Article

Nearly 40 antihyperglycemic agents have been approved by the US Food and Drug Administration (FDA) since the approval of human insulin in 1982.¹ In addition, existing antihyperglycemic medications are constantly gaining FDA approval for new indications for common type 2 diabetes (T2D) comorbidities. For example, in addition to their glycemic benefits, the sodium-glucose cotransporter-2 (SGLT2) inhibitors have been approved for use in patients with T2D and established atherosclerotic cardiovascular disease (ASCVD) to reduce the risk for major adverse cardiovascular events (MACE; canagliflozin), risk for hospitalization for heart failure (dapagliflozin), and cardiovascular death (empagliflozin).^2-4

The plethora of new agents and new data for existing agents, coupled with the annual release of guidelines from the American Diabetes Association (ADA) and practice recommendations from several other professional organizations,^5-7 make it challenging for family physicians to stay current and provide the most up-to-date, evidence-based care. In this article, we provide advice on how to approach the screening, diagnosis, and evaluation of T2D, and on how to manage newly diagnosed T2D.

Screening, Dx, and evaluation: A quick review

Screening

Screening recommendations vary among professional organizations (TABLE 1^5,6,8). The US Preventive Services Task Force (USPSTF) recommends screening adults ages 35 to 70 years who are overweight or obese. Clinicians also can consider screening patients with a higher risk for diabetes.⁵ The ADA suggests screening all adults starting at 35 years, regardless of risk factors.⁸ Asymptomatic adults of any age with overweight or obesity and 1 or more risk factors should be screened.⁸ The American Association of Clinical Endocrinology (AACE) recommends screening adults of any age who have risk factors.⁶ If the screening result is normal, repeat testing in 3 years is appropriate, unless there is a change in symptoms or risks.^5,8 Annual testing can be considered in patients with ≥ 2 risk factors or with prediabetes (glycosylated hemoglobin [A1C] ≥ 5.7%).^6,8

Making the diagnosis

The initial diagnosis of diabetes can be made by a fasting plasma glucose level ≥ 126 mg/dL (7.0 mmol/L); a 2-hour plasma glucose level ≥ 200 mg/dL (11.0 mmol/L) following an oral glucose tolerance test; or an A1C level ≥ 6.5%. Prioritize lab-drawn A1C measurements over point-of-care tests to diagnose T2D. In ­patients with classic symptoms of hyper­glycemia, a random plasma glucose level ≥ 200 mg/dL (11.0 mmol/L) is also diagnostic. Generally, these tests are considered equally appropriate in screening for diabetes and may be used to detect prediabetes. In the absence of clear symptoms of hyperglycemia, the diagnosis of diabetes requires 2 abnormal screening test results, either via 1 blood sample (such as an abnormal A1C and glucose) or 2 separate blood samples of the same test. Further evaluation is advised if there is discordance between the 2 samples.⁸

Extended evaluations

Patients with newly diagnosed T2D require a thorough evaluation for comorbidities and complications of diabetes. Refer patients to an ophthalmologist for a dilated eye examination, with subsequent exams occurring every 1 to 2 years.^6,9 Additional referrals for diabetes education, family planning for women of reproductive age, and dental, social, or mental health services may be clinically appropriate.⁹

Setting goals for glycemic control

Glycemic control is commonly monitored by the A1C level and by blood glucose monitoring either through traditional point-of-care glucometers or continuous glucose monitors (CGMs).¹⁰ Generally, CGMs provide more glycemic data than traditional glucometers and may cue patients to choose healthier dietary options and engage in physical exercise.¹¹ Patients with T2D who use CGMs exhibit lower A1Cs, greater time in glycemic range, and reduced hypoglycemic episodes.¹¹ Generally, CGMs are reserved for patients with type 1 diabetes and patients with T2D who use multiple daily injections, subcutaneous insulin infusions, or basal insulin only.¹² Most professional organizations recommend that clinicians consider patient-specific factors to set individualized glycemic goals.^6,10,13,14 For example, more stringent glycemic goals could be pursued for patients with longer life expectancy, shorter disease duration, absence of complications (eg, nephropathy, neuropathy, or cardiovascular disease), fewer comorbid conditions, lower hypoglycemia risk, or higher cognitive function.⁶

With newer agents, more aggressive A1C goals can be targeted safely in select patients, particularly those with long life expectancy.

More specific A1C goals vary by professional organization. For nonpregnant adults, the ADA recommends an A1C goal of < 7% and a preprandial blood glucose level of 80 to 130 mg/dL (4.4-7.2 mmol/L).¹⁰ However, a lower A1C goal may be appropriate if it can be attained safely without causing hypoglycemia or other adverse effects.¹⁰ The AACE suggests an A1C goal of ≤ 6.5% and a fasting blood glucose level of < 110 mg/dL when it can be achieved safely.⁶ More stringent A1C goals may reduce long-term micro- and macrovascular complications—especially in patients with newly diagnosed T2D.¹⁰ While older studies such as the ACCORD trial found increased mortality in groups with more stringent glycemic targets, they did not include newer agents (SGLT2 inhibitors or glucagon-like peptide-1 [GLP-1] receptor agonists) that reduce cardiovascular events by mechanisms outside their glycemic-lowering effect. With these newer agents, more aggressive A1C goals can be targeted safely in select patients, particularly those with long life expectancy.¹⁰ Both the ADA and AACE recommend a less stringent A1C goal of 7% to 8% for patients with limited life expectancy or risks (eg, a history of hypoglycemia) that outweigh expected benefits.^6,10

Continue to: Lifestyle modifications

 

 

Lifestyle modifications: As important as medication

Nutrition

The energy-dense Western diet, combined with sedentary behavior, are thought to be a primary cause of T2D.¹⁵ Therefore, include lifestyle modifications in the initial management of newly diagnosed T2D. Diets that replace carbohydrates with saturated and trans fats are related to increased mortality in patients with T2D.¹⁶ Increased consumption of vegetables, fruits, legumes, nuts, fish, cereal, and oils reduces concentrations of saturated and trans fats and increases dietary intake of monounsaturated fatty acids, fiber, antioxidants, and polyphenols.¹⁷

Combined endurance and resistance training is superior for improving glycemic control, cardiorespiratory fitness, and body composition, compared with either type of training alone.

Increasing the intake of fiber, an undigestible carbohydrate, offers numerous benefits in T2D management. High-fiber diets can help regulate blood sugar and lipid levels, increase satiety, reduce inflammation, aid in weight management, and reduce premature mortality.¹⁸ Insoluble fiber, found in foods such as whole wheat flour, nuts, and cauliflower, helps food pass more quickly through the stomach and intestines and adds bulk to stool. Soluble fiber, found in foods such as chickpeas, lentils, and Brussels sprouts, absorbs water and forms a gel-like substance that protects nutrients from digestive enzymes and slows down digestion. The result is a more gradual rise in postprandial glucose levels and improved insulin sensitivity.¹⁹ Dietary fiber may produce short-chain fatty acids which in turn activate incretin secretion and stimulate a glucose-dependent release of insulin from the pancreas.²⁰

Simple dietary substitutions, such as whole grains and legumes for white rice, can reduce fasting blood glucose and A1C levels.²¹ In a randomized controlled trial (RCT), increasing whole grain oat intake improved measures of glycemic control, reducing A1C by 1% at 1-year follow-up.¹⁹ Encourage patients with T2D to increase consumption of high-fiber foods and replace animal fats and refined grains with vegetable fats (eg, nuts, avocados, olives).
Nutritional therapies should be individualized, taking into account personal preferences and cultural customs.²² Nutritional habits may be based on race/ethnicity, ­religion/spirituality, or even the city in which an individual resides. Nutrition recommendations should account for these differences as well as access to healthy foods. For instance, ethnic groups whose dietary patterns include tortillas could be counseled to choose high-fiber options such as corn instead of flour tortillas and to incorporate vegetables in place of high-fat foods. Additionally, ethnic groups who favor using animal fats in foods such as greens could be advised on ways to add flavor to vegetables without adding saturated fats. Taking this approach may lessen barriers to change and increase ability to make dietary modifications.²³

Exercise

Encourage all patients with T2D to exercise regularly. The atherosclerotic plaques found in patients with T2D have increased inflammatory properties and result in worse cardiovascular outcomes compared with plaques in individuals without T2D.²⁴ Regular exercise reduces levels of pro-inflammatory markers—C-reactive protein, interleukin (IL)-6, and tumor necrosis factor alpha—and increases levels of anti-­inflammatory markers (IL-4 and IL-10).²⁴ Regular exercise can improve body composition, physical fitness, lipid and glucose metabolism, and insulin sensitivity.^25,26

A meta-analysis of RCTs demonstrated that structured exercise > 150 minutes per week resulted in A1C reductions of 0.89%,²⁷ which is comparable to the effect of many oral antihyperglycemic medications.²⁶ The Health Benefits of Aerobic and Resistance Training in individuals with T2D (HART-D) and Diabetes Aerobic and Resistance Exercise (DARE) studies demonstrated that combining endurance and resistance training was superior for improving glycemic control, cardiorespiratory fitness, and body composition, than using either type of training alone.²⁵ Both the American College of Sports Medicine (ACSM) and the ADA recommend that adults engage in at least 150 total minutes of moderate-intensity aerobic activity per week and resistance training 2 to 3 times weekly.²⁶ ACSM defines moderate-intensity exercise as 65% to 75% of maximal heart rate, a rating of perceived exertion of 3 to 4, or a step rate of 100 steps per minute.²⁸

Continue to: Because of their longitudinal relationships...

 

Because of their longitudinal relationships with patients, family physicians are in an optimal position to assess a patient’s physical capacity level and provide individualized counseling. Several systematic reviews have demonstrated that counseling on exercise increases patients’ participation in physical activity.²⁹ Encourage your patients with T2D to exercise regularly, considering each individual’s ability to engage in physical activity.

Weight loss

Include weight management in the initial treatment of patients with newly diagnosed T2D. Weight loss decreases hepatic glucose production and increases peripheral insulin sensitivity and insulin secretion.³⁰ Moderate decreases in weight (5%-10%) can reduce complications related to diabetes, and sustained significant weight loss (> 10%) can potentially cause T2D remission (A1C < 6.5% after stopping diabetes medications).^31,32

Several systematic reviews have demonstrated that counseling on exercise increases patients’ participation in physical activity.

Diabetes self-management education supports patients by giving them tools for making and maintaining lifestyle changes. Understanding individual barriers to change and addressing these during motivational interviews is important. Through a qualitative interview study, participants in a diabetes self-management program revealed 4 factors that motivated them to maintain lifestyle changes: support from others, experiencing the impact of the changes they made, fear of T2D complications, and forming new habits.³³ Family physicians are key in helping patients acquire knowledge and support to make the lifestyle modifications needed to manage newly diagnosed T2D.

Individualized pharmacotherapy considerations

For decades, the initial pharmacotherapeutic regimen for patients with newly diagnosed T2D considered the patient’s baseline A1C as a major driver for therapy. Metformin has been the mainstay in T2D treatment due to its clinical efficacy, minimal risk for hypoglycemia, and low cost. Regardless of the regimen, pharmacotherapy should be initiated at the time of T2D diagnosis in conjunction with the aforementioned lifestyle modifications.³⁴

When selecting pharmacotherapy, practice guidelines recommend considering the efficacy and adverse effects of medications, patient-specific comorbidities, adherence, cost, and a patient’s lifestyle factors.³⁴ Drug classes with pertinent information are listed in TABLE 2.^34-54 After starting medication, monitor the A1C level every 3 months to determine whether therapy should be intensified. Patients should have their labs drawn ahead of the quarterly visit, or point-of-care measurements may be used to facilitate in-person patient–provider discussions.

Continue to: Consider patient-specific factors when starting pharmacotherapy

 

Consider patient-specific factors when starting pharmacotherapy

ASCVD. Regardless of baseline glycemic control, offer patients who have ASCVD, or who are at high risk for it, an SGLT2 inhibitor (canagliflozin, dapagliflozin, or empagliflozin) or a long-acting GLP-1 receptor agonist (dulaglutide, liraglutide, or semaglutide).^34,35 SGLT2 inhibitors reduced the risk for MACE by 11% in patients with established ASCVD.⁵⁵ They also reduced a composite outcome of cardiovascular death or hospitalization for heart failure by 23% in patients with or without ASCVD or heart failure at baseline.⁵⁵ GLP-1 receptor agonists offer a similar reduction in MACE to SGLT2 inhibitors, but they do not have significant effects in heart failure.⁵⁶ Thiazolidinediones (TZDs), saxagliptin, and alogliptin should be avoided in patients with heart failure.⁵⁷ TZDs may reduce the risk for recurrent stroke in patients with T2D.⁵⁸

Chronic kidney disease (CKD). As with ASCVD, prioritize SGLT2 inhibitors and ­GLP-1 receptor agonists in patients with CKD. While both classes reduced the risk for progression of kidney disease such as macroalbuminuria, SGLT2 inhibitors offer additional benefits in their reduction of the worsening of estimated glomerular filtration rate, end-stage kidney disease, and renal death.⁵⁶

Obesity. Consider the effect of each drug class on weight when making initial treatment choices, taking special care to minimize weight gain and potentially promote weight loss.³⁴ The ADA prefers GLP-1 receptor agonists, but also suggests SGLT2 inhibitors in these patients. While all GLP-1 receptor agonists have an impact on weight, weekly subcutaneous semaglutide offers the most pronounced weight loss of 2 to 7 kg over 56 weeks.⁵⁹ SGLT2 inhibitors promote sustainable weight loss to a lesser degree, contributing to an average loss of 3 kg at 2 years.⁶⁰ Weight gain is common in patients taking sulfonylureas (2.01-2.3 kg)³¹ and insulin (3-9 kg weight gain in the first year)⁶¹ and should be avoided in patients with T2D and obesity.³⁴

Hypoglycemia risk. In addition to counseling patients on hypoglycemia management and prescribing glucagon rescue kits, offer medications with no or very low risk for hypoglycemia (eg, GLP-1 receptor agonists, SGLT2 inhibitors, dipeptidyl ­peptidase-4 inhibitors, and TZDs). Generally, avoid insulin and sulfonylureas in patients in whom hypoglycemia is a major concern (eg, older adults, individuals with labile blood glucose levels).³⁴ Patients with reduced renal function are at higher risk for hypoglycemia with insulin or sulfonylureas due to reduced drug clearance. However, insulin is often the only treatment for patients with advanced renal disease. Pay close attention to insulin dosing in patients with advanced renal disease, which may necessitate lower doses and smaller dose adjustments due to this risk.

Social determinants of health. Medication access and cost is a major burden in T2D management and should be considered for every patient. Compared with the period of 2005 to 2007, the annual cost of diabetes medications for an individual in 2015 to 2017 increased by 147%, rising from $1106 to $2727 per year.⁶² This increase is driven by the cost of insulin and newer medications without generic options.⁶² Identify local resources in your community, such as patient assistance programs and pharmacies with reduced-price generic prescription programs, which may be useful for patients who are underinsured or uninsured.

Continue to: Even if cost weren't an issue...

 

Even if cost weren’t an issue, many ­medications such as insulin and GLP-1 receptor agonists should be kept refrigerated and are only stable at room temperature for a limited time. Medications that are stable at room temperature should be prioritized in patients with limited or inconsistent access to refrigeration or unstable housing who may find it difficult to store their medications ­appropriately.

Do not delay insulin initiation in patients with high baseline A1C

Whenever possible, a GLP-1 receptor agonist is the preferred injectable medication to insulin. Starting insulin introduces numerous risks, including hypoglycemia, weight gain, and stigma. However, in the patient with newly diagnosed T2D, choose basal insulin when the baseline hyperglycemia is severe,³⁴ as indicated by:

• blood glucose > 300 mg/dL (16.7 mmol/L),
• A1C > 10% (86 mmol/mol),
• symptoms of hyperglycemia (polyuria or polydipsia), or
• evidence of catabolism (weight loss, hypertriglyceridemia, ketosis).

Basal insulin analogs are preferred over NPH given their reduced variability, dosing, and hypoglycemic risk.³⁵ Mixed insulins may be used if a patient is unable to afford an insulin analog, which can be quite costly. However, extensive counseling on dosing and management of hypoglycemia is crucial to patient safety with these agents. The ADA ­recommends initiating 0.1 to 0.2 units/kg of basal insulin daily or 10 units daily.³⁴ The AACE follows this recommendation for ­patients with baseline A1C < 8%, but it proposes a more aggressive initiation of 0.2 to 0.3 units/kg/d for patients with baseline A1C > 8%.³⁵ Titrate the dose by 2 units every 3 days to reach the target fasting blood glucose level. As hyperglycemia resolves, simplify the regimen and transition to noninsulin options per the previously discussed considerations.

It’s not just about glycemic control

In addition to the direct effects of hyperglycemia, a T2D diagnosis introduces an increased risk for ASCVD, a reduced ability to fight infection, and heightened risk for depression. Order a lipid panel at the time of T2D diagnosis and initiate lipid management as needed (TABLE 3^35,63,64). Both the ADA and the American Heart Association recommend starting a moderate-intensity statin as primary prevention for all patients with T2D between 40 and 75 years of age regardless of the 10-year ASCVD risk.⁶³ The AACE uses specific lipid targets and recommends moderate- to high-intensity statin therapy for patients with T2D.³⁵ All recommendations by professional organizations list high-intensity statins for patients with established ASCVD.

Both the ADA and the AHA recommend starting a moderate-intensity statin as primary prevention for all patients with T2D between 40 and 75 years of age regardless of the 10-year ASCVD risk.

It is also vital to recommend that patients with newly diagnosed T2D remain up to date on all indicated vaccinations. They should promptly receive the hepatitis B and pneumococcal vaccines if they have not already done so for a previous indication. COVID-19 and annual influenza vaccines also should be prioritized for these patients.⁶⁵

Finally, patients with diabetes are twice as likely to develop depression than patients without diabetes.⁶⁶ Individuals with T2D and depression exhibit poorer medication adherence, lifestyle choices, and glycemic control.⁶⁶ Screen for and treat these issues in all patients with T2D across the course of the disease.

Overall, work closely with patients to support them in managing their new diagnosis with evidence-based pharmacologic and nonpharmacologic approaches. The importance of lifestyle changes including high-fiber diets, regular exercise, and weight loss should not be overlooked. Do not delay starting pharmacotherapy after diagnosing T2D and consider medication-specific and patient-specific factors to individualize therapy, improve adherence, and prevent complications.

CORRESPONDENCE
Jennie B. Jarrett, PharmD, MMedEd, 833 South Wood Street (MC 886), Chicago, IL 60612; [email protected]

Nearly 40 antihyperglycemic agents have been approved by the US Food and Drug Administration (FDA) since the approval of human insulin in 1982.¹ In addition, existing antihyperglycemic medications are constantly gaining FDA approval for new indications for common type 2 diabetes (T2D) comorbidities. For example, in addition to their glycemic benefits, the sodium-glucose cotransporter-2 (SGLT2) inhibitors have been approved for use in patients with T2D and established atherosclerotic cardiovascular disease (ASCVD) to reduce the risk for major adverse cardiovascular events (MACE; canagliflozin), risk for hospitalization for heart failure (dapagliflozin), and cardiovascular death (empagliflozin).^2-4

The plethora of new agents and new data for existing agents, coupled with the annual release of guidelines from the American Diabetes Association (ADA) and practice recommendations from several other professional organizations,^5-7 make it challenging for family physicians to stay current and provide the most up-to-date, evidence-based care. In this article, we provide advice on how to approach the screening, diagnosis, and evaluation of T2D, and on how to manage newly diagnosed T2D.

Screening, Dx, and evaluation: A quick review

Screening

Screening recommendations vary among professional organizations (TABLE 1^5,6,8). The US Preventive Services Task Force (USPSTF) recommends screening adults ages 35 to 70 years who are overweight or obese. Clinicians also can consider screening patients with a higher risk for diabetes.⁵ The ADA suggests screening all adults starting at 35 years, regardless of risk factors.⁸ Asymptomatic adults of any age with overweight or obesity and 1 or more risk factors should be screened.⁸ The American Association of Clinical Endocrinology (AACE) recommends screening adults of any age who have risk factors.⁶ If the screening result is normal, repeat testing in 3 years is appropriate, unless there is a change in symptoms or risks.^5,8 Annual testing can be considered in patients with ≥ 2 risk factors or with prediabetes (glycosylated hemoglobin [A1C] ≥ 5.7%).^6,8

Making the diagnosis

The initial diagnosis of diabetes can be made by a fasting plasma glucose level ≥ 126 mg/dL (7.0 mmol/L); a 2-hour plasma glucose level ≥ 200 mg/dL (11.0 mmol/L) following an oral glucose tolerance test; or an A1C level ≥ 6.5%. Prioritize lab-drawn A1C measurements over point-of-care tests to diagnose T2D. In ­patients with classic symptoms of hyper­glycemia, a random plasma glucose level ≥ 200 mg/dL (11.0 mmol/L) is also diagnostic. Generally, these tests are considered equally appropriate in screening for diabetes and may be used to detect prediabetes. In the absence of clear symptoms of hyperglycemia, the diagnosis of diabetes requires 2 abnormal screening test results, either via 1 blood sample (such as an abnormal A1C and glucose) or 2 separate blood samples of the same test. Further evaluation is advised if there is discordance between the 2 samples.⁸

Extended evaluations

Patients with newly diagnosed T2D require a thorough evaluation for comorbidities and complications of diabetes. Refer patients to an ophthalmologist for a dilated eye examination, with subsequent exams occurring every 1 to 2 years.^6,9 Additional referrals for diabetes education, family planning for women of reproductive age, and dental, social, or mental health services may be clinically appropriate.⁹

Setting goals for glycemic control

Glycemic control is commonly monitored by the A1C level and by blood glucose monitoring either through traditional point-of-care glucometers or continuous glucose monitors (CGMs).¹⁰ Generally, CGMs provide more glycemic data than traditional glucometers and may cue patients to choose healthier dietary options and engage in physical exercise.¹¹ Patients with T2D who use CGMs exhibit lower A1Cs, greater time in glycemic range, and reduced hypoglycemic episodes.¹¹ Generally, CGMs are reserved for patients with type 1 diabetes and patients with T2D who use multiple daily injections, subcutaneous insulin infusions, or basal insulin only.¹² Most professional organizations recommend that clinicians consider patient-specific factors to set individualized glycemic goals.^6,10,13,14 For example, more stringent glycemic goals could be pursued for patients with longer life expectancy, shorter disease duration, absence of complications (eg, nephropathy, neuropathy, or cardiovascular disease), fewer comorbid conditions, lower hypoglycemia risk, or higher cognitive function.⁶

With newer agents, more aggressive A1C goals can be targeted safely in select patients, particularly those with long life expectancy.

More specific A1C goals vary by professional organization. For nonpregnant adults, the ADA recommends an A1C goal of < 7% and a preprandial blood glucose level of 80 to 130 mg/dL (4.4-7.2 mmol/L).¹⁰ However, a lower A1C goal may be appropriate if it can be attained safely without causing hypoglycemia or other adverse effects.¹⁰ The AACE suggests an A1C goal of ≤ 6.5% and a fasting blood glucose level of < 110 mg/dL when it can be achieved safely.⁶ More stringent A1C goals may reduce long-term micro- and macrovascular complications—especially in patients with newly diagnosed T2D.¹⁰ While older studies such as the ACCORD trial found increased mortality in groups with more stringent glycemic targets, they did not include newer agents (SGLT2 inhibitors or glucagon-like peptide-1 [GLP-1] receptor agonists) that reduce cardiovascular events by mechanisms outside their glycemic-lowering effect. With these newer agents, more aggressive A1C goals can be targeted safely in select patients, particularly those with long life expectancy.¹⁰ Both the ADA and AACE recommend a less stringent A1C goal of 7% to 8% for patients with limited life expectancy or risks (eg, a history of hypoglycemia) that outweigh expected benefits.^6,10

Continue to: Lifestyle modifications

 

 

Lifestyle modifications: As important as medication

Nutrition

The energy-dense Western diet, combined with sedentary behavior, are thought to be a primary cause of T2D.¹⁵ Therefore, include lifestyle modifications in the initial management of newly diagnosed T2D. Diets that replace carbohydrates with saturated and trans fats are related to increased mortality in patients with T2D.¹⁶ Increased consumption of vegetables, fruits, legumes, nuts, fish, cereal, and oils reduces concentrations of saturated and trans fats and increases dietary intake of monounsaturated fatty acids, fiber, antioxidants, and polyphenols.¹⁷

Combined endurance and resistance training is superior for improving glycemic control, cardiorespiratory fitness, and body composition, compared with either type of training alone.

Increasing the intake of fiber, an undigestible carbohydrate, offers numerous benefits in T2D management. High-fiber diets can help regulate blood sugar and lipid levels, increase satiety, reduce inflammation, aid in weight management, and reduce premature mortality.¹⁸ Insoluble fiber, found in foods such as whole wheat flour, nuts, and cauliflower, helps food pass more quickly through the stomach and intestines and adds bulk to stool. Soluble fiber, found in foods such as chickpeas, lentils, and Brussels sprouts, absorbs water and forms a gel-like substance that protects nutrients from digestive enzymes and slows down digestion. The result is a more gradual rise in postprandial glucose levels and improved insulin sensitivity.¹⁹ Dietary fiber may produce short-chain fatty acids which in turn activate incretin secretion and stimulate a glucose-dependent release of insulin from the pancreas.²⁰

Simple dietary substitutions, such as whole grains and legumes for white rice, can reduce fasting blood glucose and A1C levels.²¹ In a randomized controlled trial (RCT), increasing whole grain oat intake improved measures of glycemic control, reducing A1C by 1% at 1-year follow-up.¹⁹ Encourage patients with T2D to increase consumption of high-fiber foods and replace animal fats and refined grains with vegetable fats (eg, nuts, avocados, olives).
Nutritional therapies should be individualized, taking into account personal preferences and cultural customs.²² Nutritional habits may be based on race/ethnicity, ­religion/spirituality, or even the city in which an individual resides. Nutrition recommendations should account for these differences as well as access to healthy foods. For instance, ethnic groups whose dietary patterns include tortillas could be counseled to choose high-fiber options such as corn instead of flour tortillas and to incorporate vegetables in place of high-fat foods. Additionally, ethnic groups who favor using animal fats in foods such as greens could be advised on ways to add flavor to vegetables without adding saturated fats. Taking this approach may lessen barriers to change and increase ability to make dietary modifications.²³

Exercise

Encourage all patients with T2D to exercise regularly. The atherosclerotic plaques found in patients with T2D have increased inflammatory properties and result in worse cardiovascular outcomes compared with plaques in individuals without T2D.²⁴ Regular exercise reduces levels of pro-inflammatory markers—C-reactive protein, interleukin (IL)-6, and tumor necrosis factor alpha—and increases levels of anti-­inflammatory markers (IL-4 and IL-10).²⁴ Regular exercise can improve body composition, physical fitness, lipid and glucose metabolism, and insulin sensitivity.^25,26

A meta-analysis of RCTs demonstrated that structured exercise > 150 minutes per week resulted in A1C reductions of 0.89%,²⁷ which is comparable to the effect of many oral antihyperglycemic medications.²⁶ The Health Benefits of Aerobic and Resistance Training in individuals with T2D (HART-D) and Diabetes Aerobic and Resistance Exercise (DARE) studies demonstrated that combining endurance and resistance training was superior for improving glycemic control, cardiorespiratory fitness, and body composition, than using either type of training alone.²⁵ Both the American College of Sports Medicine (ACSM) and the ADA recommend that adults engage in at least 150 total minutes of moderate-intensity aerobic activity per week and resistance training 2 to 3 times weekly.²⁶ ACSM defines moderate-intensity exercise as 65% to 75% of maximal heart rate, a rating of perceived exertion of 3 to 4, or a step rate of 100 steps per minute.²⁸

Continue to: Because of their longitudinal relationships...

 

Because of their longitudinal relationships with patients, family physicians are in an optimal position to assess a patient’s physical capacity level and provide individualized counseling. Several systematic reviews have demonstrated that counseling on exercise increases patients’ participation in physical activity.²⁹ Encourage your patients with T2D to exercise regularly, considering each individual’s ability to engage in physical activity.

