect other conditions including dementia, delirium, peripheral neuropathy, depression, cancer, and cardiovascular disease.[4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18] Most of these latter assertions are based on case reports or observational studies, with randomized controlled trials failing to demonstrate benefit of folic acid supplementation.[19, 20, 21]

Prior to mandatory folic acid fortification in the United States, the prevalence of folate deficiency was estimated to be between 3% and 16%.[16, 22, 23] In a study conducted prior to fortification, serum folate levels were evaluated in patients presenting with macrocytosis and anemia.[24] The study found that 2.3% of patients were serum folate deficient, with a change in management occurring in 24% of the deficient patients. The study also found that patients were charged $9979 per result that changed physician management.

In 1998, mandatory folic acid fortification began in the United States, and the prevalence of folate deficiency in the general population decreased to an estimated 0.5%.[23, 25] In a postfortification study, serum folate levels were evaluated in patients with anemia, dementia, or altered mental status.[26] The overall rate of serum folate deficiency was 0.4%, with the authors concluding that there was a lack of utility in serum folate testing. Despite this, algorithms addressing the evaluation of anemia continue to include serum folate levels.[2, 27, 28]

To our knowledge, the use of serum folate testing in the inpatient and emergency department population has never been independently evaluated. In our study, we aimed to characterize the indications, rate of deficiency, charge and cost per deficient result, and change in management per deficient result in inpatient and emergency department serum folate testing. We hypothesized that serum folate testing in these populations would have poor utility and would not be cost‐effective for any indication.

METHODS

We conducted a retrospective review of all serum folate tests ordered in inpatient units and the emergency department at a large academic medical center in Boston, Massachusetts from January 1, 2011 through December 31, 2011. The test was considered to be an inpatient or emergency department test based on the location of the blood draw on which the test was performed. Serum folate values were determined using a chemiluminescent competitive binding protein assay on an E170 analyzer as prescribed by the manufacturer (Roche Diagnostics, Indianapolis, IN). We defined serum folate levels as deficient (3.0 ng/mL), low‐normal (3.0 ng/mL3.9 ng/mL),[26] normal (4.0 ng/mL20.0 ng/mL), and high (>20.0 ng/mL). Erythrocyte folate levels are not routinely ordered at our institution and were not measured in our study.[29] Macrocytosis was defined as mean corpuscular volume of >99 fL. Vitamin B12 deficiency was defined as vitamin B12 level of under 200 pg/mL or vitamin B12 level of 200 to 300 pg/mL, with a methylmalonic acid >270 nmol/L and a normal homocysteine level (514 mol/L).[30, 31]

We evaluated 250 randomly selected serum folate levels and all deficient or low‐normal serum folate levels and recorded indication, comorbidities, age, sex, race or ethnicity, hemoglobin, hematocrit, mean corpuscular volume, vitamin B12 level, folic acid supplement on presentation, and folic acid supplement on discharge. Indications were determined by chart review. If serum folate was checked at the same time as iron studies, it was assumed that the indication was anemia without macrocytosis or anemia with macrocytosis unless otherwise documented. Comorbidities were selected based on historical risk factors and included depression, peripheral neuropathy, intestinal surgery, gastric bypass, cirrhosis, inflammatory bowel disease, celiac disease, delirium, dementia, alcohol abuse, malnutrition, anemia, end‐stage renal disease, vitamin B12 deficiency, or current use of phenytoin, valproic acid, or methotrexate.[32]

A charge analysis was performed using the same methodology as Robinson and Mladenovic.[24] We defined the charge of serum folate testing as our institution's charge to the patient or payer, which was $151.00 per test. Because hospital charges are variable, we also made a second calculation based on the charge per patient or payer from the Robinson and Mladenovic study,[24] which was $71.00. The analytical cost to our hospital of performing each serum folate test was <$2.00. We determined the total charge and cost for all serum folate tests and the charge and cost per deficient result.

The study was reviewed by the institutional review board and determined to be exempt.

RESULTS

In 2011, a total of 2093 serum folate levels were obtained on 1944 inpatients and emergency department patients. Of the total patients, 79.9% were inpatients and 20.1% were emergency department patients. Of the patients with tests performed in the emergency department, 98.1% were admitted to an inpatient unit.

Of the 250 random chart reviews, all had normal or high serum folate levels. The demographics, indications, and comorbidities are listed in Table 1. The most common indications were anemia without macrocytosis (43.2%), anemia with macrocytosis (13.2%; mean corpuscular volume [MCV], 106.8 fL), delirium (12.0%), malnutrition (6.4%), and peripheral neuropathy (6.0%). The other indications included thrombocytopenia, macrocytosis (without anemia), methotrexate use, alcohol abuse, frequent falls, syncope, headache, lethargy, optic nerve neuropathy, paranoia, psychosis, leukopenia, anxiety, and suicidal ideation. All of these individual indications were 2% of total reviewed indications. There were 16 cases (6.4%) without a documented indication.

Of the 2093 serum folate levels, there were 2 deficient (0.1%), 7 low‐normal (0.3%), 1487 normal (71.1%), and 597 high (28.5%) levels (Table 2). There were 128 patients (6.6%) who had more than 1 serum folate level checked within the prior 12 months, with 1 patient having 5 levels obtained during that time period. All of the deficient and low‐normal serum folate results are listed in Table 3. Of the 9 deficient or low‐normal serum folate levels, 8 had comorbid risk factors for folate deficiency. One of the deficient cases was on folic acid and multivitamin supplementation on presentation, although nonadherence with these supplements was documented in the medical record. The other deficient case was not on folic acid supplementation and did not receive folic acid supplementation for the deficient result. Vitamin B12 levels were checked simultaneously to serum folate levels in 85.2% of cases and within 6 months in 99.2% of cases. Of these patients, 2.0% were found to have vitamin B12 deficiency.