Weight loss

Include weight management in the initial treatment of patients with newly diagnosed T2D. Weight loss decreases hepatic glucose production and increases peripheral insulin sensitivity and insulin secretion.³⁰ Moderate decreases in weight (5%-10%) can reduce complications related to diabetes, and sustained significant weight loss (> 10%) can potentially cause T2D remission (A1C < 6.5% after stopping diabetes medications).^31,32

Several systematic reviews have demonstrated that counseling on exercise increases patients’ participation in physical activity.

Diabetes self-management education supports patients by giving them tools for making and maintaining lifestyle changes. Understanding individual barriers to change and addressing these during motivational interviews is important. Through a qualitative interview study, participants in a diabetes self-management program revealed 4 factors that motivated them to maintain lifestyle changes: support from others, experiencing the impact of the changes they made, fear of T2D complications, and forming new habits.³³ Family physicians are key in helping patients acquire knowledge and support to make the lifestyle modifications needed to manage newly diagnosed T2D.

Individualized pharmacotherapy considerations

For decades, the initial pharmacotherapeutic regimen for patients with newly diagnosed T2D considered the patient’s baseline A1C as a major driver for therapy. Metformin has been the mainstay in T2D treatment due to its clinical efficacy, minimal risk for hypoglycemia, and low cost. Regardless of the regimen, pharmacotherapy should be initiated at the time of T2D diagnosis in conjunction with the aforementioned lifestyle modifications.³⁴

When selecting pharmacotherapy, practice guidelines recommend considering the efficacy and adverse effects of medications, patient-specific comorbidities, adherence, cost, and a patient’s lifestyle factors.³⁴ Drug classes with pertinent information are listed in TABLE 2.^34-54 After starting medication, monitor the A1C level every 3 months to determine whether therapy should be intensified. Patients should have their labs drawn ahead of the quarterly visit, or point-of-care measurements may be used to facilitate in-person patient–provider discussions.

Continue to: Consider patient-specific factors when starting pharmacotherapy

 

Consider patient-specific factors when starting pharmacotherapy

ASCVD. Regardless of baseline glycemic control, offer patients who have ASCVD, or who are at high risk for it, an SGLT2 inhibitor (canagliflozin, dapagliflozin, or empagliflozin) or a long-acting GLP-1 receptor agonist (dulaglutide, liraglutide, or semaglutide).^34,35 SGLT2 inhibitors reduced the risk for MACE by 11% in patients with established ASCVD.⁵⁵ They also reduced a composite outcome of cardiovascular death or hospitalization for heart failure by 23% in patients with or without ASCVD or heart failure at baseline.⁵⁵ GLP-1 receptor agonists offer a similar reduction in MACE to SGLT2 inhibitors, but they do not have significant effects in heart failure.⁵⁶ Thiazolidinediones (TZDs), saxagliptin, and alogliptin should be avoided in patients with heart failure.⁵⁷ TZDs may reduce the risk for recurrent stroke in patients with T2D.⁵⁸

Chronic kidney disease (CKD). As with ASCVD, prioritize SGLT2 inhibitors and ­GLP-1 receptor agonists in patients with CKD. While both classes reduced the risk for progression of kidney disease such as macroalbuminuria, SGLT2 inhibitors offer additional benefits in their reduction of the worsening of estimated glomerular filtration rate, end-stage kidney disease, and renal death.⁵⁶

Obesity. Consider the effect of each drug class on weight when making initial treatment choices, taking special care to minimize weight gain and potentially promote weight loss.³⁴ The ADA prefers GLP-1 receptor agonists, but also suggests SGLT2 inhibitors in these patients. While all GLP-1 receptor agonists have an impact on weight, weekly subcutaneous semaglutide offers the most pronounced weight loss of 2 to 7 kg over 56 weeks.⁵⁹ SGLT2 inhibitors promote sustainable weight loss to a lesser degree, contributing to an average loss of 3 kg at 2 years.⁶⁰ Weight gain is common in patients taking sulfonylureas (2.01-2.3 kg)³¹ and insulin (3-9 kg weight gain in the first year)⁶¹ and should be avoided in patients with T2D and obesity.³⁴

Hypoglycemia risk. In addition to counseling patients on hypoglycemia management and prescribing glucagon rescue kits, offer medications with no or very low risk for hypoglycemia (eg, GLP-1 receptor agonists, SGLT2 inhibitors, dipeptidyl ­peptidase-4 inhibitors, and TZDs). Generally, avoid insulin and sulfonylureas in patients in whom hypoglycemia is a major concern (eg, older adults, individuals with labile blood glucose levels).³⁴ Patients with reduced renal function are at higher risk for hypoglycemia with insulin or sulfonylureas due to reduced drug clearance. However, insulin is often the only treatment for patients with advanced renal disease. Pay close attention to insulin dosing in patients with advanced renal disease, which may necessitate lower doses and smaller dose adjustments due to this risk.

Social determinants of health. Medication access and cost is a major burden in T2D management and should be considered for every patient. Compared with the period of 2005 to 2007, the annual cost of diabetes medications for an individual in 2015 to 2017 increased by 147%, rising from $1106 to $2727 per year.⁶² This increase is driven by the cost of insulin and newer medications without generic options.⁶² Identify local resources in your community, such as patient assistance programs and pharmacies with reduced-price generic prescription programs, which may be useful for patients who are underinsured or uninsured.

Continue to: Even if cost weren't an issue...

 

Even if cost weren’t an issue, many ­medications such as insulin and GLP-1 receptor agonists should be kept refrigerated and are only stable at room temperature for a limited time. Medications that are stable at room temperature should be prioritized in patients with limited or inconsistent access to refrigeration or unstable housing who may find it difficult to store their medications ­appropriately.

Do not delay insulin initiation in patients with high baseline A1C

Whenever possible, a GLP-1 receptor agonist is the preferred injectable medication to insulin. Starting insulin introduces numerous risks, including hypoglycemia, weight gain, and stigma. However, in the patient with newly diagnosed T2D, choose basal insulin when the baseline hyperglycemia is severe,³⁴ as indicated by:

• blood glucose > 300 mg/dL (16.7 mmol/L),
• A1C > 10% (86 mmol/mol),
• symptoms of hyperglycemia (polyuria or polydipsia), or
• evidence of catabolism (weight loss, hypertriglyceridemia, ketosis).

Basal insulin analogs are preferred over NPH given their reduced variability, dosing, and hypoglycemic risk.³⁵ Mixed insulins may be used if a patient is unable to afford an insulin analog, which can be quite costly. However, extensive counseling on dosing and management of hypoglycemia is crucial to patient safety with these agents. The ADA ­recommends initiating 0.1 to 0.2 units/kg of basal insulin daily or 10 units daily.³⁴ The AACE follows this recommendation for ­patients with baseline A1C < 8%, but it proposes a more aggressive initiation of 0.2 to 0.3 units/kg/d for patients with baseline A1C > 8%.³⁵ Titrate the dose by 2 units every 3 days to reach the target fasting blood glucose level. As hyperglycemia resolves, simplify the regimen and transition to noninsulin options per the previously discussed considerations.

It’s not just about glycemic control

In addition to the direct effects of hyperglycemia, a T2D diagnosis introduces an increased risk for ASCVD, a reduced ability to fight infection, and heightened risk for depression. Order a lipid panel at the time of T2D diagnosis and initiate lipid management as needed (TABLE 3^35,63,64). Both the ADA and the American Heart Association recommend starting a moderate-intensity statin as primary prevention for all patients with T2D between 40 and 75 years of age regardless of the 10-year ASCVD risk.⁶³ The AACE uses specific lipid targets and recommends moderate- to high-intensity statin therapy for patients with T2D.³⁵ All recommendations by professional organizations list high-intensity statins for patients with established ASCVD.

Both the ADA and the AHA recommend starting a moderate-intensity statin as primary prevention for all patients with T2D between 40 and 75 years of age regardless of the 10-year ASCVD risk.

It is also vital to recommend that patients with newly diagnosed T2D remain up to date on all indicated vaccinations. They should promptly receive the hepatitis B and pneumococcal vaccines if they have not already done so for a previous indication. COVID-19 and annual influenza vaccines also should be prioritized for these patients.⁶⁵

Finally, patients with diabetes are twice as likely to develop depression than patients without diabetes.⁶⁶ Individuals with T2D and depression exhibit poorer medication adherence, lifestyle choices, and glycemic control.⁶⁶ Screen for and treat these issues in all patients with T2D across the course of the disease.

Overall, work closely with patients to support them in managing their new diagnosis with evidence-based pharmacologic and nonpharmacologic approaches. The importance of lifestyle changes including high-fiber diets, regular exercise, and weight loss should not be overlooked. Do not delay starting pharmacotherapy after diagnosing T2D and consider medication-specific and patient-specific factors to individualize therapy, improve adherence, and prevent complications.

CORRESPONDENCE
Jennie B. Jarrett, PharmD, MMedEd, 833 South Wood Street (MC 886), Chicago, IL 60612; [email protected]

Nearly 40 antihyperglycemic agents have been approved by the US Food and Drug Administration (FDA) since the approval of human insulin in 1982.¹ In addition, existing antihyperglycemic medications are constantly gaining FDA approval for new indications for common type 2 diabetes (T2D) comorbidities. For example, in addition to their glycemic benefits, the sodium-glucose cotransporter-2 (SGLT2) inhibitors have been approved for use in patients with T2D and established atherosclerotic cardiovascular disease (ASCVD) to reduce the risk for major adverse cardiovascular events (MACE; canagliflozin), risk for hospitalization for heart failure (dapagliflozin), and cardiovascular death (empagliflozin).^2-4

The plethora of new agents and new data for existing agents, coupled with the annual release of guidelines from the American Diabetes Association (ADA) and practice recommendations from several other professional organizations,^5-7 make it challenging for family physicians to stay current and provide the most up-to-date, evidence-based care. In this article, we provide advice on how to approach the screening, diagnosis, and evaluation of T2D, and on how to manage newly diagnosed T2D.

Screening, Dx, and evaluation: A quick review

Screening

Screening recommendations vary among professional organizations (TABLE 1^5,6,8). The US Preventive Services Task Force (USPSTF) recommends screening adults ages 35 to 70 years who are overweight or obese. Clinicians also can consider screening patients with a higher risk for diabetes.⁵ The ADA suggests screening all adults starting at 35 years, regardless of risk factors.⁸ Asymptomatic adults of any age with overweight or obesity and 1 or more risk factors should be screened.⁸ The American Association of Clinical Endocrinology (AACE) recommends screening adults of any age who have risk factors.⁶ If the screening result is normal, repeat testing in 3 years is appropriate, unless there is a change in symptoms or risks.^5,8 Annual testing can be considered in patients with ≥ 2 risk factors or with prediabetes (glycosylated hemoglobin [A1C] ≥ 5.7%).^6,8

Making the diagnosis

The initial diagnosis of diabetes can be made by a fasting plasma glucose level ≥ 126 mg/dL (7.0 mmol/L); a 2-hour plasma glucose level ≥ 200 mg/dL (11.0 mmol/L) following an oral glucose tolerance test; or an A1C level ≥ 6.5%. Prioritize lab-drawn A1C measurements over point-of-care tests to diagnose T2D. In ­patients with classic symptoms of hyper­glycemia, a random plasma glucose level ≥ 200 mg/dL (11.0 mmol/L) is also diagnostic. Generally, these tests are considered equally appropriate in screening for diabetes and may be used to detect prediabetes. In the absence of clear symptoms of hyperglycemia, the diagnosis of diabetes requires 2 abnormal screening test results, either via 1 blood sample (such as an abnormal A1C and glucose) or 2 separate blood samples of the same test. Further evaluation is advised if there is discordance between the 2 samples.⁸

Extended evaluations

Patients with newly diagnosed T2D require a thorough evaluation for comorbidities and complications of diabetes. Refer patients to an ophthalmologist for a dilated eye examination, with subsequent exams occurring every 1 to 2 years.^6,9 Additional referrals for diabetes education, family planning for women of reproductive age, and dental, social, or mental health services may be clinically appropriate.⁹

Setting goals for glycemic control

Glycemic control is commonly monitored by the A1C level and by blood glucose monitoring either through traditional point-of-care glucometers or continuous glucose monitors (CGMs).¹⁰ Generally, CGMs provide more glycemic data than traditional glucometers and may cue patients to choose healthier dietary options and engage in physical exercise.¹¹ Patients with T2D who use CGMs exhibit lower A1Cs, greater time in glycemic range, and reduced hypoglycemic episodes.¹¹ Generally, CGMs are reserved for patients with type 1 diabetes and patients with T2D who use multiple daily injections, subcutaneous insulin infusions, or basal insulin only.¹² Most professional organizations recommend that clinicians consider patient-specific factors to set individualized glycemic goals.^6,10,13,14 For example, more stringent glycemic goals could be pursued for patients with longer life expectancy, shorter disease duration, absence of complications (eg, nephropathy, neuropathy, or cardiovascular disease), fewer comorbid conditions, lower hypoglycemia risk, or higher cognitive function.⁶

With newer agents, more aggressive A1C goals can be targeted safely in select patients, particularly those with long life expectancy.

More specific A1C goals vary by professional organization. For nonpregnant adults, the ADA recommends an A1C goal of < 7% and a preprandial blood glucose level of 80 to 130 mg/dL (4.4-7.2 mmol/L).¹⁰ However, a lower A1C goal may be appropriate if it can be attained safely without causing hypoglycemia or other adverse effects.¹⁰ The AACE suggests an A1C goal of ≤ 6.5% and a fasting blood glucose level of < 110 mg/dL when it can be achieved safely.⁶ More stringent A1C goals may reduce long-term micro- and macrovascular complications—especially in patients with newly diagnosed T2D.¹⁰ While older studies such as the ACCORD trial found increased mortality in groups with more stringent glycemic targets, they did not include newer agents (SGLT2 inhibitors or glucagon-like peptide-1 [GLP-1] receptor agonists) that reduce cardiovascular events by mechanisms outside their glycemic-lowering effect. With these newer agents, more aggressive A1C goals can be targeted safely in select patients, particularly those with long life expectancy.¹⁰ Both the ADA and AACE recommend a less stringent A1C goal of 7% to 8% for patients with limited life expectancy or risks (eg, a history of hypoglycemia) that outweigh expected benefits.^6,10

Continue to: Lifestyle modifications

 

 

Lifestyle modifications: As important as medication

Nutrition

The energy-dense Western diet, combined with sedentary behavior, are thought to be a primary cause of T2D.¹⁵ Therefore, include lifestyle modifications in the initial management of newly diagnosed T2D. Diets that replace carbohydrates with saturated and trans fats are related to increased mortality in patients with T2D.¹⁶ Increased consumption of vegetables, fruits, legumes, nuts, fish, cereal, and oils reduces concentrations of saturated and trans fats and increases dietary intake of monounsaturated fatty acids, fiber, antioxidants, and polyphenols.¹⁷

Combined endurance and resistance training is superior for improving glycemic control, cardiorespiratory fitness, and body composition, compared with either type of training alone.

Increasing the intake of fiber, an undigestible carbohydrate, offers numerous benefits in T2D management. High-fiber diets can help regulate blood sugar and lipid levels, increase satiety, reduce inflammation, aid in weight management, and reduce premature mortality.¹⁸ Insoluble fiber, found in foods such as whole wheat flour, nuts, and cauliflower, helps food pass more quickly through the stomach and intestines and adds bulk to stool. Soluble fiber, found in foods such as chickpeas, lentils, and Brussels sprouts, absorbs water and forms a gel-like substance that protects nutrients from digestive enzymes and slows down digestion. The result is a more gradual rise in postprandial glucose levels and improved insulin sensitivity.¹⁹ Dietary fiber may produce short-chain fatty acids which in turn activate incretin secretion and stimulate a glucose-dependent release of insulin from the pancreas.²⁰

Simple dietary substitutions, such as whole grains and legumes for white rice, can reduce fasting blood glucose and A1C levels.²¹ In a randomized controlled trial (RCT), increasing whole grain oat intake improved measures of glycemic control, reducing A1C by 1% at 1-year follow-up.¹⁹ Encourage patients with T2D to increase consumption of high-fiber foods and replace animal fats and refined grains with vegetable fats (eg, nuts, avocados, olives).
Nutritional therapies should be individualized, taking into account personal preferences and cultural customs.²² Nutritional habits may be based on race/ethnicity, ­religion/spirituality, or even the city in which an individual resides. Nutrition recommendations should account for these differences as well as access to healthy foods. For instance, ethnic groups whose dietary patterns include tortillas could be counseled to choose high-fiber options such as corn instead of flour tortillas and to incorporate vegetables in place of high-fat foods. Additionally, ethnic groups who favor using animal fats in foods such as greens could be advised on ways to add flavor to vegetables without adding saturated fats. Taking this approach may lessen barriers to change and increase ability to make dietary modifications.²³

Exercise

Encourage all patients with T2D to exercise regularly. The atherosclerotic plaques found in patients with T2D have increased inflammatory properties and result in worse cardiovascular outcomes compared with plaques in individuals without T2D.²⁴ Regular exercise reduces levels of pro-inflammatory markers—C-reactive protein, interleukin (IL)-6, and tumor necrosis factor alpha—and increases levels of anti-­inflammatory markers (IL-4 and IL-10).²⁴ Regular exercise can improve body composition, physical fitness, lipid and glucose metabolism, and insulin sensitivity.^25,26

A meta-analysis of RCTs demonstrated that structured exercise > 150 minutes per week resulted in A1C reductions of 0.89%,²⁷ which is comparable to the effect of many oral antihyperglycemic medications.²⁶ The Health Benefits of Aerobic and Resistance Training in individuals with T2D (HART-D) and Diabetes Aerobic and Resistance Exercise (DARE) studies demonstrated that combining endurance and resistance training was superior for improving glycemic control, cardiorespiratory fitness, and body composition, than using either type of training alone.²⁵ Both the American College of Sports Medicine (ACSM) and the ADA recommend that adults engage in at least 150 total minutes of moderate-intensity aerobic activity per week and resistance training 2 to 3 times weekly.²⁶ ACSM defines moderate-intensity exercise as 65% to 75% of maximal heart rate, a rating of perceived exertion of 3 to 4, or a step rate of 100 steps per minute.²⁸

Continue to: Because of their longitudinal relationships...

 

Because of their longitudinal relationships with patients, family physicians are in an optimal position to assess a patient’s physical capacity level and provide individualized counseling. Several systematic reviews have demonstrated that counseling on exercise increases patients’ participation in physical activity.²⁹ Encourage your patients with T2D to exercise regularly, considering each individual’s ability to engage in physical activity.

Weight loss

Include weight management in the initial treatment of patients with newly diagnosed T2D. Weight loss decreases hepatic glucose production and increases peripheral insulin sensitivity and insulin secretion.³⁰ Moderate decreases in weight (5%-10%) can reduce complications related to diabetes, and sustained significant weight loss (> 10%) can potentially cause T2D remission (A1C < 6.5% after stopping diabetes medications).^31,32

Several systematic reviews have demonstrated that counseling on exercise increases patients’ participation in physical activity.

Diabetes self-management education supports patients by giving them tools for making and maintaining lifestyle changes. Understanding individual barriers to change and addressing these during motivational interviews is important. Through a qualitative interview study, participants in a diabetes self-management program revealed 4 factors that motivated them to maintain lifestyle changes: support from others, experiencing the impact of the changes they made, fear of T2D complications, and forming new habits.³³ Family physicians are key in helping patients acquire knowledge and support to make the lifestyle modifications needed to manage newly diagnosed T2D.

Individualized pharmacotherapy considerations

For decades, the initial pharmacotherapeutic regimen for patients with newly diagnosed T2D considered the patient’s baseline A1C as a major driver for therapy. Metformin has been the mainstay in T2D treatment due to its clinical efficacy, minimal risk for hypoglycemia, and low cost. Regardless of the regimen, pharmacotherapy should be initiated at the time of T2D diagnosis in conjunction with the aforementioned lifestyle modifications.³⁴

When selecting pharmacotherapy, practice guidelines recommend considering the efficacy and adverse effects of medications, patient-specific comorbidities, adherence, cost, and a patient’s lifestyle factors.³⁴ Drug classes with pertinent information are listed in TABLE 2.^34-54 After starting medication, monitor the A1C level every 3 months to determine whether therapy should be intensified. Patients should have their labs drawn ahead of the quarterly visit, or point-of-care measurements may be used to facilitate in-person patient–provider discussions.

Continue to: Consider patient-specific factors when starting pharmacotherapy

 

Consider patient-specific factors when starting pharmacotherapy

ASCVD. Regardless of baseline glycemic control, offer patients who have ASCVD, or who are at high risk for it, an SGLT2 inhibitor (canagliflozin, dapagliflozin, or empagliflozin) or a long-acting GLP-1 receptor agonist (dulaglutide, liraglutide, or semaglutide).^34,35 SGLT2 inhibitors reduced the risk for MACE by 11% in patients with established ASCVD.⁵⁵ They also reduced a composite outcome of cardiovascular death or hospitalization for heart failure by 23% in patients with or without ASCVD or heart failure at baseline.⁵⁵ GLP-1 receptor agonists offer a similar reduction in MACE to SGLT2 inhibitors, but they do not have significant effects in heart failure.⁵⁶ Thiazolidinediones (TZDs), saxagliptin, and alogliptin should be avoided in patients with heart failure.⁵⁷ TZDs may reduce the risk for recurrent stroke in patients with T2D.⁵⁸

Chronic kidney disease (CKD). As with ASCVD, prioritize SGLT2 inhibitors and ­GLP-1 receptor agonists in patients with CKD. While both classes reduced the risk for progression of kidney disease such as macroalbuminuria, SGLT2 inhibitors offer additional benefits in their reduction of the worsening of estimated glomerular filtration rate, end-stage kidney disease, and renal death.⁵⁶

Obesity. Consider the effect of each drug class on weight when making initial treatment choices, taking special care to minimize weight gain and potentially promote weight loss.³⁴ The ADA prefers GLP-1 receptor agonists, but also suggests SGLT2 inhibitors in these patients. While all GLP-1 receptor agonists have an impact on weight, weekly subcutaneous semaglutide offers the most pronounced weight loss of 2 to 7 kg over 56 weeks.⁵⁹ SGLT2 inhibitors promote sustainable weight loss to a lesser degree, contributing to an average loss of 3 kg at 2 years.⁶⁰ Weight gain is common in patients taking sulfonylureas (2.01-2.3 kg)³¹ and insulin (3-9 kg weight gain in the first year)⁶¹ and should be avoided in patients with T2D and obesity.³⁴

Hypoglycemia risk. In addition to counseling patients on hypoglycemia management and prescribing glucagon rescue kits, offer medications with no or very low risk for hypoglycemia (eg, GLP-1 receptor agonists, SGLT2 inhibitors, dipeptidyl ­peptidase-4 inhibitors, and TZDs). Generally, avoid insulin and sulfonylureas in patients in whom hypoglycemia is a major concern (eg, older adults, individuals with labile blood glucose levels).³⁴ Patients with reduced renal function are at higher risk for hypoglycemia with insulin or sulfonylureas due to reduced drug clearance. However, insulin is often the only treatment for patients with advanced renal disease. Pay close attention to insulin dosing in patients with advanced renal disease, which may necessitate lower doses and smaller dose adjustments due to this risk.

Social determinants of health. Medication access and cost is a major burden in T2D management and should be considered for every patient. Compared with the period of 2005 to 2007, the annual cost of diabetes medications for an individual in 2015 to 2017 increased by 147%, rising from $1106 to $2727 per year.⁶² This increase is driven by the cost of insulin and newer medications without generic options.⁶² Identify local resources in your community, such as patient assistance programs and pharmacies with reduced-price generic prescription programs, which may be useful for patients who are underinsured or uninsured.

Continue to: Even if cost weren't an issue...

 

Even if cost weren’t an issue, many ­medications such as insulin and GLP-1 receptor agonists should be kept refrigerated and are only stable at room temperature for a limited time. Medications that are stable at room temperature should be prioritized in patients with limited or inconsistent access to refrigeration or unstable housing who may find it difficult to store their medications ­appropriately.

Do not delay insulin initiation in patients with high baseline A1C

Whenever possible, a GLP-1 receptor agonist is the preferred injectable medication to insulin. Starting insulin introduces numerous risks, including hypoglycemia, weight gain, and stigma. However, in the patient with newly diagnosed T2D, choose basal insulin when the baseline hyperglycemia is severe,³⁴ as indicated by:

• blood glucose > 300 mg/dL (16.7 mmol/L),
• A1C > 10% (86 mmol/mol),
• symptoms of hyperglycemia (polyuria or polydipsia), or
• evidence of catabolism (weight loss, hypertriglyceridemia, ketosis).

Basal insulin analogs are preferred over NPH given their reduced variability, dosing, and hypoglycemic risk.³⁵ Mixed insulins may be used if a patient is unable to afford an insulin analog, which can be quite costly. However, extensive counseling on dosing and management of hypoglycemia is crucial to patient safety with these agents. The ADA ­recommends initiating 0.1 to 0.2 units/kg of basal insulin daily or 10 units daily.³⁴ The AACE follows this recommendation for ­patients with baseline A1C < 8%, but it proposes a more aggressive initiation of 0.2 to 0.3 units/kg/d for patients with baseline A1C > 8%.³⁵ Titrate the dose by 2 units every 3 days to reach the target fasting blood glucose level. As hyperglycemia resolves, simplify the regimen and transition to noninsulin options per the previously discussed considerations.

It’s not just about glycemic control

In addition to the direct effects of hyperglycemia, a T2D diagnosis introduces an increased risk for ASCVD, a reduced ability to fight infection, and heightened risk for depression. Order a lipid panel at the time of T2D diagnosis and initiate lipid management as needed (TABLE 3^35,63,64). Both the ADA and the American Heart Association recommend starting a moderate-intensity statin as primary prevention for all patients with T2D between 40 and 75 years of age regardless of the 10-year ASCVD risk.⁶³ The AACE uses specific lipid targets and recommends moderate- to high-intensity statin therapy for patients with T2D.³⁵ All recommendations by professional organizations list high-intensity statins for patients with established ASCVD.

Both the ADA and the AHA recommend starting a moderate-intensity statin as primary prevention for all patients with T2D between 40 and 75 years of age regardless of the 10-year ASCVD risk.

It is also vital to recommend that patients with newly diagnosed T2D remain up to date on all indicated vaccinations. They should promptly receive the hepatitis B and pneumococcal vaccines if they have not already done so for a previous indication. COVID-19 and annual influenza vaccines also should be prioritized for these patients.⁶⁵

Finally, patients with diabetes are twice as likely to develop depression than patients without diabetes.⁶⁶ Individuals with T2D and depression exhibit poorer medication adherence, lifestyle choices, and glycemic control.⁶⁶ Screen for and treat these issues in all patients with T2D across the course of the disease.

Overall, work closely with patients to support them in managing their new diagnosis with evidence-based pharmacologic and nonpharmacologic approaches. The importance of lifestyle changes including high-fiber diets, regular exercise, and weight loss should not be overlooked. Do not delay starting pharmacotherapy after diagnosing T2D and consider medication-specific and patient-specific factors to individualize therapy, improve adherence, and prevent complications.

CORRESPONDENCE
Jennie B. Jarrett, PharmD, MMedEd, 833 South Wood Street (MC 886), Chicago, IL 60612; [email protected]

Platelet-rich plasma (PRP) injections have become a popular treatment option in a variety of specialties including sports medicine, maxillofacial surgery, dermatology, cosmetology, and reproductive medicine.¹ PRP is an autologous blood product derived from whole blood, using a centrifuge to isolate a concentrated layer of platelets. The ­a-granules in platelets release transforming growth factor b 1, vascular endothelial growth factor, platelet-derived growth factor, basic fibroblast growth factor, epidermal growth factor, insulin-like growth factor 1, and other mediators that enhance the natural healing process.²

When patients ask. Familiarity with the use of PRP to treat specific musculoskeletal (MSK) conditions is essential for family physicians who frequently are asked by patients about whether PRP is right for them. These patients may have experienced failure of medication therapy or declined surgical intervention, or may not be surgical candidates. This review details the evidence surrounding common intra-articular and extra-articular applications of PRP. But first, a word about how PRP is prepared, its contraindications, and costs.