Based on our institution's charge for serum folate, a total of $316,043 was charged for the 2093 serum folate tests. The amount charged per deficient result was $158,022. Substituting the charge from the Robinson and Mladenovic study,[24] we calculated the corresponding total charge and charge per deficient result as $149,545 and $74,772, respectively. The actual total cost to our hospital was <$4186, with a cost per deficient test of <$2093.

DISCUSSION

Serum folate levels are often obtained when evaluating anemia without macrocytosis and anemia with macrocytosis.[2] They are also frequently obtained in the evaluation of delirium and dementia. A prior study evaluated both inpatient and outpatient serum folate levels in anemia, dementia, and altered mental status and found only 0.4% of serum folate results to be deficient.[26] In their study, the indications for serum folate tests were anemia or macrocytic anemia (60%) and dementia or altered mental status (30%).

We found the indications for serum folate testing in inpatients and emergency department patients to be different than prior studies. The majority of tests were done to evaluate anemia without macrocytosis (43.2%) or anemia with macrocytosis (13.2%). Lower percentages were done for the evaluation of delirium (12.0%) or dementia (3.2%). In addition, there were multiple indications that have not been noted in previous studies, including depression, peripheral neuropathy, malnutrition, pancytopenia, and others. These accounted for 28.0% of all indications. The reason for the difference in indications compared to prior studies is unknown but may be related to our cohort of exclusively inpatients and emergency department patients. Also, we observed a high concurrence of serum folate and vitamin B12 testing, with 85.2% of serum folate levels ordered at the same time as vitamin B12 levels. It appears that the tests are often ordered together even when the indication suggests that vitamin B12 alone may be more appropriate, such as peripheral neuropathy.

We found that serum folate deficiency was rare, occurring in only 2 of 2093 results. Furthermore, the deficient serum folate results may have been checked for inappropriate indications. The first deficient result was noted as part of a stroke workup in a patient not taking folic acid supplementation. Current guidelines do not recommend serum folate testing in patients with new stroke.[33] In the second deficient case, serum folate testing was performed for evaluation of macrocytic anemia with an MCV of 119 fL. Although reasonable, this was an alcoholic patient presenting with acute gastrointestinal bleeding already on folic acid and multivitamin supplementation and known nonadherence with these supplements. In neither case was there a change in management based on the deficient result.

Given the low rate of serum folate deficiency and the lack of change in management based on deficient results, we conclude that there is a low utility of serum folate testing for any indication in inpatients and emergency department patients in folic acid‐fortified countries. Based on prior studies, and supported by our results, there is no evidence for checking serum folate levels in delirium, dementia, peripheral neuropathy, malnutrition, or any of the other indications. In addition, our results demonstrate a low utility even in patients with anemia or macrocytic anemia.

The rate of serum folate deficiency in our study was significantly lower than prior studies.[24, 26] There may have been geographical factors that led to a lower prevalence of folate deficiency in our study population. Our cohort included inpatients and emergency department patients, whereas previous studies had a majority of outpatients. It is known that serum folate levels can rapidly fluctuate with proper nutrition.[34] It may be that our patients received nutrition in the hospital that corrected serum folate levels prior to laboratory testing.

In addition to the low utility of serum folate testing, the charge per deficient result in our study ($158,022) was more than 100‐fold higher than that in the Robinson and Mladenovic study ($1321).[24] Even when correcting for variability in hospital charges by using the charge from the latter study, the charge per deficient serum folate test remained 50‐fold higher ($74,772). This implies that the increase in charge per deficient result was driven in part by a decreased rate of deficient tests. Folic acid fortification is likely responsible for some of the decrease. However, we believe another source is the excessive ordering of serum folate tests in patients without previously accepted indications. Because no change in management was made for the deficient patients in our study, the charge per serum folate deficient result that changed management approached infinity. This compares to $9979 in the Robinson and Mladenovic analysis.[24]

The cost to the hospital of a serum folate test was much lower than the charge, and estimated to be <$2093 per deficient result. Because serum folate tests are performed on a highly automated, random access analyzer that performs thousands of other measurements daily, the capital and labor costs for each test was well below $0.50 combined. With the addition of reagent costs, our total cost for each serum folate measurement was <$2.00. It is somewhat difficult to extrapolate these values to other hospitals, as exact costs and charges are variable. Nonetheless, the exceptionally low utility of serum folate testing makes the costs associated with these tests excessive.

Our study has several limitations. We conducted our study at a single institution in a country with mandatory folic acid fortification. Our results may not be generalizable to other institutions or patient populations, such as those in countries without mandatory folic acid fortification. Only 259 (12.4%) charts were reviewed, and indications were determined in 93.6% of charts, which may have caused our frequency to vary from the true frequency. Additionally, the low rate of deficient serum folate results limited our ability to identify associations with deficiency. Further evaluation for geographic variations of serum folate deficiency may reveal variable rates.

We conclude that in folic acid fortified countries, the rate of serum folate deficiency is increasingly rare, and the charge to patients and payers per deficient result is exceptionally high. In addition, testing in our study did not change clinical management, which makes the costs associated with these test wasteful. Further evaluation of serum folate testing of inpatients and emergency department patients in folic acid fortified countries is warranted; however, based on our results the utility appears poor for all indications.