Preparation and types of PRP

Although there are many commercial systems for preparing PRP, there is no consensus on the optimal formulation.² Other terms for PRP, such as autologous concentrated platelets and super-concentrated platelets, are based on concentration of red blood cells, leukocytes, and fibrin.³ PRP therapies usually are categorized as leukocyte-rich PRP (LR-PRP) or leukocyte-poor PRP (LP-PRP), based on neutrophil concentrations that are above and below baseline.² Leukocyte concentration is one of the most debated topics in PRP therapy.⁴

Common commercially available preparation systems produce platelet concentrations between 3 to 6 times the baseline platelet count.⁵ Although there is no universally agreed upon PRP formulation, studies have shown 2 centrifugation cycles (“double-spun” or “dual centrifugation”) that yield platelet concentrations between 1.8 to 1.9 times the baseline values significantly improve MSK conditions.^6-8

Familiarity with the use of platelet-rich plasma to treat specific musculoskeletal conditions is essential for FPs who frequently are asked by patients about whether it is right for them.

For MSK purposes, PRP may be injected into intratendinous, peritendinous, and intra-articular spaces. Currently, there is no consensus regarding injection frequency. Many studies have incorporated single-­injection protocols, while some have used 2 to 3 injections repeated over several weeks to months. PRP commonly is injected at point-of-care without requiring storage.

Contraindications. PRP has been shown to be safe, with most adverse effects attributed to local injection site pain, bleeding, swelling, and bruising.⁹

Contraindications to PRP include active malignancy or recent remission from malignancy with the exception of nonmetastatic skin tumors.¹⁰ PRP is not recommended for patients with an allergy to manufacturing components (eg, dimethyl sulfoxide), thrombocytopenia, nonsteroidal anti-­inflammatory drug use within 2 weeks, active infection causing fever, and local infection at the injection site.¹⁰ Since local anesthetics may impair platelet function, they should not be given at the same injection site as PRP.¹⁰

Continue to: Cost

 

Cost. PRP is not covered by most insurance plans.^11,12 The cost for PRP may range from $500 to $2500 for a single injection.¹²

Evidence-based summary by condition

Knee osteoarthritis

❯❯❯ Consider using PRP

Knee osteoarthritis (OA) is a common cause of pain and disability. Treatment options include physical therapy, pharmacotherapy, and surgery. PRP has gained popularity as a nonsurgical option. A recent meta-analysis by Costa et al¹³ of 40 studies with 3035 participants comparing intra-articular PRP with hyaluronic acid (HA), corticosteroid, and saline injections, found that PRP appears to be more effective or as effective as other nonsurgical modalities. However, due to study heterogeneity and high risk for bias, the authors could not recommend PRP for knee OA in clinical practice.¹³

Despite Costa et al’s findings, reproducible data have demonstrated the superiority of PRP over other nonsurgical treatment options for knee OA. A 2021 systematic review and meta-analysis of 18 randomized controlled trials (RCTs; N = 811) by Belk et al⁶ comparing PRP to HA injections showed a higher mean improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores in the PRP group compared to the HA group (44.7% vs 12.6%, respectively; P < .01).⁶ Six of 11 studies using the visual analog scale (VAS) for pain reported significantly less pain in the PRP group compared to the HA group (P < .05).⁶ The mean follow-up time was 11.1 months.⁶ Three of 6 studies reported improved subjective International Knee Documentation Committee (IKDC) scores (range from 0-100, with higher scores representing higher levels of function and lower levels of symptoms) in the PRP group compared to the HA group: 75.7 ± 15.1 vs 65.6 ± 16.9 (P = .004); 65.5 ± 3.6 vs 55.8 ± 3.8 (P = .01); and 60.8 ± 9.8 vs 48.4 ± 6.2 (P < .05).⁶ There was concern for moderate-to-high heterogeneity.⁶

PRP has been shown to be safe, with most adverse effects attributed to local injectionsite pain, bleeding, swelling, and bruising.

Other systematic reviews and meta-­analyses found similar efficacy of PRP for knee OA, including improved WOMAC scores and patient-reported outcomes (eg, pain, physical function, stiffness) compared to other injectable options.^14,15 A systematic review of 14 RCTs (N = 1423) by Shen et al¹⁵ showed improved WOMAC scores at 3 months (mean differences [MD] = –14.53; 95% CI, –29.97 to –7.09; P < .001), 6 months (MD = –18.21; 95% CI, –27.84 to –8.95; P < .001), and 12 months (MD = –19.45; 95% CI, –26.90 to –12.82; P < .001) in favor of PRP vs controls (saline placebo, ozone, corticosteroids, HA).¹⁵

Despite a lack of consensus regarding the optimal preparation of PRP for knee OA, another recent RCT (N = 192) found significant improvement in mean subjective IKDC scores in the LR-PRP group (45.5 ± 15.5 to 60.7 ± 21.1; P < .0005) and the LP-PRP group (46.8 ± 15.8 to 62.9 ± 19.9; P < .0005), indicating efficacy regardless of PRP type.⁴

Continue to: Ankle osteoarthritis

 

 

Ankle osteoarthritis

❯ ❯ ❯   Additional research is needed

Ankle OA affects 3.4% of all adults and is more common in the younger population than knee or hip OA.¹⁶ An RCT (N = 100) investigating PRP vs placebo (saline) injections showed no statistically significant difference in American Orthopedic Foot and Ankle Society scores evaluating pain and function over 26 weeks (–2 points; 95% CI, –5 to 1; P = .16).¹⁶ Limitations to this study include its small sample size and the PRP formulation used. (The intervention group received 2 injections of 2 mL of PRP, and the platelet concentration was not reported.)¹⁶

A 2020 systematic review and meta-­analysis of 4 RCTs and 5 case series by Evans et al¹⁷ concluded that PRP improves pain and function in small-joint OA compared to controls of saline, corticosteroids, and HA.¹⁷ One of the case series (N = 20) included in the study demonstrated improvement in ankle OA pain and function scores at 24 weeks posttreatment (P = .04), although improvement in pain and function peaked at 12 weeks.¹⁷ In addition, a 2017 retrospective study (N = 20) from the review reported improved VAS scores and function at 17 months following 4 injections of PRP over 4 weeks (P < .001).¹⁷ Given that RCT data found no benefit with PRP in treating small-joint OA, additional research is indicated.

Hip osteoarthritis

❯ ❯ ❯   Additional research is needed

Symptomatic hip OA occurs in 40% of adults older than 65 years, with a higher prevalence in women.¹⁸ Currently, corticosteroid injections are the only intra-articular therapy recommended by international guidelines for hip OA.¹⁹ A systematic review and meta-analysis comparing PRP to HA injections that included 4 RCTs (N = 303) showed a statistically significant reduction in VAS scores at 2 months in the PRP group compared to the HA group (weighted mean difference [WMD] = –0.376; 95% CI, –0.614 to –0.138; P = .002).¹⁸ However, there were no significant differences in VAS scores between the PRP and HA groups at 6 months (WMD = –0.141; 95% CI, –0.401 to 0.119; P = .289) and 12 months (WMD = –0.083; 95% CI, –0.343 to 0.117; P = .534). Likewise, no significant differences were found in WOMAC scores at 6 months (WMD = –2.841; 95% CI, –6.248 to 0.565; P = .102) and 12 months (WMD = –3.134; 95% CI, –6.624 to 0.356; P = .078) and Harris Hip Scores (HHS) at 6 months (WMD = 2.782; 95% CI, –6.639 to 12.203; P =.563) and 12 months (WMD = 0.706; 95% CI, –6.333 to 7.745; P = .844).¹⁸

A systematic review of 6 RCTs (N = 408) by Belk et al²⁰ comparing PRP to HA for hip OA found similar short-term improvements in WOMAC scores (standardized mean differences [SMD] = 0.27; 95% CI, –0.05 to 0.59; P = .09), VAS scores (MD = 0.59; 95% CI, –0.741 to 1.92; P = .39), and HHS (MD = -0.81; 95% CI, –10.06 to 8.43; P = .93). The average follow-up time was 12.2 and 11.9 months for the PRP and HA groups, respectively.²⁰

LR-PRP, which was used in 1 of the 6 RCTs, showed improvement in VAS scores and HHS from baseline, but no significant difference compared to HA at the latest follow-­up.²⁰ A pooled subanalysis of the 3 studies that used LP-PRP found no difference in WOMAC scores between the PRP and HA groups (SMD = 0.42; 95% CI, –0.01 to 0.86; P = .06).²⁰ Future studies comparing the efficacy of intra-articular steroid vs PRP for hip OA would be beneficial.¹⁸

Continue to: Rotator cuff tendinopathy

 

Rotator cuff tendinopathy

❯ ❯ ❯   Consider PRP for short-term pain relief

Painful conditions of the rotator cuff include impingement syndrome, tendonitis, and partial and complete tears. A 2021 RCT (N = 58) by Dadgostar et al²¹ comparing PRP injection to corticosteroid therapy (methylprednisolone and lidocaine) for the treatment of rotator cuff tendinopathy showed significant improvement in VAS scores at 3 months in the PRP group compared to the corticosteroid group (6.66 ± 2.26 to 3.08 ± 2.14 vs 5.53 ± 1.80 to 3.88 ± 1.99, respectively; P = .023). There also were more significant improvements in adduction in the PRP group compared to the corticosteroid group (20.50° ± 8.23° to 28° ± 3.61° vs 23.21° ± 7.09° to 28.46° ± 4.18°, respectively; P = .011), and external rotation (59.66° ± 23.81° to 76.66° ± 18.30° vs 57.14°± 24.69° to 65.57° ± 26.39° for the PRP and corticosteroid groups, respectively; P = .036).²¹

Another RCT (N = 99) by Kwong et al²² comparing PRP to corticosteroids found similar short-term advantages of LP-PRP with an improved VAS score (–13.6 vs 0.4; P = .03), American Shoulder and Elbow Surgeons score (13.0 vs 2.9; P = .02), and Western Ontario Rotator Cuff Index score (16.8 vs 5.8; P = .03). However, there was no long-term benefit of PRP over corticosteroids found at 12 months.²²

A 2021 systematic review and meta-­analysis by Hamid et al²³ that included 8 RCTs (N = 976) favored PRP over control (no injection, saline injections, and/or shoulder rehabilitation) with improved VAS scores at 12 months (SMD = –0.5; 95% CI, –0.7 to –0.2; P < .001). The evidence on functional outcome was mixed. Data pooled from 2 studies (n = 228) found better Shoulder Pain and Disability Index (SPADI) scores compared to controls at 3- and 6-month follow-ups. However, there were no significant differences in Disabilities of the Arm, Shoulder and Hand (DASH) scores between the 2 groups.²³

Patellar tendinopathy

❯ ❯ ❯   Consider using PRP for return to sport

Patellar tendinopathy, a common MSK condition encountered in the primary care setting, has an overall prevalence of 22% in elite athletes at some point in their career.^{24 ­}Nonsurgical management options include rest, ice, eccentric and isometric exercises, anti-­inflammatory drugs, extracorporeal shock wave therapy (ESWT), and dry needling (DN).

Currently, corticosteroid injections are the only intraarticular therapy recommended by international guidelines for hip OA.

A 2014 RCT (N = 23) evaluating DN vs PRP for patellar tendinopathy favored PRP with improved VAS scores (mean ± SD = 25.4 ± 23.2 points; P = .01 vs 5.2 ± 12.5 points; P = .20) at 12 weeks (P = .02). However, at ≥ 26 weeks, the improvement in pain and function scores was similar between the DN and PRP groups (33.2 ± 14.0 points; P = .001 vs 28.9 ± 25.2 points; P = .01). Notably, there was significantly more improvement in the PRP group at 12 weeks (P = .02) but not at 26 weeks (P = .66).²⁵

Continue to: Another perspective study...

 

Another prospective study (N = 31) comparing PRP to physiotherapy showed a greater improvement in sport activity level reflected by the Tegner score in the PRP group (percentage improvement, 39 ± 22%) compared to control (20 ± 27%; P = .048) at 6 months.⁷

A recent RCT (N = 20) revealed improved VAS scores at 6 months with rehabilitation paired with either bone marrow mesenchymal stem cells (BM-MSC) or LP-PRP when compared with baseline (BM-MSC group: 4.23 ± 2.13 to 2.52 ± 2.37; P = .0621; LP-PRP group: 3.10 ± 1.20 to 1.13 ± 1.25; P = .0083). Pain was significantly reduced during sport play in both groups at 6 months when compared with baseline (BM-MSC group: 6.91 ± 1.11 to 3.06 ± 2.89, P = .0049; PRP group: 7.03 ± 1.42 to 1.94 ± 1.24, P = .0001).²⁶

A 2019 systematic review and meta-analysis (N = 2530) demonstrated greater improvements in Victorian Institute of Sport Assessment scale for patellar tendinopathy (VISA-P) with multiple injections of PRP (38.7 points; 95% CI, 26.3-51.2 points) compared to single injections of PRP (24.3 points; 95% CI, 18.2-30.5 points), eccentric exercise (28.3 points; 95% CI, 18.9-37.8 points) and ESWT (27.4 points; 95% CI, 10.0-39.8 points) after 6 months.²⁷ In contrast, an RCT (n = 57) comparing a single injection of LR-PRP or LP-PRP was no more effective than a single injection of saline for improvement in mean VISA-P scores (P > .05) at 1 year.²⁸

Lateral epicondylitis

❯ ❯ ❯   Consider using PRP

Lateral epicondylitis (“tennis elbow”) is caused by overuse of the elbow extensors at the site of the lateral epicondyle. Chronic lateral epicondylosis involves tissue degeneration and microtrauma. Most cases of epicondylar tendinopathies are treated nonoperatively, with corticosteroid injections being a mainstay of treatment despite their short-term benefit²⁹ and potential to deteriorate connective tissue over time. Recent studies suggest PRP therapy for epicondylitis and epicondylosis may increase long-term pain relief and improve function.

The evidence on functional outcome of platelet-rich plasma for rotator cuff tendinopathy is mixed.

A 2017 systematic review and meta-­analysis of 16 RCTs (N = 1018) concluded PRP was more efficacious than control injections (bupivacaine) for pain reduction in tendinopathies (effect size = 0.47; 95% CI, 0.22-0.72).³⁰ In the review, lateral epicondylitis was evaluated in 12 studies and was most responsive to PRP (effect size = 0.57) when compared to control injection.³⁰ In another systematic review (5 RCTs; 250 patients), corticosteroid injections improved pain within the first 6 weeks of treatment. However, PRP outperformed corticosteroid in VAS scores (21.3 ± 28.1 vs 42.4 ± 26.8) and DASH scores (17.6 ± 24.0 vs 36.5 ± 23.8) (P < .001) at 2 years.³¹

Continue to: A 2022 systematic review...

 

A 2022 systematic review and meta-­analysis (26 studies; N = 1040) comparing scores at baseline vs 2 years post-PRP showed improvement in VAS scores (7.4 ± 1.30 vs 3.71 ± 2.35; P < .001), DASH scores (60.8 ± 12.5 vs 13.0 ± 18.5; P < .001), Patient-Rated Tennis Elbow Evaluation (55.6 ± 14.7 vs 48.8 ± 4.1; P < .001), and Mayo Clinic Performance Index (55.5 ± 6.1 vs 93.0 ± 6.7; P < .001).³²

Regarding the therapeutic effects of different PRP types in lateral epicondylitis, a 2022 systematic review of 33 studies (N = 2420) found improved function and pain relief with LR-PRP and LP-PRP with no significant differences.³³ Pretreatment VAS scores in the LR-PRP group, which ranged from 6.1 to 8.0, improved to 1.5 to 4.0 at 3 months and 0.6 to 3.3 after 1 year.³³ Similarly, pretreatment VAS scores in the LP-PRP group, which ranged from 4.2 to 8.4, improved to 1.6 to 5.9 at 3 months and 0.7 to 2.7 after 1 year.³⁴ DASH scores also improved in the LR-PRP and LP-PRP groups, with pretreatment scores (LR-PRP, 47.0 to 54.3; LP-PRP, 30.0 to 67.7) improving to 20.0 to 22.0 and 5.5 to 19.0, respectively, at 1 year.³³

Achilles tendinopathy

❯ ❯ ❯   Do not use PRP; evidence is lacking

Achilles tendinopathy, caused by chronic overuse and overload resulting in microtrauma and poor tissue healing, typically occurs in the most poorly vascularized portion of the tendon and is common in runners. First-line treatments for Achilles tendinopathy include eccentric strength training and anti-­inflammatory drugs.^34,35 Corticosteroid injections are not recommended, given concern for degraded tendon tissue over time and worse function.³⁴

A 2020 systematic review of 11 randomized and nonrandomized clinical trials (N = 406) found PRP improved Victorian Institute of Sports Assessment—Achilles (VISA-A) scores at 24 weeks compared to other nonsurgical treatment options (41.2 vs 70.12; P < .018).³⁴ However, a higher-quality 2021 systematic review and meta-analysis of 4 RCTs (N = 170) comparing PRP injections with placebo showed no significant difference in VISA-A scores at 3 months (0.23; 95% CI, –0.45 to 0.91), 6 months (0.83; 95% CI, –0.26 to 1.92), and 12 months (0.83; 95% CI, –0.77 to 2.44).³⁶ Therefore, further studies are warranted to evaluate the benefit of PRP injections for Achilles tendinopathy.

Conclusions

While high-quality studies support the use of PRP for knee OA and lateral epicondylitis, they have a moderate-to-high risk for bias. Several RCTs show that PRP provides superior short-term pain relief and range of motion compared to corticosteroids for rotator cuff tendinopathy. Multiple injections of PRP for patellar tendinopathy may accelerate return to sport and improve symptoms over the long term. However, current evidence does not support PRP therapy for Achilles tendinopathy. Given variability in PRP preparation, an accurate interpretation of the literature regarding its use in MSK conditions is recommended (TABLE^{4,6,7,14-18,20-23,25-28,30-34,36}).

Continue to: Concerning the effectiveness of PRP...

 

Concerning the effectiveness of PRP, it is important to consider early publication bias. Although recent studies have shown its benefits,^6,14,15,37 additional studies comparing PRP to placebo will help demonstrate its efficacy. Interestingly, a literature search by Bar-Or et al³⁸ found intra-articular saline may have a therapeutic effect on knee OA and confound findings when used as a placebo.

RCT data showed no benefit with platelet-rich plasma in treating small-joint osteoarthritis.

Recognizing the presence or lack of clinically significant improvement in the literature is important. For example, while some recent studies have shown PRP exceeds the minimal clinically significant difference for knee OA and lateral epicondylitis, others have not.^32,37 A 2021 systematic review of 11 clinical practice guidelines for the use of PRP in knee OA found that 9 were “uncertain or unable to make a recommendation” and 2 recommended against it.³⁹

In its 2021 position statement for the responsible use of regenerative medicine, the American Medical Society for Sports Medicine includes guidance on integrating orthobiologics into clinical practice. The guideline emphasizes informed consent and provides an evidence-based rationale for using PRP in certain patient populations (lateral epicondylitis and younger patients with mild-to-­moderate knee OA), recommending its use only after exhausting other conservative options.⁴⁰ Patients should be referred to physicians with experience using PRP and image-guided procedures.

CORRESPONDENCE
Gregory D. Bentz Jr, MD, 3640 High Street Suite 3B, Portsmouth, VA 23707; [email protected]

Platelet-rich plasma (PRP) injections have become a popular treatment option in a variety of specialties including sports medicine, maxillofacial surgery, dermatology, cosmetology, and reproductive medicine.¹ PRP is an autologous blood product derived from whole blood, using a centrifuge to isolate a concentrated layer of platelets. The ­a-granules in platelets release transforming growth factor b 1, vascular endothelial growth factor, platelet-derived growth factor, basic fibroblast growth factor, epidermal growth factor, insulin-like growth factor 1, and other mediators that enhance the natural healing process.²

When patients ask. Familiarity with the use of PRP to treat specific musculoskeletal (MSK) conditions is essential for family physicians who frequently are asked by patients about whether PRP is right for them. These patients may have experienced failure of medication therapy or declined surgical intervention, or may not be surgical candidates. This review details the evidence surrounding common intra-articular and extra-articular applications of PRP. But first, a word about how PRP is prepared, its contraindications, and costs.

Preparation and types of PRP

Although there are many commercial systems for preparing PRP, there is no consensus on the optimal formulation.² Other terms for PRP, such as autologous concentrated platelets and super-concentrated platelets, are based on concentration of red blood cells, leukocytes, and fibrin.³ PRP therapies usually are categorized as leukocyte-rich PRP (LR-PRP) or leukocyte-poor PRP (LP-PRP), based on neutrophil concentrations that are above and below baseline.² Leukocyte concentration is one of the most debated topics in PRP therapy.⁴

Common commercially available preparation systems produce platelet concentrations between 3 to 6 times the baseline platelet count.⁵ Although there is no universally agreed upon PRP formulation, studies have shown 2 centrifugation cycles (“double-spun” or “dual centrifugation”) that yield platelet concentrations between 1.8 to 1.9 times the baseline values significantly improve MSK conditions.^6-8

Familiarity with the use of platelet-rich plasma to treat specific musculoskeletal conditions is essential for FPs who frequently are asked by patients about whether it is right for them.

For MSK purposes, PRP may be injected into intratendinous, peritendinous, and intra-articular spaces. Currently, there is no consensus regarding injection frequency. Many studies have incorporated single-­injection protocols, while some have used 2 to 3 injections repeated over several weeks to months. PRP commonly is injected at point-of-care without requiring storage.

Contraindications. PRP has been shown to be safe, with most adverse effects attributed to local injection site pain, bleeding, swelling, and bruising.⁹

Contraindications to PRP include active malignancy or recent remission from malignancy with the exception of nonmetastatic skin tumors.¹⁰ PRP is not recommended for patients with an allergy to manufacturing components (eg, dimethyl sulfoxide), thrombocytopenia, nonsteroidal anti-­inflammatory drug use within 2 weeks, active infection causing fever, and local infection at the injection site.¹⁰ Since local anesthetics may impair platelet function, they should not be given at the same injection site as PRP.¹⁰

Continue to: Cost

 

Cost. PRP is not covered by most insurance plans.^11,12 The cost for PRP may range from $500 to $2500 for a single injection.¹²

Evidence-based summary by condition

Knee osteoarthritis

❯❯❯ Consider using PRP

Knee osteoarthritis (OA) is a common cause of pain and disability. Treatment options include physical therapy, pharmacotherapy, and surgery. PRP has gained popularity as a nonsurgical option. A recent meta-analysis by Costa et al¹³ of 40 studies with 3035 participants comparing intra-articular PRP with hyaluronic acid (HA), corticosteroid, and saline injections, found that PRP appears to be more effective or as effective as other nonsurgical modalities. However, due to study heterogeneity and high risk for bias, the authors could not recommend PRP for knee OA in clinical practice.¹³

Despite Costa et al’s findings, reproducible data have demonstrated the superiority of PRP over other nonsurgical treatment options for knee OA. A 2021 systematic review and meta-analysis of 18 randomized controlled trials (RCTs; N = 811) by Belk et al⁶ comparing PRP to HA injections showed a higher mean improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores in the PRP group compared to the HA group (44.7% vs 12.6%, respectively; P < .01).⁶ Six of 11 studies using the visual analog scale (VAS) for pain reported significantly less pain in the PRP group compared to the HA group (P < .05).⁶ The mean follow-up time was 11.1 months.⁶ Three of 6 studies reported improved subjective International Knee Documentation Committee (IKDC) scores (range from 0-100, with higher scores representing higher levels of function and lower levels of symptoms) in the PRP group compared to the HA group: 75.7 ± 15.1 vs 65.6 ± 16.9 (P = .004); 65.5 ± 3.6 vs 55.8 ± 3.8 (P = .01); and 60.8 ± 9.8 vs 48.4 ± 6.2 (P < .05).⁶ There was concern for moderate-to-high heterogeneity.⁶

PRP has been shown to be safe, with most adverse effects attributed to local injectionsite pain, bleeding, swelling, and bruising.

Other systematic reviews and meta-­analyses found similar efficacy of PRP for knee OA, including improved WOMAC scores and patient-reported outcomes (eg, pain, physical function, stiffness) compared to other injectable options.^14,15 A systematic review of 14 RCTs (N = 1423) by Shen et al¹⁵ showed improved WOMAC scores at 3 months (mean differences [MD] = –14.53; 95% CI, –29.97 to –7.09; P < .001), 6 months (MD = –18.21; 95% CI, –27.84 to –8.95; P < .001), and 12 months (MD = –19.45; 95% CI, –26.90 to –12.82; P < .001) in favor of PRP vs controls (saline placebo, ozone, corticosteroids, HA).¹⁵

Despite a lack of consensus regarding the optimal preparation of PRP for knee OA, another recent RCT (N = 192) found significant improvement in mean subjective IKDC scores in the LR-PRP group (45.5 ± 15.5 to 60.7 ± 21.1; P < .0005) and the LP-PRP group (46.8 ± 15.8 to 62.9 ± 19.9; P < .0005), indicating efficacy regardless of PRP type.⁴

Continue to: Ankle osteoarthritis

 

 

Ankle osteoarthritis

❯ ❯ ❯   Additional research is needed

Ankle OA affects 3.4% of all adults and is more common in the younger population than knee or hip OA.¹⁶ An RCT (N = 100) investigating PRP vs placebo (saline) injections showed no statistically significant difference in American Orthopedic Foot and Ankle Society scores evaluating pain and function over 26 weeks (–2 points; 95% CI, –5 to 1; P = .16).¹⁶ Limitations to this study include its small sample size and the PRP formulation used. (The intervention group received 2 injections of 2 mL of PRP, and the platelet concentration was not reported.)¹⁶

A 2020 systematic review and meta-­analysis of 4 RCTs and 5 case series by Evans et al¹⁷ concluded that PRP improves pain and function in small-joint OA compared to controls of saline, corticosteroids, and HA.¹⁷ One of the case series (N = 20) included in the study demonstrated improvement in ankle OA pain and function scores at 24 weeks posttreatment (P = .04), although improvement in pain and function peaked at 12 weeks.¹⁷ In addition, a 2017 retrospective study (N = 20) from the review reported improved VAS scores and function at 17 months following 4 injections of PRP over 4 weeks (P < .001).¹⁷ Given that RCT data found no benefit with PRP in treating small-joint OA, additional research is indicated.

Hip osteoarthritis

❯ ❯ ❯   Additional research is needed

Symptomatic hip OA occurs in 40% of adults older than 65 years, with a higher prevalence in women.¹⁸ Currently, corticosteroid injections are the only intra-articular therapy recommended by international guidelines for hip OA.¹⁹ A systematic review and meta-analysis comparing PRP to HA injections that included 4 RCTs (N = 303) showed a statistically significant reduction in VAS scores at 2 months in the PRP group compared to the HA group (weighted mean difference [WMD] = –0.376; 95% CI, –0.614 to –0.138; P = .002).¹⁸ However, there were no significant differences in VAS scores between the PRP and HA groups at 6 months (WMD = –0.141; 95% CI, –0.401 to 0.119; P = .289) and 12 months (WMD = –0.083; 95% CI, –0.343 to 0.117; P = .534). Likewise, no significant differences were found in WOMAC scores at 6 months (WMD = –2.841; 95% CI, –6.248 to 0.565; P = .102) and 12 months (WMD = –3.134; 95% CI, –6.624 to 0.356; P = .078) and Harris Hip Scores (HHS) at 6 months (WMD = 2.782; 95% CI, –6.639 to 12.203; P =.563) and 12 months (WMD = 0.706; 95% CI, –6.333 to 7.745; P = .844).¹⁸

A systematic review of 6 RCTs (N = 408) by Belk et al²⁰ comparing PRP to HA for hip OA found similar short-term improvements in WOMAC scores (standardized mean differences [SMD] = 0.27; 95% CI, –0.05 to 0.59; P = .09), VAS scores (MD = 0.59; 95% CI, –0.741 to 1.92; P = .39), and HHS (MD = -0.81; 95% CI, –10.06 to 8.43; P = .93). The average follow-up time was 12.2 and 11.9 months for the PRP and HA groups, respectively.²⁰

LR-PRP, which was used in 1 of the 6 RCTs, showed improvement in VAS scores and HHS from baseline, but no significant difference compared to HA at the latest follow-­up.²⁰ A pooled subanalysis of the 3 studies that used LP-PRP found no difference in WOMAC scores between the PRP and HA groups (SMD = 0.42; 95% CI, –0.01 to 0.86; P = .06).²⁰ Future studies comparing the efficacy of intra-articular steroid vs PRP for hip OA would be beneficial.¹⁸

Continue to: Rotator cuff tendinopathy

 

Rotator cuff tendinopathy

❯ ❯ ❯   Consider PRP for short-term pain relief

Painful conditions of the rotator cuff include impingement syndrome, tendonitis, and partial and complete tears. A 2021 RCT (N = 58) by Dadgostar et al²¹ comparing PRP injection to corticosteroid therapy (methylprednisolone and lidocaine) for the treatment of rotator cuff tendinopathy showed significant improvement in VAS scores at 3 months in the PRP group compared to the corticosteroid group (6.66 ± 2.26 to 3.08 ± 2.14 vs 5.53 ± 1.80 to 3.88 ± 1.99, respectively; P = .023). There also were more significant improvements in adduction in the PRP group compared to the corticosteroid group (20.50° ± 8.23° to 28° ± 3.61° vs 23.21° ± 7.09° to 28.46° ± 4.18°, respectively; P = .011), and external rotation (59.66° ± 23.81° to 76.66° ± 18.30° vs 57.14°± 24.69° to 65.57° ± 26.39° for the PRP and corticosteroid groups, respectively; P = .036).²¹

Another RCT (N = 99) by Kwong et al²² comparing PRP to corticosteroids found similar short-term advantages of LP-PRP with an improved VAS score (–13.6 vs 0.4; P = .03), American Shoulder and Elbow Surgeons score (13.0 vs 2.9; P = .02), and Western Ontario Rotator Cuff Index score (16.8 vs 5.8; P = .03). However, there was no long-term benefit of PRP over corticosteroids found at 12 months.²²

A 2021 systematic review and meta-­analysis by Hamid et al²³ that included 8 RCTs (N = 976) favored PRP over control (no injection, saline injections, and/or shoulder rehabilitation) with improved VAS scores at 12 months (SMD = –0.5; 95% CI, –0.7 to –0.2; P < .001). The evidence on functional outcome was mixed. Data pooled from 2 studies (n = 228) found better Shoulder Pain and Disability Index (SPADI) scores compared to controls at 3- and 6-month follow-ups. However, there were no significant differences in Disabilities of the Arm, Shoulder and Hand (DASH) scores between the 2 groups.²³

Patellar tendinopathy

❯ ❯ ❯   Consider using PRP for return to sport

Patellar tendinopathy, a common MSK condition encountered in the primary care setting, has an overall prevalence of 22% in elite athletes at some point in their career.^{24 ­}Nonsurgical management options include rest, ice, eccentric and isometric exercises, anti-­inflammatory drugs, extracorporeal shock wave therapy (ESWT), and dry needling (DN).

Currently, corticosteroid injections are the only intraarticular therapy recommended by international guidelines for hip OA.

A 2014 RCT (N = 23) evaluating DN vs PRP for patellar tendinopathy favored PRP with improved VAS scores (mean ± SD = 25.4 ± 23.2 points; P = .01 vs 5.2 ± 12.5 points; P = .20) at 12 weeks (P = .02). However, at ≥ 26 weeks, the improvement in pain and function scores was similar between the DN and PRP groups (33.2 ± 14.0 points; P = .001 vs 28.9 ± 25.2 points; P = .01). Notably, there was significantly more improvement in the PRP group at 12 weeks (P = .02) but not at 26 weeks (P = .66).²⁵

Continue to: Another perspective study...

 

Another prospective study (N = 31) comparing PRP to physiotherapy showed a greater improvement in sport activity level reflected by the Tegner score in the PRP group (percentage improvement, 39 ± 22%) compared to control (20 ± 27%; P = .048) at 6 months.⁷

A recent RCT (N = 20) revealed improved VAS scores at 6 months with rehabilitation paired with either bone marrow mesenchymal stem cells (BM-MSC) or LP-PRP when compared with baseline (BM-MSC group: 4.23 ± 2.13 to 2.52 ± 2.37; P = .0621; LP-PRP group: 3.10 ± 1.20 to 1.13 ± 1.25; P = .0083). Pain was significantly reduced during sport play in both groups at 6 months when compared with baseline (BM-MSC group: 6.91 ± 1.11 to 3.06 ± 2.89, P = .0049; PRP group: 7.03 ± 1.42 to 1.94 ± 1.24, P = .0001).²⁶

A 2019 systematic review and meta-analysis (N = 2530) demonstrated greater improvements in Victorian Institute of Sport Assessment scale for patellar tendinopathy (VISA-P) with multiple injections of PRP (38.7 points; 95% CI, 26.3-51.2 points) compared to single injections of PRP (24.3 points; 95% CI, 18.2-30.5 points), eccentric exercise (28.3 points; 95% CI, 18.9-37.8 points) and ESWT (27.4 points; 95% CI, 10.0-39.8 points) after 6 months.²⁷ In contrast, an RCT (n = 57) comparing a single injection of LR-PRP or LP-PRP was no more effective than a single injection of saline for improvement in mean VISA-P scores (P > .05) at 1 year.²⁸

Lateral epicondylitis

❯ ❯ ❯   Consider using PRP

Lateral epicondylitis (“tennis elbow”) is caused by overuse of the elbow extensors at the site of the lateral epicondyle. Chronic lateral epicondylosis involves tissue degeneration and microtrauma. Most cases of epicondylar tendinopathies are treated nonoperatively, with corticosteroid injections being a mainstay of treatment despite their short-term benefit²⁹ and potential to deteriorate connective tissue over time. Recent studies suggest PRP therapy for epicondylitis and epicondylosis may increase long-term pain relief and improve function.

The evidence on functional outcome of platelet-rich plasma for rotator cuff tendinopathy is mixed.

A 2017 systematic review and meta-­analysis of 16 RCTs (N = 1018) concluded PRP was more efficacious than control injections (bupivacaine) for pain reduction in tendinopathies (effect size = 0.47; 95% CI, 0.22-0.72).³⁰ In the review, lateral epicondylitis was evaluated in 12 studies and was most responsive to PRP (effect size = 0.57) when compared to control injection.³⁰ In another systematic review (5 RCTs; 250 patients), corticosteroid injections improved pain within the first 6 weeks of treatment. However, PRP outperformed corticosteroid in VAS scores (21.3 ± 28.1 vs 42.4 ± 26.8) and DASH scores (17.6 ± 24.0 vs 36.5 ± 23.8) (P < .001) at 2 years.³¹

Continue to: A 2022 systematic review...

 

A 2022 systematic review and meta-­analysis (26 studies; N = 1040) comparing scores at baseline vs 2 years post-PRP showed improvement in VAS scores (7.4 ± 1.30 vs 3.71 ± 2.35; P < .001), DASH scores (60.8 ± 12.5 vs 13.0 ± 18.5; P < .001), Patient-Rated Tennis Elbow Evaluation (55.6 ± 14.7 vs 48.8 ± 4.1; P < .001), and Mayo Clinic Performance Index (55.5 ± 6.1 vs 93.0 ± 6.7; P < .001).³²

Regarding the therapeutic effects of different PRP types in lateral epicondylitis, a 2022 systematic review of 33 studies (N = 2420) found improved function and pain relief with LR-PRP and LP-PRP with no significant differences.³³ Pretreatment VAS scores in the LR-PRP group, which ranged from 6.1 to 8.0, improved to 1.5 to 4.0 at 3 months and 0.6 to 3.3 after 1 year.³³ Similarly, pretreatment VAS scores in the LP-PRP group, which ranged from 4.2 to 8.4, improved to 1.6 to 5.9 at 3 months and 0.7 to 2.7 after 1 year.³⁴ DASH scores also improved in the LR-PRP and LP-PRP groups, with pretreatment scores (LR-PRP, 47.0 to 54.3; LP-PRP, 30.0 to 67.7) improving to 20.0 to 22.0 and 5.5 to 19.0, respectively, at 1 year.³³

Achilles tendinopathy

❯ ❯ ❯   Do not use PRP; evidence is lacking

Achilles tendinopathy, caused by chronic overuse and overload resulting in microtrauma and poor tissue healing, typically occurs in the most poorly vascularized portion of the tendon and is common in runners. First-line treatments for Achilles tendinopathy include eccentric strength training and anti-­inflammatory drugs.^34,35 Corticosteroid injections are not recommended, given concern for degraded tendon tissue over time and worse function.³⁴

A 2020 systematic review of 11 randomized and nonrandomized clinical trials (N = 406) found PRP improved Victorian Institute of Sports Assessment—Achilles (VISA-A) scores at 24 weeks compared to other nonsurgical treatment options (41.2 vs 70.12; P < .018).³⁴ However, a higher-quality 2021 systematic review and meta-analysis of 4 RCTs (N = 170) comparing PRP injections with placebo showed no significant difference in VISA-A scores at 3 months (0.23; 95% CI, –0.45 to 0.91), 6 months (0.83; 95% CI, –0.26 to 1.92), and 12 months (0.83; 95% CI, –0.77 to 2.44).³⁶ Therefore, further studies are warranted to evaluate the benefit of PRP injections for Achilles tendinopathy.

Conclusions

While high-quality studies support the use of PRP for knee OA and lateral epicondylitis, they have a moderate-to-high risk for bias. Several RCTs show that PRP provides superior short-term pain relief and range of motion compared to corticosteroids for rotator cuff tendinopathy. Multiple injections of PRP for patellar tendinopathy may accelerate return to sport and improve symptoms over the long term. However, current evidence does not support PRP therapy for Achilles tendinopathy. Given variability in PRP preparation, an accurate interpretation of the literature regarding its use in MSK conditions is recommended (TABLE^{4,6,7,14-18,20-23,25-28,30-34,36}).

Continue to: Concerning the effectiveness of PRP...

 

Concerning the effectiveness of PRP, it is important to consider early publication bias. Although recent studies have shown its benefits,^6,14,15,37 additional studies comparing PRP to placebo will help demonstrate its efficacy. Interestingly, a literature search by Bar-Or et al³⁸ found intra-articular saline may have a therapeutic effect on knee OA and confound findings when used as a placebo.

RCT data showed no benefit with platelet-rich plasma in treating small-joint osteoarthritis.

Recognizing the presence or lack of clinically significant improvement in the literature is important. For example, while some recent studies have shown PRP exceeds the minimal clinically significant difference for knee OA and lateral epicondylitis, others have not.^32,37 A 2021 systematic review of 11 clinical practice guidelines for the use of PRP in knee OA found that 9 were “uncertain or unable to make a recommendation” and 2 recommended against it.³⁹

In its 2021 position statement for the responsible use of regenerative medicine, the American Medical Society for Sports Medicine includes guidance on integrating orthobiologics into clinical practice. The guideline emphasizes informed consent and provides an evidence-based rationale for using PRP in certain patient populations (lateral epicondylitis and younger patients with mild-to-­moderate knee OA), recommending its use only after exhausting other conservative options.⁴⁰ Patients should be referred to physicians with experience using PRP and image-guided procedures.

CORRESPONDENCE
Gregory D. Bentz Jr, MD, 3640 High Street Suite 3B, Portsmouth, VA 23707; [email protected]

Platelet-rich plasma (PRP) injections have become a popular treatment option in a variety of specialties including sports medicine, maxillofacial surgery, dermatology, cosmetology, and reproductive medicine.¹ PRP is an autologous blood product derived from whole blood, using a centrifuge to isolate a concentrated layer of platelets. The ­a-granules in platelets release transforming growth factor b 1, vascular endothelial growth factor, platelet-derived growth factor, basic fibroblast growth factor, epidermal growth factor, insulin-like growth factor 1, and other mediators that enhance the natural healing process.²

When patients ask. Familiarity with the use of PRP to treat specific musculoskeletal (MSK) conditions is essential for family physicians who frequently are asked by patients about whether PRP is right for them. These patients may have experienced failure of medication therapy or declined surgical intervention, or may not be surgical candidates. This review details the evidence surrounding common intra-articular and extra-articular applications of PRP. But first, a word about how PRP is prepared, its contraindications, and costs.

Preparation and types of PRP

Although there are many commercial systems for preparing PRP, there is no consensus on the optimal formulation.² Other terms for PRP, such as autologous concentrated platelets and super-concentrated platelets, are based on concentration of red blood cells, leukocytes, and fibrin.³ PRP therapies usually are categorized as leukocyte-rich PRP (LR-PRP) or leukocyte-poor PRP (LP-PRP), based on neutrophil concentrations that are above and below baseline.² Leukocyte concentration is one of the most debated topics in PRP therapy.⁴

Common commercially available preparation systems produce platelet concentrations between 3 to 6 times the baseline platelet count.⁵ Although there is no universally agreed upon PRP formulation, studies have shown 2 centrifugation cycles (“double-spun” or “dual centrifugation”) that yield platelet concentrations between 1.8 to 1.9 times the baseline values significantly improve MSK conditions.^6-8

Familiarity with the use of platelet-rich plasma to treat specific musculoskeletal conditions is essential for FPs who frequently are asked by patients about whether it is right for them.

For MSK purposes, PRP may be injected into intratendinous, peritendinous, and intra-articular spaces. Currently, there is no consensus regarding injection frequency. Many studies have incorporated single-­injection protocols, while some have used 2 to 3 injections repeated over several weeks to months. PRP commonly is injected at point-of-care without requiring storage.

Contraindications. PRP has been shown to be safe, with most adverse effects attributed to local injection site pain, bleeding, swelling, and bruising.⁹

Contraindications to PRP include active malignancy or recent remission from malignancy with the exception of nonmetastatic skin tumors.¹⁰ PRP is not recommended for patients with an allergy to manufacturing components (eg, dimethyl sulfoxide), thrombocytopenia, nonsteroidal anti-­inflammatory drug use within 2 weeks, active infection causing fever, and local infection at the injection site.¹⁰ Since local anesthetics may impair platelet function, they should not be given at the same injection site as PRP.¹⁰

Continue to: Cost

 

Cost. PRP is not covered by most insurance plans.^11,12 The cost for PRP may range from $500 to $2500 for a single injection.¹²

Evidence-based summary by condition

Knee osteoarthritis

❯❯❯ Consider using PRP

Knee osteoarthritis (OA) is a common cause of pain and disability. Treatment options include physical therapy, pharmacotherapy, and surgery. PRP has gained popularity as a nonsurgical option. A recent meta-analysis by Costa et al¹³ of 40 studies with 3035 participants comparing intra-articular PRP with hyaluronic acid (HA), corticosteroid, and saline injections, found that PRP appears to be more effective or as effective as other nonsurgical modalities. However, due to study heterogeneity and high risk for bias, the authors could not recommend PRP for knee OA in clinical practice.¹³

Despite Costa et al’s findings, reproducible data have demonstrated the superiority of PRP over other nonsurgical treatment options for knee OA. A 2021 systematic review and meta-analysis of 18 randomized controlled trials (RCTs; N = 811) by Belk et al⁶ comparing PRP to HA injections showed a higher mean improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores in the PRP group compared to the HA group (44.7% vs 12.6%, respectively; P < .01).⁶ Six of 11 studies using the visual analog scale (VAS) for pain reported significantly less pain in the PRP group compared to the HA group (P < .05).⁶ The mean follow-up time was 11.1 months.⁶ Three of 6 studies reported improved subjective International Knee Documentation Committee (IKDC) scores (range from 0-100, with higher scores representing higher levels of function and lower levels of symptoms) in the PRP group compared to the HA group: 75.7 ± 15.1 vs 65.6 ± 16.9 (P = .004); 65.5 ± 3.6 vs 55.8 ± 3.8 (P = .01); and 60.8 ± 9.8 vs 48.4 ± 6.2 (P < .05).⁶ There was concern for moderate-to-high heterogeneity.⁶

PRP has been shown to be safe, with most adverse effects attributed to local injectionsite pain, bleeding, swelling, and bruising.

Other systematic reviews and meta-­analyses found similar efficacy of PRP for knee OA, including improved WOMAC scores and patient-reported outcomes (eg, pain, physical function, stiffness) compared to other injectable options.^14,15 A systematic review of 14 RCTs (N = 1423) by Shen et al¹⁵ showed improved WOMAC scores at 3 months (mean differences [MD] = –14.53; 95% CI, –29.97 to –7.09; P < .001), 6 months (MD = –18.21; 95% CI, –27.84 to –8.95; P < .001), and 12 months (MD = –19.45; 95% CI, –26.90 to –12.82; P < .001) in favor of PRP vs controls (saline placebo, ozone, corticosteroids, HA).¹⁵

Despite a lack of consensus regarding the optimal preparation of PRP for knee OA, another recent RCT (N = 192) found significant improvement in mean subjective IKDC scores in the LR-PRP group (45.5 ± 15.5 to 60.7 ± 21.1; P < .0005) and the LP-PRP group (46.8 ± 15.8 to 62.9 ± 19.9; P < .0005), indicating efficacy regardless of PRP type.⁴

Continue to: Ankle osteoarthritis

 

 

Ankle osteoarthritis

❯ ❯ ❯   Additional research is needed

Ankle OA affects 3.4% of all adults and is more common in the younger population than knee or hip OA.¹⁶ An RCT (N = 100) investigating PRP vs placebo (saline) injections showed no statistically significant difference in American Orthopedic Foot and Ankle Society scores evaluating pain and function over 26 weeks (–2 points; 95% CI, –5 to 1; P = .16).¹⁶ Limitations to this study include its small sample size and the PRP formulation used. (The intervention group received 2 injections of 2 mL of PRP, and the platelet concentration was not reported.)¹⁶

A 2020 systematic review and meta-­analysis of 4 RCTs and 5 case series by Evans et al¹⁷ concluded that PRP improves pain and function in small-joint OA compared to controls of saline, corticosteroids, and HA.¹⁷ One of the case series (N = 20) included in the study demonstrated improvement in ankle OA pain and function scores at 24 weeks posttreatment (P = .04), although improvement in pain and function peaked at 12 weeks.¹⁷ In addition, a 2017 retrospective study (N = 20) from the review reported improved VAS scores and function at 17 months following 4 injections of PRP over 4 weeks (P < .001).¹⁷ Given that RCT data found no benefit with PRP in treating small-joint OA, additional research is indicated.

Hip osteoarthritis

❯ ❯ ❯   Additional research is needed

Symptomatic hip OA occurs in 40% of adults older than 65 years, with a higher prevalence in women.¹⁸ Currently, corticosteroid injections are the only intra-articular therapy recommended by international guidelines for hip OA.¹⁹ A systematic review and meta-analysis comparing PRP to HA injections that included 4 RCTs (N = 303) showed a statistically significant reduction in VAS scores at 2 months in the PRP group compared to the HA group (weighted mean difference [WMD] = –0.376; 95% CI, –0.614 to –0.138; P = .002).¹⁸ However, there were no significant differences in VAS scores between the PRP and HA groups at 6 months (WMD = –0.141; 95% CI, –0.401 to 0.119; P = .289) and 12 months (WMD = –0.083; 95% CI, –0.343 to 0.117; P = .534). Likewise, no significant differences were found in WOMAC scores at 6 months (WMD = –2.841; 95% CI, –6.248 to 0.565; P = .102) and 12 months (WMD = –3.134; 95% CI, –6.624 to 0.356; P = .078) and Harris Hip Scores (HHS) at 6 months (WMD = 2.782; 95% CI, –6.639 to 12.203; P =.563) and 12 months (WMD = 0.706; 95% CI, –6.333 to 7.745; P = .844).¹⁸

A systematic review of 6 RCTs (N = 408) by Belk et al²⁰ comparing PRP to HA for hip OA found similar short-term improvements in WOMAC scores (standardized mean differences [SMD] = 0.27; 95% CI, –0.05 to 0.59; P = .09), VAS scores (MD = 0.59; 95% CI, –0.741 to 1.92; P = .39), and HHS (MD = -0.81; 95% CI, –10.06 to 8.43; P = .93). The average follow-up time was 12.2 and 11.9 months for the PRP and HA groups, respectively.²⁰

LR-PRP, which was used in 1 of the 6 RCTs, showed improvement in VAS scores and HHS from baseline, but no significant difference compared to HA at the latest follow-­up.²⁰ A pooled subanalysis of the 3 studies that used LP-PRP found no difference in WOMAC scores between the PRP and HA groups (SMD = 0.42; 95% CI, –0.01 to 0.86; P = .06).²⁰ Future studies comparing the efficacy of intra-articular steroid vs PRP for hip OA would be beneficial.¹⁸

Continue to: Rotator cuff tendinopathy

 

Rotator cuff tendinopathy

❯ ❯ ❯   Consider PRP for short-term pain relief

Painful conditions of the rotator cuff include impingement syndrome, tendonitis, and partial and complete tears. A 2021 RCT (N = 58) by Dadgostar et al²¹ comparing PRP injection to corticosteroid therapy (methylprednisolone and lidocaine) for the treatment of rotator cuff tendinopathy showed significant improvement in VAS scores at 3 months in the PRP group compared to the corticosteroid group (6.66 ± 2.26 to 3.08 ± 2.14 vs 5.53 ± 1.80 to 3.88 ± 1.99, respectively; P = .023). There also were more significant improvements in adduction in the PRP group compared to the corticosteroid group (20.50° ± 8.23° to 28° ± 3.61° vs 23.21° ± 7.09° to 28.46° ± 4.18°, respectively; P = .011), and external rotation (59.66° ± 23.81° to 76.66° ± 18.30° vs 57.14°± 24.69° to 65.57° ± 26.39° for the PRP and corticosteroid groups, respectively; P = .036).²¹

Another RCT (N = 99) by Kwong et al²² comparing PRP to corticosteroids found similar short-term advantages of LP-PRP with an improved VAS score (–13.6 vs 0.4; P = .03), American Shoulder and Elbow Surgeons score (13.0 vs 2.9; P = .02), and Western Ontario Rotator Cuff Index score (16.8 vs 5.8; P = .03). However, there was no long-term benefit of PRP over corticosteroids found at 12 months.²²

A 2021 systematic review and meta-­analysis by Hamid et al²³ that included 8 RCTs (N = 976) favored PRP over control (no injection, saline injections, and/or shoulder rehabilitation) with improved VAS scores at 12 months (SMD = –0.5; 95% CI, –0.7 to –0.2; P < .001). The evidence on functional outcome was mixed. Data pooled from 2 studies (n = 228) found better Shoulder Pain and Disability Index (SPADI) scores compared to controls at 3- and 6-month follow-ups. However, there were no significant differences in Disabilities of the Arm, Shoulder and Hand (DASH) scores between the 2 groups.²³

Patellar tendinopathy

❯ ❯ ❯   Consider using PRP for return to sport

Patellar tendinopathy, a common MSK condition encountered in the primary care setting, has an overall prevalence of 22% in elite athletes at some point in their career.^{24 ­}Nonsurgical management options include rest, ice, eccentric and isometric exercises, anti-­inflammatory drugs, extracorporeal shock wave therapy (ESWT), and dry needling (DN).

Currently, corticosteroid injections are the only intraarticular therapy recommended by international guidelines for hip OA.

A 2014 RCT (N = 23) evaluating DN vs PRP for patellar tendinopathy favored PRP with improved VAS scores (mean ± SD = 25.4 ± 23.2 points; P = .01 vs 5.2 ± 12.5 points; P = .20) at 12 weeks (P = .02). However, at ≥ 26 weeks, the improvement in pain and function scores was similar between the DN and PRP groups (33.2 ± 14.0 points; P = .001 vs 28.9 ± 25.2 points; P = .01). Notably, there was significantly more improvement in the PRP group at 12 weeks (P = .02) but not at 26 weeks (P = .66).²⁵

Continue to: Another perspective study...

 

Another prospective study (N = 31) comparing PRP to physiotherapy showed a greater improvement in sport activity level reflected by the Tegner score in the PRP group (percentage improvement, 39 ± 22%) compared to control (20 ± 27%; P = .048) at 6 months.⁷

A recent RCT (N = 20) revealed improved VAS scores at 6 months with rehabilitation paired with either bone marrow mesenchymal stem cells (BM-MSC) or LP-PRP when compared with baseline (BM-MSC group: 4.23 ± 2.13 to 2.52 ± 2.37; P = .0621; LP-PRP group: 3.10 ± 1.20 to 1.13 ± 1.25; P = .0083). Pain was significantly reduced during sport play in both groups at 6 months when compared with baseline (BM-MSC group: 6.91 ± 1.11 to 3.06 ± 2.89, P = .0049; PRP group: 7.03 ± 1.42 to 1.94 ± 1.24, P = .0001).²⁶

A 2019 systematic review and meta-analysis (N = 2530) demonstrated greater improvements in Victorian Institute of Sport Assessment scale for patellar tendinopathy (VISA-P) with multiple injections of PRP (38.7 points; 95% CI, 26.3-51.2 points) compared to single injections of PRP (24.3 points; 95% CI, 18.2-30.5 points), eccentric exercise (28.3 points; 95% CI, 18.9-37.8 points) and ESWT (27.4 points; 95% CI, 10.0-39.8 points) after 6 months.²⁷ In contrast, an RCT (n = 57) comparing a single injection of LR-PRP or LP-PRP was no more effective than a single injection of saline for improvement in mean VISA-P scores (P > .05) at 1 year.²⁸

Lateral epicondylitis

❯ ❯ ❯   Consider using PRP

Lateral epicondylitis (“tennis elbow”) is caused by overuse of the elbow extensors at the site of the lateral epicondyle. Chronic lateral epicondylosis involves tissue degeneration and microtrauma. Most cases of epicondylar tendinopathies are treated nonoperatively, with corticosteroid injections being a mainstay of treatment despite their short-term benefit²⁹ and potential to deteriorate connective tissue over time. Recent studies suggest PRP therapy for epicondylitis and epicondylosis may increase long-term pain relief and improve function.

The evidence on functional outcome of platelet-rich plasma for rotator cuff tendinopathy is mixed.

A 2017 systematic review and meta-­analysis of 16 RCTs (N = 1018) concluded PRP was more efficacious than control injections (bupivacaine) for pain reduction in tendinopathies (effect size = 0.47; 95% CI, 0.22-0.72).³⁰ In the review, lateral epicondylitis was evaluated in 12 studies and was most responsive to PRP (effect size = 0.57) when compared to control injection.³⁰ In another systematic review (5 RCTs; 250 patients), corticosteroid injections improved pain within the first 6 weeks of treatment. However, PRP outperformed corticosteroid in VAS scores (21.3 ± 28.1 vs 42.4 ± 26.8) and DASH scores (17.6 ± 24.0 vs 36.5 ± 23.8) (P < .001) at 2 years.³¹

Continue to: A 2022 systematic review...

 

A 2022 systematic review and meta-­analysis (26 studies; N = 1040) comparing scores at baseline vs 2 years post-PRP showed improvement in VAS scores (7.4 ± 1.30 vs 3.71 ± 2.35; P < .001), DASH scores (60.8 ± 12.5 vs 13.0 ± 18.5; P < .001), Patient-Rated Tennis Elbow Evaluation (55.6 ± 14.7 vs 48.8 ± 4.1; P < .001), and Mayo Clinic Performance Index (55.5 ± 6.1 vs 93.0 ± 6.7; P < .001).³²

Regarding the therapeutic effects of different PRP types in lateral epicondylitis, a 2022 systematic review of 33 studies (N = 2420) found improved function and pain relief with LR-PRP and LP-PRP with no significant differences.³³ Pretreatment VAS scores in the LR-PRP group, which ranged from 6.1 to 8.0, improved to 1.5 to 4.0 at 3 months and 0.6 to 3.3 after 1 year.³³ Similarly, pretreatment VAS scores in the LP-PRP group, which ranged from 4.2 to 8.4, improved to 1.6 to 5.9 at 3 months and 0.7 to 2.7 after 1 year.³⁴ DASH scores also improved in the LR-PRP and LP-PRP groups, with pretreatment scores (LR-PRP, 47.0 to 54.3; LP-PRP, 30.0 to 67.7) improving to 20.0 to 22.0 and 5.5 to 19.0, respectively, at 1 year.³³

Achilles tendinopathy

❯ ❯ ❯   Do not use PRP; evidence is lacking

Achilles tendinopathy, caused by chronic overuse and overload resulting in microtrauma and poor tissue healing, typically occurs in the most poorly vascularized portion of the tendon and is common in runners. First-line treatments for Achilles tendinopathy include eccentric strength training and anti-­inflammatory drugs.^34,35 Corticosteroid injections are not recommended, given concern for degraded tendon tissue over time and worse function.³⁴

A 2020 systematic review of 11 randomized and nonrandomized clinical trials (N = 406) found PRP improved Victorian Institute of Sports Assessment—Achilles (VISA-A) scores at 24 weeks compared to other nonsurgical treatment options (41.2 vs 70.12; P < .018).³⁴ However, a higher-quality 2021 systematic review and meta-analysis of 4 RCTs (N = 170) comparing PRP injections with placebo showed no significant difference in VISA-A scores at 3 months (0.23; 95% CI, –0.45 to 0.91), 6 months (0.83; 95% CI, –0.26 to 1.92), and 12 months (0.83; 95% CI, –0.77 to 2.44).³⁶ Therefore, further studies are warranted to evaluate the benefit of PRP injections for Achilles tendinopathy.

Conclusions

While high-quality studies support the use of PRP for knee OA and lateral epicondylitis, they have a moderate-to-high risk for bias. Several RCTs show that PRP provides superior short-term pain relief and range of motion compared to corticosteroids for rotator cuff tendinopathy. Multiple injections of PRP for patellar tendinopathy may accelerate return to sport and improve symptoms over the long term. However, current evidence does not support PRP therapy for Achilles tendinopathy. Given variability in PRP preparation, an accurate interpretation of the literature regarding its use in MSK conditions is recommended (TABLE^{4,6,7,14-18,20-23,25-28,30-34,36}).

Continue to: Concerning the effectiveness of PRP...

 

Concerning the effectiveness of PRP, it is important to consider early publication bias. Although recent studies have shown its benefits,^6,14,15,37 additional studies comparing PRP to placebo will help demonstrate its efficacy. Interestingly, a literature search by Bar-Or et al³⁸ found intra-articular saline may have a therapeutic effect on knee OA and confound findings when used as a placebo.

RCT data showed no benefit with platelet-rich plasma in treating small-joint osteoarthritis.

Recognizing the presence or lack of clinically significant improvement in the literature is important. For example, while some recent studies have shown PRP exceeds the minimal clinically significant difference for knee OA and lateral epicondylitis, others have not.^32,37 A 2021 systematic review of 11 clinical practice guidelines for the use of PRP in knee OA found that 9 were “uncertain or unable to make a recommendation” and 2 recommended against it.³⁹

In its 2021 position statement for the responsible use of regenerative medicine, the American Medical Society for Sports Medicine includes guidance on integrating orthobiologics into clinical practice. The guideline emphasizes informed consent and provides an evidence-based rationale for using PRP in certain patient populations (lateral epicondylitis and younger patients with mild-to-­moderate knee OA), recommending its use only after exhausting other conservative options.⁴⁰ Patients should be referred to physicians with experience using PRP and image-guided procedures.

CORRESPONDENCE
Gregory D. Bentz Jr, MD, 3640 High Street Suite 3B, Portsmouth, VA 23707; [email protected]

 

CASE 1 Multiparous female with short-interval pregnancies desires contraception

A 24-year-old woman (G4P3) presents for a routine prenatal visit in the third trimester. Her last 2 pregnancies have occurred within 3 months of her prior birth. She endorses feeling overwhelmed with having 4 children under the age of 5 years, and she specifies that she would like to avoid another pregnancy for several years. She plans to breast and bottle feed, and she notes that she tends to forget to take pills. When you look back at her prior charts, you note that she did not return for her last 2 postpartum visits. What can you offer her? What would be a safe contraceptive option for her?
 

Intrauterine devices (IUDs) are safe, effective, and reported by patients to be satisfactory methods of contraception precisely because they are prone to less user error. The Contraceptive Choice Project demonstrated that patients are more apt to choose them when barriers such as cost and access are removed and nondirective counseling is provided.¹ Given that unintended pregnancy rates hover around 48%, the American College of Obstetricians and Gynecologists (ACOG) recommends them as first-line methods for pregnancy prevention.^2,3

For repeat pregnancies, the postpartum period is an especially vulnerable time—non-breastfeeding women will ovulate as soon as 25 days after birth, and by 8 weeks 30% will have ovulated.⁴ Approximately 40% to 57% of women report having unprotected intercourse before 6 weeks postpartum, and nearly 70% of all pregnancies in the first year postpartum are unintended.^3,5 Furthermore, patients at highest risk for short-interval pregnancy, such as adolescents, are less likely to return for a postpartum visit.³

Short-interval pregnancies confer greater fetal risk, including risks of low-birth weight, preterm birth, small for gestational age and increased risk of neonatal intensive care unit admission.⁶ Additionally, maternal health may be compromised during a short-interval pregnancy, particularly in medically complex patients due to increased risks of adverse pregnancy outcomes, such as postpartum bleeding or uterine rupture and disease progression.⁷ A 2006 meta-analysis by Conde-Agudelo and colleagues found that waiting at least 18 months between pregnancies was optimal for reducing these risks.⁶

Thus, the immediate postpartum period is an optimal time for addressing contraceptive needs and for preventing short-interval and unintended pregnancy. This article aims to provide evidence supporting the use of immediate postpartum IUDs, as well as their associated risks and barriers to use.

IUD types and routes for immediate postpartum insertion

There are several randomized controlled trials (RCTs) that examine the immediate postpartum use of copper IUDs and levonorgestrel-releasing (LNG) IUDs.^8-11 In 2010, Chen and colleagues compared placement of the immediate postpartum IUD following vaginal delivery with interval placement at 6–8 weeks postpartum. Of 51 patients enrolled in each arm, 98% received an IUD immediately postpartum, and 90% received one during their postpartum visit. There were 12 expulsions (24%) in the immediate postpartum IUD group, compared with 2 (4.4%) in the interval group. Expelled IUDs were replaced, and at 6 months both groups had similar rates of IUD use.⁸

Whitaker and colleagues demonstrated similar findings after randomizing a small group of women who had a cesarean delivery (CD) to interval or immediate placement. There were significantly more expulsions in the post-placental group (20%) than the interval group (0%), but there were more users of the IUD in the post-placental group than in the interval group at 12 months.⁹

Two RCTs, by Lester and colleagues and Levi et al, demonstrated successful placement of the copper IUD or LNG-IUD following CD, with few expulsions (0% and 8%, respectively). Patients who were randomized to immediate postpartum IUD placement were more likely to receive an IUD than those who were randomized to interval insertion, mostly due to lack of postpartum follow up. Both studies followed patients out to 6 months, and rates of IUD continuation and satisfaction were higher at this time in the immediate postpartum IUD groups.^10,11

Continue to: Risks, contraindications, and breastfeeding impact...

 

 

Risks, contraindications, and breastfeeding impact

What are the risks of immediate postpartum IUD placement? The highest risk of IUD placement in the immediate postpartum period appears to be expulsion (TABLE 1). In a meta-analysis conducted in 2022, which looked at 11 studies of immediate IUD insertion, the rates of expulsion were between 5% and 27%.^3,8,12,13 Results of a study by Cohen and colleagues demonstrated that most expulsions occurred within the first 12 weeks following delivery; of those expulsions that occurred, only 11% went unrecognized.¹³ Immediate postpartum IUD insertion does not increase the IUD-associated risks of perforation, infection, or immediate postpartum bleeding (although prolonged bleeding may be more common).¹²

Are there contraindications to placing an IUD immediately postpartum? The main contraindication to immediate postpartum IUD use is peripartum infection, including Triple I, endomyometritis, and puerperal sepsis. Other contraindications include retained placenta requiring manual or surgical removal, uterine anomalies, and other medical contraindications to IUD use as recommended by the US Medical Eligibility Criteria.¹⁴

Does immediate IUD placement affect breastfeeding? There is theoretical risk of decreased milk supply or difficulty breastfeeding with initiation of progestin-only methods of contraception in the immediate postpartum period, as the rapid fall in progesterone levels initiates lactogenesis. However, progestin-only methods appear to have limited effect on initiation and continuation of breastfeeding in the immediate postpartum period.¹⁵

There were 2 secondary analyses of a pair of RCTs comparing immediate and delayed postpartum IUD use. Results from Levi and colleagues demonstrated no difference between immediate and interval IUD placement groups in the proportion of women who were breastfeeding at 6, 12, and 24 weeks.¹⁶ Chen and colleagues’ study was smaller; researchers found that women with interval IUD placement were more likely to be exclusively breastfeeding and continuing to breastfeed at 6 months compared with the immediate postpartum group.¹⁷

To better characterize the impact of progestin implants, in a recent meta-analysis, authors examined the use of subcutaneous levonorgestrel rods and found no difference in breastfeeding initiation and continuation rates between women who had them placed immediately versus 6 ̶ 8 weeks postpartum.¹²

Benefits of immediate postpartum IUD placement

One benefit of immediate postpartum IUD insertion is a reduction in short-interval pregnancies. In a study by Cohen and colleagues¹³ of young women aged 13 to 22 years choosing immediate postpartum IUDs (82) or implants (162), the authors found that 61% of women retained their IUDs at 12 months postpartum. Because few requested IUD removal over that time frame, the discontinuation rate at 1 year was primarily due to expulsions. Pregnancy rates at 1 year were 7.6% in the IUD group and 1.5% in the implant group. However, the 7.6% rate in the IUD group was lower than in previously studied adolescent control groups: 18.6% of control adolescents (38 of 204) using a contraceptive form other than a postpartum etonogestrel implant had repeat pregnancy at 1 year.^13,18

Not only are patients who receive immediate postpartum IUDs more likely to receive them and continue their use, but they are also satisfied with the experience of receiving the IUD and with the method of contraception. A small mixed methods study of 66 patients demonstrated that women were interested in obtaining immediate postpartum contraception to avoid some of the logistical and financial challenges of returning for a postpartum visit. They also felt that the IUD placement was less painful than expected, and they didn’t feel that the insertion process imposed on their birth experience. Many described relief to know that they had a safe and effective contraceptive method upon leaving the hospital.¹⁹ Other studies have shown that even among women who expel an IUD following immediate postpartum placement, many choose to replace it in order to continue it as a contraceptive method.^8,9,13

Continue to: Instructions for placement...

 

 

Instructions for placement

1. Counsel appropriately. Thoroughly counsel patients regarding their options for postpartum contraception, with emphasis on the benefits, risks, and contraindications. Current recommendations to reduce the risk of expulsion are to place the IUD in the delivery room or operating room within 10 minutes of placental delivery.

2. Post ̶ vaginal delivery. Following vaginal delivery, remove the IUD from the inserter, cut the strings to 10 cm and, using either fingers to grasp the wings of the IUD or ring forceps, advance the IUD to the fundus. Ultrasound guidance may be used, but it does not appear to be helpful in preventing expulsion.²⁰

3. Post ̶ cesarean delivery. Once the placenta is delivered, place the IUD using the inserter or a ring forceps at the fundus and guide the strings into the cervix, then close the hysterotomy.

ACOG does recommend formal trainingbefore placing postpartum IUDs. One resource they provide is a free online webinar (https://www.acog.org/education-and-events/webinars/long-acting-reversible-contra ception-overview-and-hands-on-practice-for-residents).³

CASE 1 Resolved

The patient was counseled in the office about her options, and she was most interested in immediate postpartum LNG-IUD placement. She went on to deliver a healthy baby vaginally at 39 weeks. Within 10 minutes of placental delivery, she received an LNG-IUD. She returned to the office 3 months later for STI screening; her examination revealed correct placement and no evidence of expulsion. She expressed that she was happy with her IUD and thankful that she was able to receive it immediately after the birth of her baby.

CASE 2 Nulliparous woman desires IUD for postpartum contraception

A 33-year-old nulliparous woman presents in the third trimester for a routine prenatal visit. She had used the LNG-IUD prior to getting pregnant and reports that she was very happy with it. She knows she wants to wait at least 2 years before trying to get pregnant again, and she would like to resume contraception as soon as it is reasonably safe to do so. She has read that it is possible to get an IUD immediately postpartum and asks about it as a possible option.

What barriers will she face in obtaining an immediate postpartum IUD?

There are many barriers for patients who may be good candidates for immediate postpartum contraception (TABLE 2). Many patients are unaware that it is a safe option, and they often have concerns about such risks as infection, perforation, and effects on breastfeeding. Additionally, providers may not prioritize adequate counseling about postpartum contraception when they face time constraints and a need to counsel about other pregnancy-related topics during the prenatal visit schedule.^7,21

System, hospital, and clinician barriers to immediate postpartum IUD use

Hospital implementation of a successful postpartum IUD program requires pharmacy, intrapartum and postpartum nursing staff, physicians, administration, and billing to be aligned. Hospital administration and pharmacists must stock IUDs in the pharmacy. Hospital nursing staff attitudes toward and knowledge of postpartum contraception can have profound influence on how they discuss safe and effective methods of postpartum contraception with patients who may not have received counseling during prenatal care.²² In a survey of 108 ACOG fellows, nearly 75% of ObGyn physicians did not offer immediate postpartum IUDs; lack of provider training, lack of IUD availability, and concern about cost and payment were found to be common reasons why.²¹ Additionally, Catholic-affiliated and rural institutions are less likely to offer it, whereas more urban, teaching hospitals are more likely to have programs in place.²³ Prior to 2012, immediate postpartum IUD insertions and device costs were part of the global Medicaid obstetric fee in most states, and both hospital systems and individual providers were concerned about loss of revenue.²³

In 2015, Washington and colleagues published a decision analysis that examined the cost-effectiveness and cost savings associated with immediate postpartum IUD use. Accounting for expulsion rates, they found that immediate postpartum IUD placement can save $282,540 per 1,000 women over 2 years; additionally, immediate postpartum IUD use can prevent 88 unintended pregnancies per 1,000 women over 2 years.²⁴ Not only do immediate postpartum IUDs have great potential to prevent individual patients from undesired short-interval pregnancies (FIGURE 1), but they can also save the system substantial health care dollars (FIGURE 2).

Overcoming barriers

Immediate postpartum IUD implementation is attainable with practice, policy, and institutional changes. Education and training programs geared toward providers and nursing staff can improve understanding of the benefits and risks of immediate postpartum IUD placement. Additionally, clinicians must provide comprehensive, nondirective counseling during the antepartum period, informing patients of all safe and effective options. Expulsion risks should be disclosed, as well as the benefit of not needing to return for a separate postpartum contraception appointment.

Since 2012, many state Medicaid agencies have decoupled reimbursement for inpatient postpartum IUD insertion from the delivery fee. By 2018, more than half of states adopted this practice. Commercial insurers have followed suit in some cases, and as such, both Medicaid and commercially insured patients have had increased access to immediate postpartum IUDs.²³ This has translated into increased uptake of immediate postpartum IUDs among both Medicaid and commercially insured patients. Koch et al conducted a retrospective cohort study comparing IUD use in patients 1 year before and 1 year after the policy changes, and they found a 10-fold increase in use of immediate postpartum IUDs.²⁵

While education, counseling, access, and changes in reimbursement may increase access in many hospital systems, some barriers, such as religious affiliation of the hospital system, may be impossible to overcome. A viable alternative to immediate postpartum IUD placement may be early postpartum IUD placement, which could allow patients to coordinate this procedure with 1- or 2-week return routine postpartum visits for CD recovery, mental health screenings, and/or well-baby visits. More data are necessary before recommending this universally, but Averbach and colleagues published a promising meta-analysis that demonstrated no complete expulsions in studies in which IUDs were placed between 2 and 4 weeks postpartum, and only a pooled partial expulsion rate (of immediate postpartum, early inpatient, early outpatient, and interval placement) of 3.7%.⁴

CASE 2 Resolved

Although the patient was interested in receiving a postpartum LNG-IUD immediately after her vaginal birth, she had to wait until her 6-week postpartum visit. The hospital did not stock IUDs for immediate postpartum IUD use, and her provider, having not been trained on immediate postpartum insertion, did not feel comfortable trying to place it in the immediate postpartum time frame. ●

 

CASE 1 Multiparous female with short-interval pregnancies desires contraception

A 24-year-old woman (G4P3) presents for a routine prenatal visit in the third trimester. Her last 2 pregnancies have occurred within 3 months of her prior birth. She endorses feeling overwhelmed with having 4 children under the age of 5 years, and she specifies that she would like to avoid another pregnancy for several years. She plans to breast and bottle feed, and she notes that she tends to forget to take pills. When you look back at her prior charts, you note that she did not return for her last 2 postpartum visits. What can you offer her? What would be a safe contraceptive option for her?
 

Intrauterine devices (IUDs) are safe, effective, and reported by patients to be satisfactory methods of contraception precisely because they are prone to less user error. The Contraceptive Choice Project demonstrated that patients are more apt to choose them when barriers such as cost and access are removed and nondirective counseling is provided.¹ Given that unintended pregnancy rates hover around 48%, the American College of Obstetricians and Gynecologists (ACOG) recommends them as first-line methods for pregnancy prevention.^2,3

For repeat pregnancies, the postpartum period is an especially vulnerable time—non-breastfeeding women will ovulate as soon as 25 days after birth, and by 8 weeks 30% will have ovulated.⁴ Approximately 40% to 57% of women report having unprotected intercourse before 6 weeks postpartum, and nearly 70% of all pregnancies in the first year postpartum are unintended.^3,5 Furthermore, patients at highest risk for short-interval pregnancy, such as adolescents, are less likely to return for a postpartum visit.³

Short-interval pregnancies confer greater fetal risk, including risks of low-birth weight, preterm birth, small for gestational age and increased risk of neonatal intensive care unit admission.⁶ Additionally, maternal health may be compromised during a short-interval pregnancy, particularly in medically complex patients due to increased risks of adverse pregnancy outcomes, such as postpartum bleeding or uterine rupture and disease progression.⁷ A 2006 meta-analysis by Conde-Agudelo and colleagues found that waiting at least 18 months between pregnancies was optimal for reducing these risks.⁶

Thus, the immediate postpartum period is an optimal time for addressing contraceptive needs and for preventing short-interval and unintended pregnancy. This article aims to provide evidence supporting the use of immediate postpartum IUDs, as well as their associated risks and barriers to use.

IUD types and routes for immediate postpartum insertion

There are several randomized controlled trials (RCTs) that examine the immediate postpartum use of copper IUDs and levonorgestrel-releasing (LNG) IUDs.^8-11 In 2010, Chen and colleagues compared placement of the immediate postpartum IUD following vaginal delivery with interval placement at 6–8 weeks postpartum. Of 51 patients enrolled in each arm, 98% received an IUD immediately postpartum, and 90% received one during their postpartum visit. There were 12 expulsions (24%) in the immediate postpartum IUD group, compared with 2 (4.4%) in the interval group. Expelled IUDs were replaced, and at 6 months both groups had similar rates of IUD use.⁸

Whitaker and colleagues demonstrated similar findings after randomizing a small group of women who had a cesarean delivery (CD) to interval or immediate placement. There were significantly more expulsions in the post-placental group (20%) than the interval group (0%), but there were more users of the IUD in the post-placental group than in the interval group at 12 months.⁹

Two RCTs, by Lester and colleagues and Levi et al, demonstrated successful placement of the copper IUD or LNG-IUD following CD, with few expulsions (0% and 8%, respectively). Patients who were randomized to immediate postpartum IUD placement were more likely to receive an IUD than those who were randomized to interval insertion, mostly due to lack of postpartum follow up. Both studies followed patients out to 6 months, and rates of IUD continuation and satisfaction were higher at this time in the immediate postpartum IUD groups.^10,11

Continue to: Risks, contraindications, and breastfeeding impact...

 

 

Risks, contraindications, and breastfeeding impact

What are the risks of immediate postpartum IUD placement? The highest risk of IUD placement in the immediate postpartum period appears to be expulsion (TABLE 1). In a meta-analysis conducted in 2022, which looked at 11 studies of immediate IUD insertion, the rates of expulsion were between 5% and 27%.^3,8,12,13 Results of a study by Cohen and colleagues demonstrated that most expulsions occurred within the first 12 weeks following delivery; of those expulsions that occurred, only 11% went unrecognized.¹³ Immediate postpartum IUD insertion does not increase the IUD-associated risks of perforation, infection, or immediate postpartum bleeding (although prolonged bleeding may be more common).¹²

Are there contraindications to placing an IUD immediately postpartum? The main contraindication to immediate postpartum IUD use is peripartum infection, including Triple I, endomyometritis, and puerperal sepsis. Other contraindications include retained placenta requiring manual or surgical removal, uterine anomalies, and other medical contraindications to IUD use as recommended by the US Medical Eligibility Criteria.¹⁴

Does immediate IUD placement affect breastfeeding? There is theoretical risk of decreased milk supply or difficulty breastfeeding with initiation of progestin-only methods of contraception in the immediate postpartum period, as the rapid fall in progesterone levels initiates lactogenesis. However, progestin-only methods appear to have limited effect on initiation and continuation of breastfeeding in the immediate postpartum period.¹⁵

There were 2 secondary analyses of a pair of RCTs comparing immediate and delayed postpartum IUD use. Results from Levi and colleagues demonstrated no difference between immediate and interval IUD placement groups in the proportion of women who were breastfeeding at 6, 12, and 24 weeks.¹⁶ Chen and colleagues’ study was smaller; researchers found that women with interval IUD placement were more likely to be exclusively breastfeeding and continuing to breastfeed at 6 months compared with the immediate postpartum group.¹⁷

To better characterize the impact of progestin implants, in a recent meta-analysis, authors examined the use of subcutaneous levonorgestrel rods and found no difference in breastfeeding initiation and continuation rates between women who had them placed immediately versus 6 ̶ 8 weeks postpartum.¹²

Benefits of immediate postpartum IUD placement

One benefit of immediate postpartum IUD insertion is a reduction in short-interval pregnancies. In a study by Cohen and colleagues¹³ of young women aged 13 to 22 years choosing immediate postpartum IUDs (82) or implants (162), the authors found that 61% of women retained their IUDs at 12 months postpartum. Because few requested IUD removal over that time frame, the discontinuation rate at 1 year was primarily due to expulsions. Pregnancy rates at 1 year were 7.6% in the IUD group and 1.5% in the implant group. However, the 7.6% rate in the IUD group was lower than in previously studied adolescent control groups: 18.6% of control adolescents (38 of 204) using a contraceptive form other than a postpartum etonogestrel implant had repeat pregnancy at 1 year.^13,18

Not only are patients who receive immediate postpartum IUDs more likely to receive them and continue their use, but they are also satisfied with the experience of receiving the IUD and with the method of contraception. A small mixed methods study of 66 patients demonstrated that women were interested in obtaining immediate postpartum contraception to avoid some of the logistical and financial challenges of returning for a postpartum visit. They also felt that the IUD placement was less painful than expected, and they didn’t feel that the insertion process imposed on their birth experience. Many described relief to know that they had a safe and effective contraceptive method upon leaving the hospital.¹⁹ Other studies have shown that even among women who expel an IUD following immediate postpartum placement, many choose to replace it in order to continue it as a contraceptive method.^8,9,13

Continue to: Instructions for placement...

 

 

Instructions for placement

1. Counsel appropriately. Thoroughly counsel patients regarding their options for postpartum contraception, with emphasis on the benefits, risks, and contraindications. Current recommendations to reduce the risk of expulsion are to place the IUD in the delivery room or operating room within 10 minutes of placental delivery.

2. Post ̶ vaginal delivery. Following vaginal delivery, remove the IUD from the inserter, cut the strings to 10 cm and, using either fingers to grasp the wings of the IUD or ring forceps, advance the IUD to the fundus. Ultrasound guidance may be used, but it does not appear to be helpful in preventing expulsion.²⁰

3. Post ̶ cesarean delivery. Once the placenta is delivered, place the IUD using the inserter or a ring forceps at the fundus and guide the strings into the cervix, then close the hysterotomy.

ACOG does recommend formal trainingbefore placing postpartum IUDs. One resource they provide is a free online webinar (https://www.acog.org/education-and-events/webinars/long-acting-reversible-contra ception-overview-and-hands-on-practice-for-residents).³

CASE 1 Resolved

The patient was counseled in the office about her options, and she was most interested in immediate postpartum LNG-IUD placement. She went on to deliver a healthy baby vaginally at 39 weeks. Within 10 minutes of placental delivery, she received an LNG-IUD. She returned to the office 3 months later for STI screening; her examination revealed correct placement and no evidence of expulsion. She expressed that she was happy with her IUD and thankful that she was able to receive it immediately after the birth of her baby.

CASE 2 Nulliparous woman desires IUD for postpartum contraception

A 33-year-old nulliparous woman presents in the third trimester for a routine prenatal visit. She had used the LNG-IUD prior to getting pregnant and reports that she was very happy with it. She knows she wants to wait at least 2 years before trying to get pregnant again, and she would like to resume contraception as soon as it is reasonably safe to do so. She has read that it is possible to get an IUD immediately postpartum and asks about it as a possible option.

What barriers will she face in obtaining an immediate postpartum IUD?

There are many barriers for patients who may be good candidates for immediate postpartum contraception (TABLE 2). Many patients are unaware that it is a safe option, and they often have concerns about such risks as infection, perforation, and effects on breastfeeding. Additionally, providers may not prioritize adequate counseling about postpartum contraception when they face time constraints and a need to counsel about other pregnancy-related topics during the prenatal visit schedule.^7,21

System, hospital, and clinician barriers to immediate postpartum IUD use

Hospital implementation of a successful postpartum IUD program requires pharmacy, intrapartum and postpartum nursing staff, physicians, administration, and billing to be aligned. Hospital administration and pharmacists must stock IUDs in the pharmacy. Hospital nursing staff attitudes toward and knowledge of postpartum contraception can have profound influence on how they discuss safe and effective methods of postpartum contraception with patients who may not have received counseling during prenatal care.²² In a survey of 108 ACOG fellows, nearly 75% of ObGyn physicians did not offer immediate postpartum IUDs; lack of provider training, lack of IUD availability, and concern about cost and payment were found to be common reasons why.²¹ Additionally, Catholic-affiliated and rural institutions are less likely to offer it, whereas more urban, teaching hospitals are more likely to have programs in place.²³ Prior to 2012, immediate postpartum IUD insertions and device costs were part of the global Medicaid obstetric fee in most states, and both hospital systems and individual providers were concerned about loss of revenue.²³

In 2015, Washington and colleagues published a decision analysis that examined the cost-effectiveness and cost savings associated with immediate postpartum IUD use. Accounting for expulsion rates, they found that immediate postpartum IUD placement can save $282,540 per 1,000 women over 2 years; additionally, immediate postpartum IUD use can prevent 88 unintended pregnancies per 1,000 women over 2 years.²⁴ Not only do immediate postpartum IUDs have great potential to prevent individual patients from undesired short-interval pregnancies (FIGURE 1), but they can also save the system substantial health care dollars (FIGURE 2).

Overcoming barriers

Immediate postpartum IUD implementation is attainable with practice, policy, and institutional changes. Education and training programs geared toward providers and nursing staff can improve understanding of the benefits and risks of immediate postpartum IUD placement. Additionally, clinicians must provide comprehensive, nondirective counseling during the antepartum period, informing patients of all safe and effective options. Expulsion risks should be disclosed, as well as the benefit of not needing to return for a separate postpartum contraception appointment.

Since 2012, many state Medicaid agencies have decoupled reimbursement for inpatient postpartum IUD insertion from the delivery fee. By 2018, more than half of states adopted this practice. Commercial insurers have followed suit in some cases, and as such, both Medicaid and commercially insured patients have had increased access to immediate postpartum IUDs.²³ This has translated into increased uptake of immediate postpartum IUDs among both Medicaid and commercially insured patients. Koch et al conducted a retrospective cohort study comparing IUD use in patients 1 year before and 1 year after the policy changes, and they found a 10-fold increase in use of immediate postpartum IUDs.²⁵

While education, counseling, access, and changes in reimbursement may increase access in many hospital systems, some barriers, such as religious affiliation of the hospital system, may be impossible to overcome. A viable alternative to immediate postpartum IUD placement may be early postpartum IUD placement, which could allow patients to coordinate this procedure with 1- or 2-week return routine postpartum visits for CD recovery, mental health screenings, and/or well-baby visits. More data are necessary before recommending this universally, but Averbach and colleagues published a promising meta-analysis that demonstrated no complete expulsions in studies in which IUDs were placed between 2 and 4 weeks postpartum, and only a pooled partial expulsion rate (of immediate postpartum, early inpatient, early outpatient, and interval placement) of 3.7%.⁴

CASE 2 Resolved

Although the patient was interested in receiving a postpartum LNG-IUD immediately after her vaginal birth, she had to wait until her 6-week postpartum visit. The hospital did not stock IUDs for immediate postpartum IUD use, and her provider, having not been trained on immediate postpartum insertion, did not feel comfortable trying to place it in the immediate postpartum time frame. ●

 

CASE 1 Multiparous female with short-interval pregnancies desires contraception

A 24-year-old woman (G4P3) presents for a routine prenatal visit in the third trimester. Her last 2 pregnancies have occurred within 3 months of her prior birth. She endorses feeling overwhelmed with having 4 children under the age of 5 years, and she specifies that she would like to avoid another pregnancy for several years. She plans to breast and bottle feed, and she notes that she tends to forget to take pills. When you look back at her prior charts, you note that she did not return for her last 2 postpartum visits. What can you offer her? What would be a safe contraceptive option for her?
 

Intrauterine devices (IUDs) are safe, effective, and reported by patients to be satisfactory methods of contraception precisely because they are prone to less user error. The Contraceptive Choice Project demonstrated that patients are more apt to choose them when barriers such as cost and access are removed and nondirective counseling is provided.¹ Given that unintended pregnancy rates hover around 48%, the American College of Obstetricians and Gynecologists (ACOG) recommends them as first-line methods for pregnancy prevention.^2,3

For repeat pregnancies, the postpartum period is an especially vulnerable time—non-breastfeeding women will ovulate as soon as 25 days after birth, and by 8 weeks 30% will have ovulated.⁴ Approximately 40% to 57% of women report having unprotected intercourse before 6 weeks postpartum, and nearly 70% of all pregnancies in the first year postpartum are unintended.^3,5 Furthermore, patients at highest risk for short-interval pregnancy, such as adolescents, are less likely to return for a postpartum visit.³

Short-interval pregnancies confer greater fetal risk, including risks of low-birth weight, preterm birth, small for gestational age and increased risk of neonatal intensive care unit admission.⁶ Additionally, maternal health may be compromised during a short-interval pregnancy, particularly in medically complex patients due to increased risks of adverse pregnancy outcomes, such as postpartum bleeding or uterine rupture and disease progression.⁷ A 2006 meta-analysis by Conde-Agudelo and colleagues found that waiting at least 18 months between pregnancies was optimal for reducing these risks.⁶

Thus, the immediate postpartum period is an optimal time for addressing contraceptive needs and for preventing short-interval and unintended pregnancy. This article aims to provide evidence supporting the use of immediate postpartum IUDs, as well as their associated risks and barriers to use.

IUD types and routes for immediate postpartum insertion

There are several randomized controlled trials (RCTs) that examine the immediate postpartum use of copper IUDs and levonorgestrel-releasing (LNG) IUDs.^8-11 In 2010, Chen and colleagues compared placement of the immediate postpartum IUD following vaginal delivery with interval placement at 6–8 weeks postpartum. Of 51 patients enrolled in each arm, 98% received an IUD immediately postpartum, and 90% received one during their postpartum visit. There were 12 expulsions (24%) in the immediate postpartum IUD group, compared with 2 (4.4%) in the interval group. Expelled IUDs were replaced, and at 6 months both groups had similar rates of IUD use.⁸

Whitaker and colleagues demonstrated similar findings after randomizing a small group of women who had a cesarean delivery (CD) to interval or immediate placement. There were significantly more expulsions in the post-placental group (20%) than the interval group (0%), but there were more users of the IUD in the post-placental group than in the interval group at 12 months.⁹

Two RCTs, by Lester and colleagues and Levi et al, demonstrated successful placement of the copper IUD or LNG-IUD following CD, with few expulsions (0% and 8%, respectively). Patients who were randomized to immediate postpartum IUD placement were more likely to receive an IUD than those who were randomized to interval insertion, mostly due to lack of postpartum follow up. Both studies followed patients out to 6 months, and rates of IUD continuation and satisfaction were higher at this time in the immediate postpartum IUD groups.^10,11

Continue to: Risks, contraindications, and breastfeeding impact...

 

 

Risks, contraindications, and breastfeeding impact

What are the risks of immediate postpartum IUD placement? The highest risk of IUD placement in the immediate postpartum period appears to be expulsion (TABLE 1). In a meta-analysis conducted in 2022, which looked at 11 studies of immediate IUD insertion, the rates of expulsion were between 5% and 27%.^3,8,12,13 Results of a study by Cohen and colleagues demonstrated that most expulsions occurred within the first 12 weeks following delivery; of those expulsions that occurred, only 11% went unrecognized.¹³ Immediate postpartum IUD insertion does not increase the IUD-associated risks of perforation, infection, or immediate postpartum bleeding (although prolonged bleeding may be more common).¹²

Are there contraindications to placing an IUD immediately postpartum? The main contraindication to immediate postpartum IUD use is peripartum infection, including Triple I, endomyometritis, and puerperal sepsis. Other contraindications include retained placenta requiring manual or surgical removal, uterine anomalies, and other medical contraindications to IUD use as recommended by the US Medical Eligibility Criteria.¹⁴

Does immediate IUD placement affect breastfeeding? There is theoretical risk of decreased milk supply or difficulty breastfeeding with initiation of progestin-only methods of contraception in the immediate postpartum period, as the rapid fall in progesterone levels initiates lactogenesis. However, progestin-only methods appear to have limited effect on initiation and continuation of breastfeeding in the immediate postpartum period.¹⁵

There were 2 secondary analyses of a pair of RCTs comparing immediate and delayed postpartum IUD use. Results from Levi and colleagues demonstrated no difference between immediate and interval IUD placement groups in the proportion of women who were breastfeeding at 6, 12, and 24 weeks.¹⁶ Chen and colleagues’ study was smaller; researchers found that women with interval IUD placement were more likely to be exclusively breastfeeding and continuing to breastfeed at 6 months compared with the immediate postpartum group.¹⁷

To better characterize the impact of progestin implants, in a recent meta-analysis, authors examined the use of subcutaneous levonorgestrel rods and found no difference in breastfeeding initiation and continuation rates between women who had them placed immediately versus 6 ̶ 8 weeks postpartum.¹²

Benefits of immediate postpartum IUD placement

One benefit of immediate postpartum IUD insertion is a reduction in short-interval pregnancies. In a study by Cohen and colleagues¹³ of young women aged 13 to 22 years choosing immediate postpartum IUDs (82) or implants (162), the authors found that 61% of women retained their IUDs at 12 months postpartum. Because few requested IUD removal over that time frame, the discontinuation rate at 1 year was primarily due to expulsions. Pregnancy rates at 1 year were 7.6% in the IUD group and 1.5% in the implant group. However, the 7.6% rate in the IUD group was lower than in previously studied adolescent control groups: 18.6% of control adolescents (38 of 204) using a contraceptive form other than a postpartum etonogestrel implant had repeat pregnancy at 1 year.^13,18

Not only are patients who receive immediate postpartum IUDs more likely to receive them and continue their use, but they are also satisfied with the experience of receiving the IUD and with the method of contraception. A small mixed methods study of 66 patients demonstrated that women were interested in obtaining immediate postpartum contraception to avoid some of the logistical and financial challenges of returning for a postpartum visit. They also felt that the IUD placement was less painful than expected, and they didn’t feel that the insertion process imposed on their birth experience. Many described relief to know that they had a safe and effective contraceptive method upon leaving the hospital.¹⁹ Other studies have shown that even among women who expel an IUD following immediate postpartum placement, many choose to replace it in order to continue it as a contraceptive method.^8,9,13

Continue to: Instructions for placement...

 

 

Instructions for placement

1. Counsel appropriately. Thoroughly counsel patients regarding their options for postpartum contraception, with emphasis on the benefits, risks, and contraindications. Current recommendations to reduce the risk of expulsion are to place the IUD in the delivery room or operating room within 10 minutes of placental delivery.

2. Post ̶ vaginal delivery. Following vaginal delivery, remove the IUD from the inserter, cut the strings to 10 cm and, using either fingers to grasp the wings of the IUD or ring forceps, advance the IUD to the fundus. Ultrasound guidance may be used, but it does not appear to be helpful in preventing expulsion.²⁰

3. Post ̶ cesarean delivery. Once the placenta is delivered, place the IUD using the inserter or a ring forceps at the fundus and guide the strings into the cervix, then close the hysterotomy.

ACOG does recommend formal trainingbefore placing postpartum IUDs. One resource they provide is a free online webinar (https://www.acog.org/education-and-events/webinars/long-acting-reversible-contra ception-overview-and-hands-on-practice-for-residents).³

CASE 1 Resolved

The patient was counseled in the office about her options, and she was most interested in immediate postpartum LNG-IUD placement. She went on to deliver a healthy baby vaginally at 39 weeks. Within 10 minutes of placental delivery, she received an LNG-IUD. She returned to the office 3 months later for STI screening; her examination revealed correct placement and no evidence of expulsion. She expressed that she was happy with her IUD and thankful that she was able to receive it immediately after the birth of her baby.

CASE 2 Nulliparous woman desires IUD for postpartum contraception

A 33-year-old nulliparous woman presents in the third trimester for a routine prenatal visit. She had used the LNG-IUD prior to getting pregnant and reports that she was very happy with it. She knows she wants to wait at least 2 years before trying to get pregnant again, and she would like to resume contraception as soon as it is reasonably safe to do so. She has read that it is possible to get an IUD immediately postpartum and asks about it as a possible option.

What barriers will she face in obtaining an immediate postpartum IUD?

There are many barriers for patients who may be good candidates for immediate postpartum contraception (TABLE 2). Many patients are unaware that it is a safe option, and they often have concerns about such risks as infection, perforation, and effects on breastfeeding. Additionally, providers may not prioritize adequate counseling about postpartum contraception when they face time constraints and a need to counsel about other pregnancy-related topics during the prenatal visit schedule.^7,21

System, hospital, and clinician barriers to immediate postpartum IUD use

Hospital implementation of a successful postpartum IUD program requires pharmacy, intrapartum and postpartum nursing staff, physicians, administration, and billing to be aligned. Hospital administration and pharmacists must stock IUDs in the pharmacy. Hospital nursing staff attitudes toward and knowledge of postpartum contraception can have profound influence on how they discuss safe and effective methods of postpartum contraception with patients who may not have received counseling during prenatal care.²² In a survey of 108 ACOG fellows, nearly 75% of ObGyn physicians did not offer immediate postpartum IUDs; lack of provider training, lack of IUD availability, and concern about cost and payment were found to be common reasons why.²¹ Additionally, Catholic-affiliated and rural institutions are less likely to offer it, whereas more urban, teaching hospitals are more likely to have programs in place.²³ Prior to 2012, immediate postpartum IUD insertions and device costs were part of the global Medicaid obstetric fee in most states, and both hospital systems and individual providers were concerned about loss of revenue.²³

In 2015, Washington and colleagues published a decision analysis that examined the cost-effectiveness and cost savings associated with immediate postpartum IUD use. Accounting for expulsion rates, they found that immediate postpartum IUD placement can save $282,540 per 1,000 women over 2 years; additionally, immediate postpartum IUD use can prevent 88 unintended pregnancies per 1,000 women over 2 years.²⁴ Not only do immediate postpartum IUDs have great potential to prevent individual patients from undesired short-interval pregnancies (FIGURE 1), but they can also save the system substantial health care dollars (FIGURE 2).

Overcoming barriers

Immediate postpartum IUD implementation is attainable with practice, policy, and institutional changes. Education and training programs geared toward providers and nursing staff can improve understanding of the benefits and risks of immediate postpartum IUD placement. Additionally, clinicians must provide comprehensive, nondirective counseling during the antepartum period, informing patients of all safe and effective options. Expulsion risks should be disclosed, as well as the benefit of not needing to return for a separate postpartum contraception appointment.

Since 2012, many state Medicaid agencies have decoupled reimbursement for inpatient postpartum IUD insertion from the delivery fee. By 2018, more than half of states adopted this practice. Commercial insurers have followed suit in some cases, and as such, both Medicaid and commercially insured patients have had increased access to immediate postpartum IUDs.²³ This has translated into increased uptake of immediate postpartum IUDs among both Medicaid and commercially insured patients. Koch et al conducted a retrospective cohort study comparing IUD use in patients 1 year before and 1 year after the policy changes, and they found a 10-fold increase in use of immediate postpartum IUDs.²⁵

While education, counseling, access, and changes in reimbursement may increase access in many hospital systems, some barriers, such as religious affiliation of the hospital system, may be impossible to overcome. A viable alternative to immediate postpartum IUD placement may be early postpartum IUD placement, which could allow patients to coordinate this procedure with 1- or 2-week return routine postpartum visits for CD recovery, mental health screenings, and/or well-baby visits. More data are necessary before recommending this universally, but Averbach and colleagues published a promising meta-analysis that demonstrated no complete expulsions in studies in which IUDs were placed between 2 and 4 weeks postpartum, and only a pooled partial expulsion rate (of immediate postpartum, early inpatient, early outpatient, and interval placement) of 3.7%.⁴

CASE 2 Resolved

Although the patient was interested in receiving a postpartum LNG-IUD immediately after her vaginal birth, she had to wait until her 6-week postpartum visit. The hospital did not stock IUDs for immediate postpartum IUD use, and her provider, having not been trained on immediate postpartum insertion, did not feel comfortable trying to place it in the immediate postpartum time frame. ●

THE COMPARISON

A A 23-year-old White woman with malar erythema from acute cutaneous lupus erythematosus. The erythema also can be seen on the nose and eyelids but spares the nasolabial folds.

B A Black woman with malar erythema and hyperpigmentation from acute cutaneous lupus erythematosus. The nasolabial folds are spared.

C A 19-year-old Latina woman with malar erythema from acute cutaneous lupus erythematosus. The erythema also can be seen on the nose, chin, and eyelids but spares the nasolabial folds. Cutaneous erosions are present on the right cheek as part of the lupus flare.

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition that affects the kidneys, lungs, brain, and heart, although it is not limited to these organs. Dermatologists and primary care physicians play a critical role in the early identification of SLE (particularly in those with skin of color), as the standardized mortality rate is 2.6-fold higher in patients with SLE compared to the general population.¹ The clinical manifestations of SLE vary.

Epidemiology

A meta-analysis of data from the Centers for Disease Control and Prevention National Lupus Registry network including 5417 patients revealed a prevalence of 72.8 cases per 100,000 person-years.² The prevalence was higher in females than males and highest among females identifying as Black. White and Asian/ Pacific Islander females had the lowest prevalence. The American Indian (indigenous)/Alaska Native–identifying population had the highest race-specific SLE estimates among both females and males compared to other racial/ethnic groups.²

Key clinical features in people with darker skin tones

The diagnosis of SLE is based on clinical and immunologic criteria from the European League Against Rheumatism/American College of Rheumatology.^3,4 An antinuclear antibody titer of 1:80 or higher at least once is required for the diagnosis of SLE, as long as there is not another more likely diagnosis. If it is present, 22 additive weighted classification criteria are considered; each criterion is assigned points, ranging from 2 to 10. Patients with at least 1 clinical criterion and 10 or more points are classified as having SLE. If more than 1 of the criteria are met in a domain, then the one with the highest numerical value is counted.^3,4

Aringer et al^3,4 outline the criteria and numerical points to make the diagnosis of SLE. The mucocutaneous component of the SLE diagnostic criteria^3,4 includes nonscarring alopecia, oral ulcers, subacute cutaneous or discoid lupus erythematosus,⁵ and acute cutaneous lupus erythematosus, with acute cutaneous lupus erythematosus being the highest-weighted criterion in that domain. The other clinical domains are constitutional, hematologic, neuropsychiatric, serosal, musculoskeletal, renal, antiphospholipid antibodies, complement proteins, and SLE-specific antibodies.^3,4

The malar (“butterfly”) rash of SLE characteristically includes erythema that spares the nasolabial folds but affects the nasal bridge and cheeks.⁶ The rash occasionally may be pruritic and painful, lasting days to weeks. Photosensitivity occurs, resulting in rashes or even an overall worsening of SLE symptoms. In those with darker skin tones, erythema may appear violaceous or may not be as readily appreciated.⁶

Worth noting

• Patients with skin of color are at an increased risk for postinflammatory hypopigmentation and hyperpigmentation (pigment alteration), hypertrophic scars, and keloids.^7,8
• The mortality rate for those with SLE is high despite early recognition and treatment when compared to the general population.^1,9

Health disparity highlight

Those at greatest risk for death from SLE in the United States are those of African descent, Hispanic individuals, men, and those with low socioeconomic status,⁹ which likely is primarily driven by social determinants of health instead of genetic patterns. Income level, educational attainment, insurance status, and environmental factors¹⁰ have farreaching effects, negatively impacting quality of life and even mortality.

THE COMPARISON

A A 23-year-old White woman with malar erythema from acute cutaneous lupus erythematosus. The erythema also can be seen on the nose and eyelids but spares the nasolabial folds.

B A Black woman with malar erythema and hyperpigmentation from acute cutaneous lupus erythematosus. The nasolabial folds are spared.

C A 19-year-old Latina woman with malar erythema from acute cutaneous lupus erythematosus. The erythema also can be seen on the nose, chin, and eyelids but spares the nasolabial folds. Cutaneous erosions are present on the right cheek as part of the lupus flare.

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition that affects the kidneys, lungs, brain, and heart, although it is not limited to these organs. Dermatologists and primary care physicians play a critical role in the early identification of SLE (particularly in those with skin of color), as the standardized mortality rate is 2.6-fold higher in patients with SLE compared to the general population.¹ The clinical manifestations of SLE vary.

Epidemiology

A meta-analysis of data from the Centers for Disease Control and Prevention National Lupus Registry network including 5417 patients revealed a prevalence of 72.8 cases per 100,000 person-years.² The prevalence was higher in females than males and highest among females identifying as Black. White and Asian/ Pacific Islander females had the lowest prevalence. The American Indian (indigenous)/Alaska Native–identifying population had the highest race-specific SLE estimates among both females and males compared to other racial/ethnic groups.²

Key clinical features in people with darker skin tones

The diagnosis of SLE is based on clinical and immunologic criteria from the European League Against Rheumatism/American College of Rheumatology.^3,4 An antinuclear antibody titer of 1:80 or higher at least once is required for the diagnosis of SLE, as long as there is not another more likely diagnosis. If it is present, 22 additive weighted classification criteria are considered; each criterion is assigned points, ranging from 2 to 10. Patients with at least 1 clinical criterion and 10 or more points are classified as having SLE. If more than 1 of the criteria are met in a domain, then the one with the highest numerical value is counted.^3,4

Aringer et al^3,4 outline the criteria and numerical points to make the diagnosis of SLE. The mucocutaneous component of the SLE diagnostic criteria^3,4 includes nonscarring alopecia, oral ulcers, subacute cutaneous or discoid lupus erythematosus,⁵ and acute cutaneous lupus erythematosus, with acute cutaneous lupus erythematosus being the highest-weighted criterion in that domain. The other clinical domains are constitutional, hematologic, neuropsychiatric, serosal, musculoskeletal, renal, antiphospholipid antibodies, complement proteins, and SLE-specific antibodies.^3,4

The malar (“butterfly”) rash of SLE characteristically includes erythema that spares the nasolabial folds but affects the nasal bridge and cheeks.⁶ The rash occasionally may be pruritic and painful, lasting days to weeks. Photosensitivity occurs, resulting in rashes or even an overall worsening of SLE symptoms. In those with darker skin tones, erythema may appear violaceous or may not be as readily appreciated.⁶

Worth noting

• Patients with skin of color are at an increased risk for postinflammatory hypopigmentation and hyperpigmentation (pigment alteration), hypertrophic scars, and keloids.^7,8
• The mortality rate for those with SLE is high despite early recognition and treatment when compared to the general population.^1,9

Health disparity highlight

Those at greatest risk for death from SLE in the United States are those of African descent, Hispanic individuals, men, and those with low socioeconomic status,⁹ which likely is primarily driven by social determinants of health instead of genetic patterns. Income level, educational attainment, insurance status, and environmental factors¹⁰ have farreaching effects, negatively impacting quality of life and even mortality.

THE COMPARISON

A A 23-year-old White woman with malar erythema from acute cutaneous lupus erythematosus. The erythema also can be seen on the nose and eyelids but spares the nasolabial folds.

B A Black woman with malar erythema and hyperpigmentation from acute cutaneous lupus erythematosus. The nasolabial folds are spared.

C A 19-year-old Latina woman with malar erythema from acute cutaneous lupus erythematosus. The erythema also can be seen on the nose, chin, and eyelids but spares the nasolabial folds. Cutaneous erosions are present on the right cheek as part of the lupus flare.

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition that affects the kidneys, lungs, brain, and heart, although it is not limited to these organs. Dermatologists and primary care physicians play a critical role in the early identification of SLE (particularly in those with skin of color), as the standardized mortality rate is 2.6-fold higher in patients with SLE compared to the general population.¹ The clinical manifestations of SLE vary.

Epidemiology

A meta-analysis of data from the Centers for Disease Control and Prevention National Lupus Registry network including 5417 patients revealed a prevalence of 72.8 cases per 100,000 person-years.² The prevalence was higher in females than males and highest among females identifying as Black. White and Asian/ Pacific Islander females had the lowest prevalence. The American Indian (indigenous)/Alaska Native–identifying population had the highest race-specific SLE estimates among both females and males compared to other racial/ethnic groups.²

Key clinical features in people with darker skin tones

The diagnosis of SLE is based on clinical and immunologic criteria from the European League Against Rheumatism/American College of Rheumatology.^3,4 An antinuclear antibody titer of 1:80 or higher at least once is required for the diagnosis of SLE, as long as there is not another more likely diagnosis. If it is present, 22 additive weighted classification criteria are considered; each criterion is assigned points, ranging from 2 to 10. Patients with at least 1 clinical criterion and 10 or more points are classified as having SLE. If more than 1 of the criteria are met in a domain, then the one with the highest numerical value is counted.^3,4

Aringer et al^3,4 outline the criteria and numerical points to make the diagnosis of SLE. The mucocutaneous component of the SLE diagnostic criteria^3,4 includes nonscarring alopecia, oral ulcers, subacute cutaneous or discoid lupus erythematosus,⁵ and acute cutaneous lupus erythematosus, with acute cutaneous lupus erythematosus being the highest-weighted criterion in that domain. The other clinical domains are constitutional, hematologic, neuropsychiatric, serosal, musculoskeletal, renal, antiphospholipid antibodies, complement proteins, and SLE-specific antibodies.^3,4

The malar (“butterfly”) rash of SLE characteristically includes erythema that spares the nasolabial folds but affects the nasal bridge and cheeks.⁶ The rash occasionally may be pruritic and painful, lasting days to weeks. Photosensitivity occurs, resulting in rashes or even an overall worsening of SLE symptoms. In those with darker skin tones, erythema may appear violaceous or may not be as readily appreciated.⁶

Worth noting

• Patients with skin of color are at an increased risk for postinflammatory hypopigmentation and hyperpigmentation (pigment alteration), hypertrophic scars, and keloids.^7,8
• The mortality rate for those with SLE is high despite early recognition and treatment when compared to the general population.^1,9

Health disparity highlight

Those at greatest risk for death from SLE in the United States are those of African descent, Hispanic individuals, men, and those with low socioeconomic status,⁹ which likely is primarily driven by social determinants of health instead of genetic patterns. Income level, educational attainment, insurance status, and environmental factors¹⁰ have farreaching effects, negatively impacting quality of life and even mortality.

Frailty is an age-associated, nonspecific vulnerability to adverse health outcomes. Frailty can also be described as a complex of symptoms characterized by impaired stress tolerance due to a decline in the functionality of different organs.¹ The prevalence of frailty varies widely depending on the method of measurement and the population studied.^2-4 It is a nonconstant factor that increases with age. A deficit accumulation frailty index (FI) is one method used to measure frailty.⁵ This approach sees frailty as a multidimensional risk state measured by quantity rather than the nature of health concerns. A deficit accumulation FI does not require physical testing but correlates well with other phenotypic FIs.⁶ It is, however, time consuming, as ≥ 30 deficits need to be measured to offer greater stability to the frailty estimate.

Health care is seeing increasing utilization of big data analytics to derive predictive models and help with resource allocation. There are currently 2 existing automated tools to predict health care utilization and mortality at the US Department of Veterans Affairs (VA): the VA Frailty Index (VA-FI-10) and the Care Assessment Need (CAN). VA-FI-10 is an International Statistical Classification of Diseases, Tenth Revision (ICD-10) update of the VA-FI that was created in March 2021. The VA-FI-10 is a claims-based frailty assessment tool using 31 health deficits. Calculating the VA-FI-10 requires defining an index date and lookback period (typically 3 years) relative to which it will be calculated.⁷

CAN is a set of risk-stratifying statistical models run on veterans receiving VA primary care services as part of a patient aligned care team (PACT) using electronic health record data.⁸ Each veteran is stratified based on the individual’s risks of hospitalization, death, and hospitalization or death. These 3 events are predicted for 90-day and 1-year time periods for a total of 6 distinct outcomes. CAN is currently on its third iteration (CAN 2.5) and scores range from 0 (low) to 99 (high). CAN scores are updated weekly. The 1-year hospitalization probabilities for all patients range from 0.8% to 93.1%. For patients with a CAN score of 50, the probability of being hospitalized within a year ranges from 4.5% to 5.2%, which increases to 32.2% to 36% for veterans with a CAN score of 95. The probability range widens significantly (32.2%-93.1%) for patients in the top 5 CAN scores (95-99).

CAN scores are a potential screening tool for frailty among older adults; they are generated automatically and provide acceptable diagnostic accuracy. Hence, the CAN score may be a useful tool for primary care practitioners for the detection of frailty in their patients. The CAN score has shown a moderate positive association with the FRAIL Scale.^9,10 The population-based studies that have used the FI approach (differing FIs, depending on the data available) give robust results: People accumulate an average of 0.03 deficits per year after the age of 70 years.¹¹ Interventions to delay or reverse frailty have not been clearly defined with heterogeneity in the definition of frailty and measurement of frailty outcomes.^12,13 The prevalence of frailty in the veteran population is substantially higher than the prevalence in community populations with a similar age distribution. There is also mounting evidence that veterans accumulate deficits more rapidly than their civilian counterparts.¹⁴

COVID-19 was declared a pandemic in March 2020 and had many impacts on global health that were most marked in the first year. These included reductions in hospital visits for non-COVID-19 health concerns, a reduction in completed screening tests, an initial reduction in other infectious diseases (attributable to quarantines), and an increase or worsening of mental health concerns.^15,16

We aimed to investigate whether frailty increased disproportionately in a subset of older veterans in the first year of the COVID-19 pandemic when compared with the previous year using CAN scores. This single institution, longitudinal cohort study was determined to be exempt from institutional review board review but was approved by the Phoenix VA Health Care System (PVAHCS) Research and Development Committee.

 

Methods

The Office of Clinical Systems Development and Evaluation (CSDE–10E2A) produces a weekly CAN Score Report to help identify the highest-risk patients in a primary care panel or cohort. CAN scores range from 0 (lowest risk) to 99 (highest risk), indicating how likely a patient is to experience hospitalization or death compared with other VA patients. CAN scores are calculated with statistical prediction models that use data elements from the following Corporate Data Warehouse (CDW) domains: demographics, health care utilization, laboratory tests, medical conditions, medications, and vital signs (eAppendix available online at 10.12788/fp.0385).

The CAN Score Report is generated weekly and stored on a CDW server. A patient will receive all 6 distinct CAN scores if they are: (1) assigned to a primary care PACT on the risk date; (2) a veteran; (3) not hospitalized in a VA facility on the risk date; and (4) alive as of the risk date. New to CAN 2.5 is that patients who meet criteria 1, 2, and 4 but are hospitalized in a VA facility on the risk date will receive CAN scores for the 1-year and 90-day mortality models.

Utilizing VA Informatics and Computing Infrastructure (VA HSR RES 13-457, US Department of Veterans Affairs [2008]), we obtained 2 lists of veterans aged 70 to 75 years on February 8, 2019, with a calculated CAN score of ≥ 75 for 1-year mortality and 1-year hospitalization on that date. A veteran with a CAN score of ≥ 75 is likely to be prefrail or frail.^9,10 Veterans who did not have a corresponding calculated CAN score on February 7, 2020, and February 12, 2021, were excluded. COVID-19 was declared a public health emergency in the United States on January 31, 2020, and the World Health Organization declared COVID-19 a pandemic on March 11, 2020.¹⁷ We picked February 7, 2020, within this time frame and without any other special significance. We picked additional CAN score calculation dates approximately 1 year prior and 1 year after this date. Veterans had to be alive on February 12, 2021, (the last date of the CAN score) to be included in the cohorts.

Statistical Analyses

The difference in CAN score from one year to the next was calculated for each patient. The difference between 2019 and 2020 was compared with the difference between 2020 to 2021 using a paired t test. Yearly CAN score values were analyzed using repeated measures analysis of variance. The number of patients that showed an increase in CAN score (ie, increased risk of either mortality or hospitalization within the year) or a decrease (lower risk) was compared using the χ² test. IBM SPSS v26 and GraphPad Prism v18 were used for statistical analysis. P < .05 was considered statistically significant.

Results

There were 3538 veterans at PVAHCS who met the inclusion criteria and had a 1-year mortality CAN score ≥ 75 on February 8, 2019.

We excluded 6 veterans from the final analysis due to lack of 1-year mortality CAN score for 2020 or 2021. The final number included in the analysis was 3532 (Figure 1). The mean (SD) age was 71.8 (1.3) years. There were 3488 male (98.8%) and 44 female (1.2%) veterans represented (Table 1).

Our data show a decrease in mean 1-year mortality CAN score in this subset of older frail veterans by 4.9 (95% CI, -5.3 to -4.5) in the year preceding the COVID-19 pandemic (Table 2). The 1-year mean mortality CAN score increased significantly by 0.2 (95% CI, -0.3 to 0.6; P < .0001 vs pre-COVID) in this same subset of patients after the first year of the COVID-19 pandemic (Figure 2).

Mean CAN scores for 1-year mortality were 81.5 (95% CI, 81.2 to 81.7), 76.5 (95% CI, 76.1 to 77.0), and 76.7 (95% CI, 76.2 to 77.2) for 2019, 2020, and 2021, respectively.

 

In the hospitalization group, there were 6046 veterans in the analysis; 57 veterans missing a 1-year hospitalization CAN score that were excluded. The mean age was 71.7 (1.3) years and included 5874 male (97.2%) and 172 female (2.8%) veterans. There was a decline in mean 1-year hospitalization CAN scores in our subset of frail older veterans by 2.8 (95% CI, -3.1 to -2.6) in the year preceding the COVID-19 pandemic. This mean decline slowed significantly to 1.5 (95% CI, -1.8 to -1.2; P < .0001) after the first year of the COVID-19 pandemic. Mean CAN scores for 1-year hospitalization were 84.6 (95% CI, 84.4 to 84.8), 81.8 (95% CI, 81.5 to 82.1), and 80.2 (95% CI, 79.9 to 80.6) for 2019, 2020, and 2021, respectively.

We also calculated the number of veterans with increasing, stable, and decreasing CAN scores across each of our defined periods in both the 1-year mortality and hospitalization groups.

The subset of veterans with stable/no change in CAN scores was the smallest in both groups (Figure 3).

A previous study used a 1-year combined hospitalization or mortality event CAN score as the most all-inclusive measure of frailty but determined that it was possible that 1 of the other 5 CAN risk measures could perform better in predicting frailty.¹⁰ We collected and presented data for 1-year mortality and hospitalization CAN scores. There were declines in pandemic-related US hospitalizations for illnesses not related to COVID-19 during the first few months of the pandemic.¹⁸ This may or may not have affected the 1-year hospitalization CAN score data; thus, we used the 1-year mortality CAN score data to predict frailty.

Discussion

We studied frailty trends in an older veteran subpopulation enrolled at the PVAHCS 1 year prior and into the COVID-19 pandemic using CAN scores. Frailty is a dynamic state. Previous frailty assessments aimed to identify patients at the highest risk of death. With the advent of advanced therapeutics for several diseases, the number of medical conditions that are now managed as chronic illnesses continues to grow. There is a role for repeated measures of frailty to try to identify frailty trends.¹⁹ These trends may assist us in resource allocation, identifying interventions that work and those that do not.

Some studies have shown an overall declining lethality of frailty. This may reflect improvements in the care and management of chronic conditions, screening tests, and increased awareness of healthy lifestyles.²⁰ Another study of frailty trajectories in a veteran population in the 5 years preceding death showed multiple trajectories (stable, gradually increasing, rapidly increasing, and recovering).¹⁹

The PACT is a primary care model implemented at VA medical centers in April 2010. It is a patient-centered medical home model (PCMH) with several components. The VA treats a population of socioeconomically vulnerable patients with complex chronic illness management needs. Some of the components of a PACT model relevant to our study include facilitated self-management support for veterans in between practitioner visits via care partners, peer-to-peer and transitional care programs, physical activity and diet programs, primary care mental health, integration between primary and specialty care, and telehealth.²¹ A previous study has shown that VA primary care clinics with the most PCMH components in place had greater improvements in several chronic disease quality measures than in clinics with a lower number of PCMH components.²²

 

Limitations

Our study is limited by our older veteran population demographics. We chose only a subset of older veterans at a single VA center for this study and cannot extrapolate the results to all older frail veterans or community dwelling older adults. Robust individuals may also transition to prefrailty and frailty over longer periods; our study monitored frailty trends over 2 years.

CAN scores are not quality measures to improve upon. Allocation and utilization of additional resources may clinically benefit a patient but increase their CAN scores. Although our results are statistically significant, we are unable to make any conclusions about clinical significance.

Conclusions

Our study results indicate frailty as determined by 1-year mortality CAN scores significantly increased in a subset of older veterans during the first year of the COVID-19 pandemic when compared with the previous year. Whether this change in frailty is temporary or long lasting remains to be seen. Automated CAN scores can be effectively utilized to monitor frailty trends in certain veteran populations over longer periods.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Phoenix Veterans Affairs Health Care System.

Frailty is an age-associated, nonspecific vulnerability to adverse health outcomes. Frailty can also be described as a complex of symptoms characterized by impaired stress tolerance due to a decline in the functionality of different organs.¹ The prevalence of frailty varies widely depending on the method of measurement and the population studied.^2-4 It is a nonconstant factor that increases with age. A deficit accumulation frailty index (FI) is one method used to measure frailty.⁵ This approach sees frailty as a multidimensional risk state measured by quantity rather than the nature of health concerns. A deficit accumulation FI does not require physical testing but correlates well with other phenotypic FIs.⁶ It is, however, time consuming, as ≥ 30 deficits need to be measured to offer greater stability to the frailty estimate.

Health care is seeing increasing utilization of big data analytics to derive predictive models and help with resource allocation. There are currently 2 existing automated tools to predict health care utilization and mortality at the US Department of Veterans Affairs (VA): the VA Frailty Index (VA-FI-10) and the Care Assessment Need (CAN). VA-FI-10 is an International Statistical Classification of Diseases, Tenth Revision (ICD-10) update of the VA-FI that was created in March 2021. The VA-FI-10 is a claims-based frailty assessment tool using 31 health deficits. Calculating the VA-FI-10 requires defining an index date and lookback period (typically 3 years) relative to which it will be calculated.⁷

CAN is a set of risk-stratifying statistical models run on veterans receiving VA primary care services as part of a patient aligned care team (PACT) using electronic health record data.⁸ Each veteran is stratified based on the individual’s risks of hospitalization, death, and hospitalization or death. These 3 events are predicted for 90-day and 1-year time periods for a total of 6 distinct outcomes. CAN is currently on its third iteration (CAN 2.5) and scores range from 0 (low) to 99 (high). CAN scores are updated weekly. The 1-year hospitalization probabilities for all patients range from 0.8% to 93.1%. For patients with a CAN score of 50, the probability of being hospitalized within a year ranges from 4.5% to 5.2%, which increases to 32.2% to 36% for veterans with a CAN score of 95. The probability range widens significantly (32.2%-93.1%) for patients in the top 5 CAN scores (95-99).

CAN scores are a potential screening tool for frailty among older adults; they are generated automatically and provide acceptable diagnostic accuracy. Hence, the CAN score may be a useful tool for primary care practitioners for the detection of frailty in their patients. The CAN score has shown a moderate positive association with the FRAIL Scale.^9,10 The population-based studies that have used the FI approach (differing FIs, depending on the data available) give robust results: People accumulate an average of 0.03 deficits per year after the age of 70 years.¹¹ Interventions to delay or reverse frailty have not been clearly defined with heterogeneity in the definition of frailty and measurement of frailty outcomes.^12,13 The prevalence of frailty in the veteran population is substantially higher than the prevalence in community populations with a similar age distribution. There is also mounting evidence that veterans accumulate deficits more rapidly than their civilian counterparts.¹⁴

COVID-19 was declared a pandemic in March 2020 and had many impacts on global health that were most marked in the first year. These included reductions in hospital visits for non-COVID-19 health concerns, a reduction in completed screening tests, an initial reduction in other infectious diseases (attributable to quarantines), and an increase or worsening of mental health concerns.^15,16

We aimed to investigate whether frailty increased disproportionately in a subset of older veterans in the first year of the COVID-19 pandemic when compared with the previous year using CAN scores. This single institution, longitudinal cohort study was determined to be exempt from institutional review board review but was approved by the Phoenix VA Health Care System (PVAHCS) Research and Development Committee.

 

Methods

The Office of Clinical Systems Development and Evaluation (CSDE–10E2A) produces a weekly CAN Score Report to help identify the highest-risk patients in a primary care panel or cohort. CAN scores range from 0 (lowest risk) to 99 (highest risk), indicating how likely a patient is to experience hospitalization or death compared with other VA patients. CAN scores are calculated with statistical prediction models that use data elements from the following Corporate Data Warehouse (CDW) domains: demographics, health care utilization, laboratory tests, medical conditions, medications, and vital signs (eAppendix available online at 10.12788/fp.0385).

The CAN Score Report is generated weekly and stored on a CDW server. A patient will receive all 6 distinct CAN scores if they are: (1) assigned to a primary care PACT on the risk date; (2) a veteran; (3) not hospitalized in a VA facility on the risk date; and (4) alive as of the risk date. New to CAN 2.5 is that patients who meet criteria 1, 2, and 4 but are hospitalized in a VA facility on the risk date will receive CAN scores for the 1-year and 90-day mortality models.

Utilizing VA Informatics and Computing Infrastructure (VA HSR RES 13-457, US Department of Veterans Affairs [2008]), we obtained 2 lists of veterans aged 70 to 75 years on February 8, 2019, with a calculated CAN score of ≥ 75 for 1-year mortality and 1-year hospitalization on that date. A veteran with a CAN score of ≥ 75 is likely to be prefrail or frail.^9,10 Veterans who did not have a corresponding calculated CAN score on February 7, 2020, and February 12, 2021, were excluded. COVID-19 was declared a public health emergency in the United States on January 31, 2020, and the World Health Organization declared COVID-19 a pandemic on March 11, 2020.¹⁷ We picked February 7, 2020, within this time frame and without any other special significance. We picked additional CAN score calculation dates approximately 1 year prior and 1 year after this date. Veterans had to be alive on February 12, 2021, (the last date of the CAN score) to be included in the cohorts.

Statistical Analyses

The difference in CAN score from one year to the next was calculated for each patient. The difference between 2019 and 2020 was compared with the difference between 2020 to 2021 using a paired t test. Yearly CAN score values were analyzed using repeated measures analysis of variance. The number of patients that showed an increase in CAN score (ie, increased risk of either mortality or hospitalization within the year) or a decrease (lower risk) was compared using the χ² test. IBM SPSS v26 and GraphPad Prism v18 were used for statistical analysis. P < .05 was considered statistically significant.

Results

There were 3538 veterans at PVAHCS who met the inclusion criteria and had a 1-year mortality CAN score ≥ 75 on February 8, 2019.

We excluded 6 veterans from the final analysis due to lack of 1-year mortality CAN score for 2020 or 2021. The final number included in the analysis was 3532 (Figure 1). The mean (SD) age was 71.8 (1.3) years. There were 3488 male (98.8%) and 44 female (1.2%) veterans represented (Table 1).

Our data show a decrease in mean 1-year mortality CAN score in this subset of older frail veterans by 4.9 (95% CI, -5.3 to -4.5) in the year preceding the COVID-19 pandemic (Table 2). The 1-year mean mortality CAN score increased significantly by 0.2 (95% CI, -0.3 to 0.6; P < .0001 vs pre-COVID) in this same subset of patients after the first year of the COVID-19 pandemic (Figure 2).

Mean CAN scores for 1-year mortality were 81.5 (95% CI, 81.2 to 81.7), 76.5 (95% CI, 76.1 to 77.0), and 76.7 (95% CI, 76.2 to 77.2) for 2019, 2020, and 2021, respectively.

 

In the hospitalization group, there were 6046 veterans in the analysis; 57 veterans missing a 1-year hospitalization CAN score that were excluded. The mean age was 71.7 (1.3) years and included 5874 male (97.2%) and 172 female (2.8%) veterans. There was a decline in mean 1-year hospitalization CAN scores in our subset of frail older veterans by 2.8 (95% CI, -3.1 to -2.6) in the year preceding the COVID-19 pandemic. This mean decline slowed significantly to 1.5 (95% CI, -1.8 to -1.2; P < .0001) after the first year of the COVID-19 pandemic. Mean CAN scores for 1-year hospitalization were 84.6 (95% CI, 84.4 to 84.8), 81.8 (95% CI, 81.5 to 82.1), and 80.2 (95% CI, 79.9 to 80.6) for 2019, 2020, and 2021, respectively.

We also calculated the number of veterans with increasing, stable, and decreasing CAN scores across each of our defined periods in both the 1-year mortality and hospitalization groups.

The subset of veterans with stable/no change in CAN scores was the smallest in both groups (Figure 3).

A previous study used a 1-year combined hospitalization or mortality event CAN score as the most all-inclusive measure of frailty but determined that it was possible that 1 of the other 5 CAN risk measures could perform better in predicting frailty.¹⁰ We collected and presented data for 1-year mortality and hospitalization CAN scores. There were declines in pandemic-related US hospitalizations for illnesses not related to COVID-19 during the first few months of the pandemic.¹⁸ This may or may not have affected the 1-year hospitalization CAN score data; thus, we used the 1-year mortality CAN score data to predict frailty.

Discussion

We studied frailty trends in an older veteran subpopulation enrolled at the PVAHCS 1 year prior and into the COVID-19 pandemic using CAN scores. Frailty is a dynamic state. Previous frailty assessments aimed to identify patients at the highest risk of death. With the advent of advanced therapeutics for several diseases, the number of medical conditions that are now managed as chronic illnesses continues to grow. There is a role for repeated measures of frailty to try to identify frailty trends.¹⁹ These trends may assist us in resource allocation, identifying interventions that work and those that do not.

Some studies have shown an overall declining lethality of frailty. This may reflect improvements in the care and management of chronic conditions, screening tests, and increased awareness of healthy lifestyles.²⁰ Another study of frailty trajectories in a veteran population in the 5 years preceding death showed multiple trajectories (stable, gradually increasing, rapidly increasing, and recovering).¹⁹

The PACT is a primary care model implemented at VA medical centers in April 2010. It is a patient-centered medical home model (PCMH) with several components. The VA treats a population of socioeconomically vulnerable patients with complex chronic illness management needs. Some of the components of a PACT model relevant to our study include facilitated self-management support for veterans in between practitioner visits via care partners, peer-to-peer and transitional care programs, physical activity and diet programs, primary care mental health, integration between primary and specialty care, and telehealth.²¹ A previous study has shown that VA primary care clinics with the most PCMH components in place had greater improvements in several chronic disease quality measures than in clinics with a lower number of PCMH components.²²

 

Limitations

Our study is limited by our older veteran population demographics. We chose only a subset of older veterans at a single VA center for this study and cannot extrapolate the results to all older frail veterans or community dwelling older adults. Robust individuals may also transition to prefrailty and frailty over longer periods; our study monitored frailty trends over 2 years.

CAN scores are not quality measures to improve upon. Allocation and utilization of additional resources may clinically benefit a patient but increase their CAN scores. Although our results are statistically significant, we are unable to make any conclusions about clinical significance.

Conclusions

Our study results indicate frailty as determined by 1-year mortality CAN scores significantly increased in a subset of older veterans during the first year of the COVID-19 pandemic when compared with the previous year. Whether this change in frailty is temporary or long lasting remains to be seen. Automated CAN scores can be effectively utilized to monitor frailty trends in certain veteran populations over longer periods.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Phoenix Veterans Affairs Health Care System.

Frailty is an age-associated, nonspecific vulnerability to adverse health outcomes. Frailty can also be described as a complex of symptoms characterized by impaired stress tolerance due to a decline in the functionality of different organs.¹ The prevalence of frailty varies widely depending on the method of measurement and the population studied.^2-4 It is a nonconstant factor that increases with age. A deficit accumulation frailty index (FI) is one method used to measure frailty.⁵ This approach sees frailty as a multidimensional risk state measured by quantity rather than the nature of health concerns. A deficit accumulation FI does not require physical testing but correlates well with other phenotypic FIs.⁶ It is, however, time consuming, as ≥ 30 deficits need to be measured to offer greater stability to the frailty estimate.

Health care is seeing increasing utilization of big data analytics to derive predictive models and help with resource allocation. There are currently 2 existing automated tools to predict health care utilization and mortality at the US Department of Veterans Affairs (VA): the VA Frailty Index (VA-FI-10) and the Care Assessment Need (CAN). VA-FI-10 is an International Statistical Classification of Diseases, Tenth Revision (ICD-10) update of the VA-FI that was created in March 2021. The VA-FI-10 is a claims-based frailty assessment tool using 31 health deficits. Calculating the VA-FI-10 requires defining an index date and lookback period (typically 3 years) relative to which it will be calculated.⁷

CAN is a set of risk-stratifying statistical models run on veterans receiving VA primary care services as part of a patient aligned care team (PACT) using electronic health record data.⁸ Each veteran is stratified based on the individual’s risks of hospitalization, death, and hospitalization or death. These 3 events are predicted for 90-day and 1-year time periods for a total of 6 distinct outcomes. CAN is currently on its third iteration (CAN 2.5) and scores range from 0 (low) to 99 (high). CAN scores are updated weekly. The 1-year hospitalization probabilities for all patients range from 0.8% to 93.1%. For patients with a CAN score of 50, the probability of being hospitalized within a year ranges from 4.5% to 5.2%, which increases to 32.2% to 36% for veterans with a CAN score of 95. The probability range widens significantly (32.2%-93.1%) for patients in the top 5 CAN scores (95-99).

CAN scores are a potential screening tool for frailty among older adults; they are generated automatically and provide acceptable diagnostic accuracy. Hence, the CAN score may be a useful tool for primary care practitioners for the detection of frailty in their patients. The CAN score has shown a moderate positive association with the FRAIL Scale.^9,10 The population-based studies that have used the FI approach (differing FIs, depending on the data available) give robust results: People accumulate an average of 0.03 deficits per year after the age of 70 years.¹¹ Interventions to delay or reverse frailty have not been clearly defined with heterogeneity in the definition of frailty and measurement of frailty outcomes.^12,13 The prevalence of frailty in the veteran population is substantially higher than the prevalence in community populations with a similar age distribution. There is also mounting evidence that veterans accumulate deficits more rapidly than their civilian counterparts.¹⁴

COVID-19 was declared a pandemic in March 2020 and had many impacts on global health that were most marked in the first year. These included reductions in hospital visits for non-COVID-19 health concerns, a reduction in completed screening tests, an initial reduction in other infectious diseases (attributable to quarantines), and an increase or worsening of mental health concerns.^15,16

We aimed to investigate whether frailty increased disproportionately in a subset of older veterans in the first year of the COVID-19 pandemic when compared with the previous year using CAN scores. This single institution, longitudinal cohort study was determined to be exempt from institutional review board review but was approved by the Phoenix VA Health Care System (PVAHCS) Research and Development Committee.

 

Methods

The Office of Clinical Systems Development and Evaluation (CSDE–10E2A) produces a weekly CAN Score Report to help identify the highest-risk patients in a primary care panel or cohort. CAN scores range from 0 (lowest risk) to 99 (highest risk), indicating how likely a patient is to experience hospitalization or death compared with other VA patients. CAN scores are calculated with statistical prediction models that use data elements from the following Corporate Data Warehouse (CDW) domains: demographics, health care utilization, laboratory tests, medical conditions, medications, and vital signs (eAppendix available online at 10.12788/fp.0385).

The CAN Score Report is generated weekly and stored on a CDW server. A patient will receive all 6 distinct CAN scores if they are: (1) assigned to a primary care PACT on the risk date; (2) a veteran; (3) not hospitalized in a VA facility on the risk date; and (4) alive as of the risk date. New to CAN 2.5 is that patients who meet criteria 1, 2, and 4 but are hospitalized in a VA facility on the risk date will receive CAN scores for the 1-year and 90-day mortality models.

Utilizing VA Informatics and Computing Infrastructure (VA HSR RES 13-457, US Department of Veterans Affairs [2008]), we obtained 2 lists of veterans aged 70 to 75 years on February 8, 2019, with a calculated CAN score of ≥ 75 for 1-year mortality and 1-year hospitalization on that date. A veteran with a CAN score of ≥ 75 is likely to be prefrail or frail.^9,10 Veterans who did not have a corresponding calculated CAN score on February 7, 2020, and February 12, 2021, were excluded. COVID-19 was declared a public health emergency in the United States on January 31, 2020, and the World Health Organization declared COVID-19 a pandemic on March 11, 2020.¹⁷ We picked February 7, 2020, within this time frame and without any other special significance. We picked additional CAN score calculation dates approximately 1 year prior and 1 year after this date. Veterans had to be alive on February 12, 2021, (the last date of the CAN score) to be included in the cohorts.

Statistical Analyses

The difference in CAN score from one year to the next was calculated for each patient. The difference between 2019 and 2020 was compared with the difference between 2020 to 2021 using a paired t test. Yearly CAN score values were analyzed using repeated measures analysis of variance. The number of patients that showed an increase in CAN score (ie, increased risk of either mortality or hospitalization within the year) or a decrease (lower risk) was compared using the χ² test. IBM SPSS v26 and GraphPad Prism v18 were used for statistical analysis. P < .05 was considered statistically significant.

Results

There were 3538 veterans at PVAHCS who met the inclusion criteria and had a 1-year mortality CAN score ≥ 75 on February 8, 2019.

We excluded 6 veterans from the final analysis due to lack of 1-year mortality CAN score for 2020 or 2021. The final number included in the analysis was 3532 (Figure 1). The mean (SD) age was 71.8 (1.3) years. There were 3488 male (98.8%) and 44 female (1.2%) veterans represented (Table 1).

Our data show a decrease in mean 1-year mortality CAN score in this subset of older frail veterans by 4.9 (95% CI, -5.3 to -4.5) in the year preceding the COVID-19 pandemic (Table 2). The 1-year mean mortality CAN score increased significantly by 0.2 (95% CI, -0.3 to 0.6; P < .0001 vs pre-COVID) in this same subset of patients after the first year of the COVID-19 pandemic (Figure 2).

Mean CAN scores for 1-year mortality were 81.5 (95% CI, 81.2 to 81.7), 76.5 (95% CI, 76.1 to 77.0), and 76.7 (95% CI, 76.2 to 77.2) for 2019, 2020, and 2021, respectively.

 

In the hospitalization group, there were 6046 veterans in the analysis; 57 veterans missing a 1-year hospitalization CAN score that were excluded. The mean age was 71.7 (1.3) years and included 5874 male (97.2%) and 172 female (2.8%) veterans. There was a decline in mean 1-year hospitalization CAN scores in our subset of frail older veterans by 2.8 (95% CI, -3.1 to -2.6) in the year preceding the COVID-19 pandemic. This mean decline slowed significantly to 1.5 (95% CI, -1.8 to -1.2; P < .0001) after the first year of the COVID-19 pandemic. Mean CAN scores for 1-year hospitalization were 84.6 (95% CI, 84.4 to 84.8), 81.8 (95% CI, 81.5 to 82.1), and 80.2 (95% CI, 79.9 to 80.6) for 2019, 2020, and 2021, respectively.

We also calculated the number of veterans with increasing, stable, and decreasing CAN scores across each of our defined periods in both the 1-year mortality and hospitalization groups.

The subset of veterans with stable/no change in CAN scores was the smallest in both groups (Figure 3).

A previous study used a 1-year combined hospitalization or mortality event CAN score as the most all-inclusive measure of frailty but determined that it was possible that 1 of the other 5 CAN risk measures could perform better in predicting frailty.¹⁰ We collected and presented data for 1-year mortality and hospitalization CAN scores. There were declines in pandemic-related US hospitalizations for illnesses not related to COVID-19 during the first few months of the pandemic.¹⁸ This may or may not have affected the 1-year hospitalization CAN score data; thus, we used the 1-year mortality CAN score data to predict frailty.

Discussion

We studied frailty trends in an older veteran subpopulation enrolled at the PVAHCS 1 year prior and into the COVID-19 pandemic using CAN scores. Frailty is a dynamic state. Previous frailty assessments aimed to identify patients at the highest risk of death. With the advent of advanced therapeutics for several diseases, the number of medical conditions that are now managed as chronic illnesses continues to grow. There is a role for repeated measures of frailty to try to identify frailty trends.¹⁹ These trends may assist us in resource allocation, identifying interventions that work and those that do not.

Some studies have shown an overall declining lethality of frailty. This may reflect improvements in the care and management of chronic conditions, screening tests, and increased awareness of healthy lifestyles.²⁰ Another study of frailty trajectories in a veteran population in the 5 years preceding death showed multiple trajectories (stable, gradually increasing, rapidly increasing, and recovering).¹⁹

The PACT is a primary care model implemented at VA medical centers in April 2010. It is a patient-centered medical home model (PCMH) with several components. The VA treats a population of socioeconomically vulnerable patients with complex chronic illness management needs. Some of the components of a PACT model relevant to our study include facilitated self-management support for veterans in between practitioner visits via care partners, peer-to-peer and transitional care programs, physical activity and diet programs, primary care mental health, integration between primary and specialty care, and telehealth.²¹ A previous study has shown that VA primary care clinics with the most PCMH components in place had greater improvements in several chronic disease quality measures than in clinics with a lower number of PCMH components.²²

 

Limitations

Our study is limited by our older veteran population demographics. We chose only a subset of older veterans at a single VA center for this study and cannot extrapolate the results to all older frail veterans or community dwelling older adults. Robust individuals may also transition to prefrailty and frailty over longer periods; our study monitored frailty trends over 2 years.

CAN scores are not quality measures to improve upon. Allocation and utilization of additional resources may clinically benefit a patient but increase their CAN scores. Although our results are statistically significant, we are unable to make any conclusions about clinical significance.

Conclusions

Our study results indicate frailty as determined by 1-year mortality CAN scores significantly increased in a subset of older veterans during the first year of the COVID-19 pandemic when compared with the previous year. Whether this change in frailty is temporary or long lasting remains to be seen. Automated CAN scores can be effectively utilized to monitor frailty trends in certain veteran populations over longer periods.

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the Phoenix Veterans Affairs Health Care System.

Pyogenic hepatic abscess (PHA) is a collection of pus in the liver caused by bacterial infection of the liver parenchyma. This potentially life-threatening condition has a mortality rate reported to be as high as 47%.¹ The incidence of PHA is reported to be 2.3 per 100,000 individuals and is more common in immunosuppressed individuals and those with diabetes mellitus, cancer, and liver transplant.^2,3 PHA infections are usually polymicrobial and most commonly include enteric organisms like Escherichia coli and Klebsiella pneumoniae.⁴

We present a rare cause of PHA with Fusobacterium nucleatum (F nucleatum) in an immunocompetent patient with poor oral health, history of diverticulitis, and recent COVID-19 infection whose only symptoms were chest pain and a 4-week history of fever and malaise.

Case Presentation

A 52-year-old man initially presented to the C.W. Bill Young Veterans Affairs Medical Center (CWBYVAMC) emergency department in Bay Pines, Florida, for fever, malaise, and right-sided chest pain on inspiration. The fever and malaise began while he was on vacation 4 weeks prior. He originally presented to an outside hospital where he tested positive for COVID-19 and was recommended ibuprofen and rest. His symptoms did not improve, and he returned a second time to the outside hospital 2 weeks later and was diagnosed with pneumonia and placed on outpatient antibiotics. The patient subsequently returned to CWBYVAMC 2 weeks after starting antibiotics when he began to develop right-sided inspiratory chest pain. He reported no other recent travel and no abdominal pain. The patient’s history was significant for diverticulitis 2 years before. A colonoscopy was performed during that time and showed no masses.

On presentation, the patient was febrile with a temperature of 100.8 °F; otherwise, his vital signs were stable. Physical examinations, including abdominal, respiratory, and cardiovascular, were unremarkable. The initial laboratory workup revealed a white blood cell (WBC) count of 18.7 K/μL (reference range, 5-10 K/μL) and microcytic anemia with a hemoglobin level of 8.8 g/dL. The comprehensive metabolic panel revealed normal aspartate transaminase, alanine transaminase, and total bilirubin levels and elevated alkaline phosphatase of 215 U/L (reference range, 44-147 U/L), revealing possible mild intrahepatic cholestasis. Urinalysis showed trace proteinuria and urobilinogen. Coagulation studies showed elevated D-dimer and procalcitonin levels at 1.9 ng/mL (reference range, < 0.1 ng/mL) and 1.21 ng/mL (reference range, < 0.5 ng/mL), respectively, with normal prothrombin and partial thromboplastin times. The patient had a normal troponin, fecal, and blood culture; entamoeba serology was negative.

A computed tomograph (CT) angiography of the chest was performed to rule out pulmonary embolism, revealing liver lesions suspicious for abscess or metastatic disease. Minimal pleural effusion was detected bilaterally. A subsequent CT confirmed the presence of hepatic lesions consistent with an abscess (Figure 1).

Empiric antibiotics with anaerobic coverage, including piperacillin-tazobactam and metronidazole, were started. Drainage and culture of the abscess by interventional radiology were performed on hospital day 2, which included placement of a pigtail catheter.

Following the procedure, the patient developed shaking chills, hypertension, fever, and acute hypoxic respiratory failure. He improved with oxygen and was transferred to the intensive care unit (ICU) where he had an increase in temperature and became septic without shock. A repeat blood culture was negative. An echocardiogram revealed no vegetation. Vancomycin was added for empiric coverage of potentially resistant organisms. The patient clinically improved and was able to leave the ICU 2 days later on hospital day 4.

The patient’s renal function worsened on day 5, and piperacillin-tazobactam and vancomycin were discontinued due to possible acute interstitial nephritis and renal toxicity. He started cefepime and continued metronidazole, and his renal function returned to normal 2 days later. Vancomycin was then re-administered. The results of the culture taken from the abscess came back positive for monomicrobial growth of F nucleatum on hospital day 9.

The patient’s mouth revealed dental caries. A maxillofacial CT confirmed signs of dental caries and periodontitis (Figure 2). The patient had not reported any oral cavity symptoms.

Due to the patient’s persisting fever and WBC count, a repeat CT of the abdomen on hospital day 10 revealed a partial decrease in the abscess with a persistent collection superior to the location of the initial pigtail catheter placement. A second pigtail catheter was then placed near the dome of the liver 1 day later on hospital day 11. Following the procedure, the patient improved significantly. The repeat CT after 1 week showed marked overall resolution of the abscess, and the repeat culture of the abscess did not reveal any organism growth. Vancomycin was discontinued on day 19, and the drains were removed on hospital day 20. He was discharged home in stable condition on metronidazole and cefdinir for 21 days with follow-up appointments for CT of the abdomen and with primary care, infectious disease, and a dental specialist.

 

Discussion

F nucleatum is a gram-negative, nonmotile, spindle-shaped rod found in dental plaques.⁵ The incidence of F nucleatum bacteremia is 0.34 per 100,000 people and increases with age, with the median age being 53.5 years.⁶ Although our patient did not present with F nucleatum bacteremia, it is possible that bacteremia was present before hospitalization but resolved by the time the sample was drawn for culture. F nucleatum bacteremia can lead to a variety of presentations. The most common primary diagnoses are intra-abdominal infections (eg, PHA, respiratory tract infections, and hematological disorders).^1,6

PHA Presentation

The most common presenting symptoms of PHA are fever (88%), abdominal pain (79%), and vomiting (50%).⁴ The patient’s presentation of inspiratory right-sided chest pain is likely due to irritation of the diaphragmatic pleura of the right lung secondary to the abscess formation. The patient did not experience abdominal pain throughout the course of this disease or on palpation of his right upper quadrant. To our knowledge, this is the only case of PHA in the literature of a patient with inspiratory chest pain without respiratory infection, abdominal pain, and cardiac abnormalities. There was no radiologic evidence or signs of hypoxia on admission to CWBYVAMC, which makes respiratory infection an unlikely cause of the chest pain. Moreover, the patient presented with new-onset chest pain 2 weeks after the diagnosis of pneumonia.

Common laboratory findings of PHA include transaminitis, leukocytosis, and bilirubinemia.⁴ Of note, increased procalcitonin has also been associated with PHA and extreme elevation (> 200 μg/L) may be a useful biomarker to identify F nucleatum infections before the presence of leukocytosis.³ CT of PHA usually reveals right lobe involvement, and F nucleatum infection usually demonstrates multiple abscesses.^4,7

Contributing Factors in F nucleatum PHA

F nucleatum is associated with several oral diseases, such as periodontitis and gingivitis.⁸ It is important to do an oral inspection on patients with F nucleatum infections because it can spread from oral cavities to different body parts.

F nucleatum is also found in the gut.⁹ Any disease that can cause a break in the gastrointestinal mucosa may result in F nucleatum bacteremia and PHA. This may be why F nucleatum has been associated with a variety of different diseases, such as diverticulitis, inflammatory bowel disease, appendicitis, and colorectal cancer.^10,11 Our patient had a history of diverticulosis with diverticulitis. Bawa and colleagues described a patient with recurrent diverticulitis who developed F nucleatum bacteremia and PHA.¹¹ Our patient did not have any signs of diverticulitis.

Our patient’s COVID-19 infection also had a role in delaying the appropriate treatment of PHA. Without any symptoms of PHA, a diagnosis is difficult in a patient with a positive COVID-19 test, and treatment was delayed 1 month. Moreover, COVID-19 has been reported to delay the diagnosis of PHA even in the absence of a positive COVID-19 test. Collins and Diamond presented a patient during the COVID-19 pandemic who developed a periodontal abscess, which resulted in F nucleatum bacteremia and PHA due to delayed hospital presentation after the patient’s practitioners recommended self-isolation, despite a negative COVID-19 test.¹² This highlights the impact that COVID-19 may have on the timely diagnosis and treatment of patients with PHA.

Malignancy has been associated with F nucleatum bacteremia.^1,13 Possibly the association is due to gastrointestinal mucosa malignancy’s ability to cause micro-abrasions, resulting in F nucleatum bacteremia.¹⁰ Additionally, F nucleatum may promote the development of colorectal neoplasms.⁸ Due to this association, screening for colorectal cancer in patients with F nucleatum infection is important. In our patient, a colonoscopy was performed during the patient’s hospitalization for diverticulitis 2 years prior. No signs of colorectal neoplasm were noted

Conclusions

PHA due to F nucleatum is a rare but potentially life-threatening condition that must be diagnosed and treated promptly. It usually presents with fever, abdominal pain, and vomiting but can present with chest pain in the absence of a respiratory infection, cardiac abnormalities, and abdominal pain, as in our patient. A wide spectrum of infections can occur with F nucleatum, including PHA.

Suspicion for infection with this organism should be kept high in middle-aged and older individuals who present with an indolent disease course and have risk factors, such as poor oral health and comorbidities. Suspicion should be kept high even in the event of COVID-19 infection, especially in individuals with prolonged fever without other signs indicating respiratory infection. We believe that the most likely causes of this patient’s infection were his dental caries and periodontal disease. The timing of his symptoms is not consistent with his previous episode of diverticulitis. Due to the mortality of PHA, diagnosis and treatment must be prompt. Initial treatment with drainage and empiric anaerobic coverage is recommended, followed by a tailored antibiotic regiment if indicated by culture, and further drainage if suggested by imaging.

Pyogenic hepatic abscess (PHA) is a collection of pus in the liver caused by bacterial infection of the liver parenchyma. This potentially life-threatening condition has a mortality rate reported to be as high as 47%.¹ The incidence of PHA is reported to be 2.3 per 100,000 individuals and is more common in immunosuppressed individuals and those with diabetes mellitus, cancer, and liver transplant.^2,3 PHA infections are usually polymicrobial and most commonly include enteric organisms like Escherichia coli and Klebsiella pneumoniae.⁴

We present a rare cause of PHA with Fusobacterium nucleatum (F nucleatum) in an immunocompetent patient with poor oral health, history of diverticulitis, and recent COVID-19 infection whose only symptoms were chest pain and a 4-week history of fever and malaise.

Case Presentation

A 52-year-old man initially presented to the C.W. Bill Young Veterans Affairs Medical Center (CWBYVAMC) emergency department in Bay Pines, Florida, for fever, malaise, and right-sided chest pain on inspiration. The fever and malaise began while he was on vacation 4 weeks prior. He originally presented to an outside hospital where he tested positive for COVID-19 and was recommended ibuprofen and rest. His symptoms did not improve, and he returned a second time to the outside hospital 2 weeks later and was diagnosed with pneumonia and placed on outpatient antibiotics. The patient subsequently returned to CWBYVAMC 2 weeks after starting antibiotics when he began to develop right-sided inspiratory chest pain. He reported no other recent travel and no abdominal pain. The patient’s history was significant for diverticulitis 2 years before. A colonoscopy was performed during that time and showed no masses.

On presentation, the patient was febrile with a temperature of 100.8 °F; otherwise, his vital signs were stable. Physical examinations, including abdominal, respiratory, and cardiovascular, were unremarkable. The initial laboratory workup revealed a white blood cell (WBC) count of 18.7 K/μL (reference range, 5-10 K/μL) and microcytic anemia with a hemoglobin level of 8.8 g/dL. The comprehensive metabolic panel revealed normal aspartate transaminase, alanine transaminase, and total bilirubin levels and elevated alkaline phosphatase of 215 U/L (reference range, 44-147 U/L), revealing possible mild intrahepatic cholestasis. Urinalysis showed trace proteinuria and urobilinogen. Coagulation studies showed elevated D-dimer and procalcitonin levels at 1.9 ng/mL (reference range, < 0.1 ng/mL) and 1.21 ng/mL (reference range, < 0.5 ng/mL), respectively, with normal prothrombin and partial thromboplastin times. The patient had a normal troponin, fecal, and blood culture; entamoeba serology was negative.

A computed tomograph (CT) angiography of the chest was performed to rule out pulmonary embolism, revealing liver lesions suspicious for abscess or metastatic disease. Minimal pleural effusion was detected bilaterally. A subsequent CT confirmed the presence of hepatic lesions consistent with an abscess (Figure 1).

Empiric antibiotics with anaerobic coverage, including piperacillin-tazobactam and metronidazole, were started. Drainage and culture of the abscess by interventional radiology were performed on hospital day 2, which included placement of a pigtail catheter.

Following the procedure, the patient developed shaking chills, hypertension, fever, and acute hypoxic respiratory failure. He improved with oxygen and was transferred to the intensive care unit (ICU) where he had an increase in temperature and became septic without shock. A repeat blood culture was negative. An echocardiogram revealed no vegetation. Vancomycin was added for empiric coverage of potentially resistant organisms. The patient clinically improved and was able to leave the ICU 2 days later on hospital day 4.

The patient’s renal function worsened on day 5, and piperacillin-tazobactam and vancomycin were discontinued due to possible acute interstitial nephritis and renal toxicity. He started cefepime and continued metronidazole, and his renal function returned to normal 2 days later. Vancomycin was then re-administered. The results of the culture taken from the abscess came back positive for monomicrobial growth of F nucleatum on hospital day 9.

The patient’s mouth revealed dental caries. A maxillofacial CT confirmed signs of dental caries and periodontitis (Figure 2). The patient had not reported any oral cavity symptoms.

Due to the patient’s persisting fever and WBC count, a repeat CT of the abdomen on hospital day 10 revealed a partial decrease in the abscess with a persistent collection superior to the location of the initial pigtail catheter placement. A second pigtail catheter was then placed near the dome of the liver 1 day later on hospital day 11. Following the procedure, the patient improved significantly. The repeat CT after 1 week showed marked overall resolution of the abscess, and the repeat culture of the abscess did not reveal any organism growth. Vancomycin was discontinued on day 19, and the drains were removed on hospital day 20. He was discharged home in stable condition on metronidazole and cefdinir for 21 days with follow-up appointments for CT of the abdomen and with primary care, infectious disease, and a dental specialist.

 

Discussion

F nucleatum is a gram-negative, nonmotile, spindle-shaped rod found in dental plaques.⁵ The incidence of F nucleatum bacteremia is 0.34 per 100,000 people and increases with age, with the median age being 53.5 years.⁶ Although our patient did not present with F nucleatum bacteremia, it is possible that bacteremia was present before hospitalization but resolved by the time the sample was drawn for culture. F nucleatum bacteremia can lead to a variety of presentations. The most common primary diagnoses are intra-abdominal infections (eg, PHA, respiratory tract infections, and hematological disorders).^1,6

PHA Presentation

The most common presenting symptoms of PHA are fever (88%), abdominal pain (79%), and vomiting (50%).⁴ The patient’s presentation of inspiratory right-sided chest pain is likely due to irritation of the diaphragmatic pleura of the right lung secondary to the abscess formation. The patient did not experience abdominal pain throughout the course of this disease or on palpation of his right upper quadrant. To our knowledge, this is the only case of PHA in the literature of a patient with inspiratory chest pain without respiratory infection, abdominal pain, and cardiac abnormalities. There was no radiologic evidence or signs of hypoxia on admission to CWBYVAMC, which makes respiratory infection an unlikely cause of the chest pain. Moreover, the patient presented with new-onset chest pain 2 weeks after the diagnosis of pneumonia.

Common laboratory findings of PHA include transaminitis, leukocytosis, and bilirubinemia.⁴ Of note, increased procalcitonin has also been associated with PHA and extreme elevation (> 200 μg/L) may be a useful biomarker to identify F nucleatum infections before the presence of leukocytosis.³ CT of PHA usually reveals right lobe involvement, and F nucleatum infection usually demonstrates multiple abscesses.^4,7

Contributing Factors in F nucleatum PHA

F nucleatum is associated with several oral diseases, such as periodontitis and gingivitis.⁸ It is important to do an oral inspection on patients with F nucleatum infections because it can spread from oral cavities to different body parts.

F nucleatum is also found in the gut.⁹ Any disease that can cause a break in the gastrointestinal mucosa may result in F nucleatum bacteremia and PHA. This may be why F nucleatum has been associated with a variety of different diseases, such as diverticulitis, inflammatory bowel disease, appendicitis, and colorectal cancer.^10,11 Our patient had a history of diverticulosis with diverticulitis. Bawa and colleagues described a patient with recurrent diverticulitis who developed F nucleatum bacteremia and PHA.¹¹ Our patient did not have any signs of diverticulitis.

Our patient’s COVID-19 infection also had a role in delaying the appropriate treatment of PHA. Without any symptoms of PHA, a diagnosis is difficult in a patient with a positive COVID-19 test, and treatment was delayed 1 month. Moreover, COVID-19 has been reported to delay the diagnosis of PHA even in the absence of a positive COVID-19 test. Collins and Diamond presented a patient during the COVID-19 pandemic who developed a periodontal abscess, which resulted in F nucleatum bacteremia and PHA due to delayed hospital presentation after the patient’s practitioners recommended self-isolation, despite a negative COVID-19 test.¹² This highlights the impact that COVID-19 may have on the timely diagnosis and treatment of patients with PHA.

Malignancy has been associated with F nucleatum bacteremia.^1,13 Possibly the association is due to gastrointestinal mucosa malignancy’s ability to cause micro-abrasions, resulting in F nucleatum bacteremia.¹⁰ Additionally, F nucleatum may promote the development of colorectal neoplasms.⁸ Due to this association, screening for colorectal cancer in patients with F nucleatum infection is important. In our patient, a colonoscopy was performed during the patient’s hospitalization for diverticulitis 2 years prior. No signs of colorectal neoplasm were noted

Conclusions

PHA due to F nucleatum is a rare but potentially life-threatening condition that must be diagnosed and treated promptly. It usually presents with fever, abdominal pain, and vomiting but can present with chest pain in the absence of a respiratory infection, cardiac abnormalities, and abdominal pain, as in our patient. A wide spectrum of infections can occur with F nucleatum, including PHA.

Suspicion for infection with this organism should be kept high in middle-aged and older individuals who present with an indolent disease course and have risk factors, such as poor oral health and comorbidities. Suspicion should be kept high even in the event of COVID-19 infection, especially in individuals with prolonged fever without other signs indicating respiratory infection. We believe that the most likely causes of this patient’s infection were his dental caries and periodontal disease. The timing of his symptoms is not consistent with his previous episode of diverticulitis. Due to the mortality of PHA, diagnosis and treatment must be prompt. Initial treatment with drainage and empiric anaerobic coverage is recommended, followed by a tailored antibiotic regiment if indicated by culture, and further drainage if suggested by imaging.

Pyogenic hepatic abscess (PHA) is a collection of pus in the liver caused by bacterial infection of the liver parenchyma. This potentially life-threatening condition has a mortality rate reported to be as high as 47%.¹ The incidence of PHA is reported to be 2.3 per 100,000 individuals and is more common in immunosuppressed individuals and those with diabetes mellitus, cancer, and liver transplant.^2,3 PHA infections are usually polymicrobial and most commonly include enteric organisms like Escherichia coli and Klebsiella pneumoniae.⁴

We present a rare cause of PHA with Fusobacterium nucleatum (F nucleatum) in an immunocompetent patient with poor oral health, history of diverticulitis, and recent COVID-19 infection whose only symptoms were chest pain and a 4-week history of fever and malaise.

Case Presentation

A 52-year-old man initially presented to the C.W. Bill Young Veterans Affairs Medical Center (CWBYVAMC) emergency department in Bay Pines, Florida, for fever, malaise, and right-sided chest pain on inspiration. The fever and malaise began while he was on vacation 4 weeks prior. He originally presented to an outside hospital where he tested positive for COVID-19 and was recommended ibuprofen and rest. His symptoms did not improve, and he returned a second time to the outside hospital 2 weeks later and was diagnosed with pneumonia and placed on outpatient antibiotics. The patient subsequently returned to CWBYVAMC 2 weeks after starting antibiotics when he began to develop right-sided inspiratory chest pain. He reported no other recent travel and no abdominal pain. The patient’s history was significant for diverticulitis 2 years before. A colonoscopy was performed during that time and showed no masses.

On presentation, the patient was febrile with a temperature of 100.8 °F; otherwise, his vital signs were stable. Physical examinations, including abdominal, respiratory, and cardiovascular, were unremarkable. The initial laboratory workup revealed a white blood cell (WBC) count of 18.7 K/μL (reference range, 5-10 K/μL) and microcytic anemia with a hemoglobin level of 8.8 g/dL. The comprehensive metabolic panel revealed normal aspartate transaminase, alanine transaminase, and total bilirubin levels and elevated alkaline phosphatase of 215 U/L (reference range, 44-147 U/L), revealing possible mild intrahepatic cholestasis. Urinalysis showed trace proteinuria and urobilinogen. Coagulation studies showed elevated D-dimer and procalcitonin levels at 1.9 ng/mL (reference range, < 0.1 ng/mL) and 1.21 ng/mL (reference range, < 0.5 ng/mL), respectively, with normal prothrombin and partial thromboplastin times. The patient had a normal troponin, fecal, and blood culture; entamoeba serology was negative.

A computed tomograph (CT) angiography of the chest was performed to rule out pulmonary embolism, revealing liver lesions suspicious for abscess or metastatic disease. Minimal pleural effusion was detected bilaterally. A subsequent CT confirmed the presence of hepatic lesions consistent with an abscess (Figure 1).

Empiric antibiotics with anaerobic coverage, including piperacillin-tazobactam and metronidazole, were started. Drainage and culture of the abscess by interventional radiology were performed on hospital day 2, which included placement of a pigtail catheter.

Following the procedure, the patient developed shaking chills, hypertension, fever, and acute hypoxic respiratory failure. He improved with oxygen and was transferred to the intensive care unit (ICU) where he had an increase in temperature and became septic without shock. A repeat blood culture was negative. An echocardiogram revealed no vegetation. Vancomycin was added for empiric coverage of potentially resistant organisms. The patient clinically improved and was able to leave the ICU 2 days later on hospital day 4.

The patient’s renal function worsened on day 5, and piperacillin-tazobactam and vancomycin were discontinued due to possible acute interstitial nephritis and renal toxicity. He started cefepime and continued metronidazole, and his renal function returned to normal 2 days later. Vancomycin was then re-administered. The results of the culture taken from the abscess came back positive for monomicrobial growth of F nucleatum on hospital day 9.

The patient’s mouth revealed dental caries. A maxillofacial CT confirmed signs of dental caries and periodontitis (Figure 2). The patient had not reported any oral cavity symptoms.

Due to the patient’s persisting fever and WBC count, a repeat CT of the abdomen on hospital day 10 revealed a partial decrease in the abscess with a persistent collection superior to the location of the initial pigtail catheter placement. A second pigtail catheter was then placed near the dome of the liver 1 day later on hospital day 11. Following the procedure, the patient improved significantly. The repeat CT after 1 week showed marked overall resolution of the abscess, and the repeat culture of the abscess did not reveal any organism growth. Vancomycin was discontinued on day 19, and the drains were removed on hospital day 20. He was discharged home in stable condition on metronidazole and cefdinir for 21 days with follow-up appointments for CT of the abdomen and with primary care, infectious disease, and a dental specialist.

 

Discussion

F nucleatum is a gram-negative, nonmotile, spindle-shaped rod found in dental plaques.⁵ The incidence of F nucleatum bacteremia is 0.34 per 100,000 people and increases with age, with the median age being 53.5 years.⁶ Although our patient did not present with F nucleatum bacteremia, it is possible that bacteremia was present before hospitalization but resolved by the time the sample was drawn for culture. F nucleatum bacteremia can lead to a variety of presentations. The most common primary diagnoses are intra-abdominal infections (eg, PHA, respiratory tract infections, and hematological disorders).^1,6

PHA Presentation

The most common presenting symptoms of PHA are fever (88%), abdominal pain (79%), and vomiting (50%).⁴ The patient’s presentation of inspiratory right-sided chest pain is likely due to irritation of the diaphragmatic pleura of the right lung secondary to the abscess formation. The patient did not experience abdominal pain throughout the course of this disease or on palpation of his right upper quadrant. To our knowledge, this is the only case of PHA in the literature of a patient with inspiratory chest pain without respiratory infection, abdominal pain, and cardiac abnormalities. There was no radiologic evidence or signs of hypoxia on admission to CWBYVAMC, which makes respiratory infection an unlikely cause of the chest pain. Moreover, the patient presented with new-onset chest pain 2 weeks after the diagnosis of pneumonia.

Common laboratory findings of PHA include transaminitis, leukocytosis, and bilirubinemia.⁴ Of note, increased procalcitonin has also been associated with PHA and extreme elevation (> 200 μg/L) may be a useful biomarker to identify F nucleatum infections before the presence of leukocytosis.³ CT of PHA usually reveals right lobe involvement, and F nucleatum infection usually demonstrates multiple abscesses.^4,7

Contributing Factors in F nucleatum PHA

F nucleatum is associated with several oral diseases, such as periodontitis and gingivitis.⁸ It is important to do an oral inspection on patients with F nucleatum infections because it can spread from oral cavities to different body parts.

F nucleatum is also found in the gut.⁹ Any disease that can cause a break in the gastrointestinal mucosa may result in F nucleatum bacteremia and PHA. This may be why F nucleatum has been associated with a variety of different diseases, such as diverticulitis, inflammatory bowel disease, appendicitis, and colorectal cancer.^10,11 Our patient had a history of diverticulosis with diverticulitis. Bawa and colleagues described a patient with recurrent diverticulitis who developed F nucleatum bacteremia and PHA.¹¹ Our patient did not have any signs of diverticulitis.

Our patient’s COVID-19 infection also had a role in delaying the appropriate treatment of PHA. Without any symptoms of PHA, a diagnosis is difficult in a patient with a positive COVID-19 test, and treatment was delayed 1 month. Moreover, COVID-19 has been reported to delay the diagnosis of PHA even in the absence of a positive COVID-19 test. Collins and Diamond presented a patient during the COVID-19 pandemic who developed a periodontal abscess, which resulted in F nucleatum bacteremia and PHA due to delayed hospital presentation after the patient’s practitioners recommended self-isolation, despite a negative COVID-19 test.¹² This highlights the impact that COVID-19 may have on the timely diagnosis and treatment of patients with PHA.

Malignancy has been associated with F nucleatum bacteremia.^1,13 Possibly the association is due to gastrointestinal mucosa malignancy’s ability to cause micro-abrasions, resulting in F nucleatum bacteremia.¹⁰ Additionally, F nucleatum may promote the development of colorectal neoplasms.⁸ Due to this association, screening for colorectal cancer in patients with F nucleatum infection is important. In our patient, a colonoscopy was performed during the patient’s hospitalization for diverticulitis 2 years prior. No signs of colorectal neoplasm were noted

Conclusions

PHA due to F nucleatum is a rare but potentially life-threatening condition that must be diagnosed and treated promptly. It usually presents with fever, abdominal pain, and vomiting but can present with chest pain in the absence of a respiratory infection, cardiac abnormalities, and abdominal pain, as in our patient. A wide spectrum of infections can occur with F nucleatum, including PHA.

Suspicion for infection with this organism should be kept high in middle-aged and older individuals who present with an indolent disease course and have risk factors, such as poor oral health and comorbidities. Suspicion should be kept high even in the event of COVID-19 infection, especially in individuals with prolonged fever without other signs indicating respiratory infection. We believe that the most likely causes of this patient’s infection were his dental caries and periodontal disease. The timing of his symptoms is not consistent with his previous episode of diverticulitis. Due to the mortality of PHA, diagnosis and treatment must be prompt. Initial treatment with drainage and empiric anaerobic coverage is recommended, followed by a tailored antibiotic regiment if indicated by culture, and further drainage if suggested by imaging.

The US Coast Guard (USCG) operates within the US Department of Homeland Security during times of peace and represents a force of > 55,000 active-duty service members (ADSMs), civilians, and reservists. ADSMs account for about 40,000 USCG personnel. The missions of the USCG include activities such as maritime law enforcement (drug interdiction), search and rescue, and defense readiness.¹ Akin to other US Department of Defense (DoD) services, USCG ADSMs are required to maintain medical readiness to maximize operational success.

Whereas the DoD centralizes its health care services at military treatment facilities, USCG health care tends to be dispersed to smaller clinics and sickbays across large geographic areas. The USCG operates 42 clinics of varying sizes and medical capabilities, providing outpatient, dentistry, pharmacy, laboratory, radiology, physical therapy, optometry, and other health care services. Many ADSMs are evaluated by a USCG medical officer in these outpatient clinics, and ADSMs may choose to fill prescriptions at the in-house pharmacy if present at that clinic.

The USCG has 14 field pharmacists. In addition to the standard dispensing role at their respective clinics, USCG pharmacists provide regional oversight of pharmaceutical services for USCG units within their area of responsibility (AOR). Therefore, USCG pharmacists clinically, operationally, and logistically support these regional assets within their AOR while serving the traditional pharmacist role. USCG pharmacists have access to ADSM electronic health records (EHRs) when evaluating prescription orders, similar to other ambulatory care settings.

New recruits and accessions into the USCG are first screened for disqualifying health conditions, and ADSMs are required to maintain medical readiness throughout their careers.² Therefore, this population tends to be younger and overall healthier compared with the general population. Equally important, medication errors or inappropriate prescribing in the ADSM group could negatively affect their duty status and mission readiness of the USCG in addition to exposing the ADSM to medication-related harms.

Duty status is an important and unique consideration in this population. ADSMs are expected to be deployable worldwide and physically and mentally capable of executing all duties associated with their position. Duty status implications and the perceived ability to stand watch are tied to an ADMS’s specialty, training, and unit role. Duty status is based on various frameworks like the USCG Medical Manual, Aeromedical Policy Letters, and other governing documents.³ Duty status determinations are initiated by privileged USCG medical practitioners and may be executed in consultation with relevant commands and other subject matter experts. An inappropriately dosed antibiotic prescription, for example, can extend the duration that an ADSM would be considered unfit for full duty due to prolonged illness. Accordingly, being on a limited duty status may negatively affect USCG total mission readiness as a whole. USCG pharmacists play a vital role in optimizing ADSMs’ medication therapies to ensure safety and efficacy.

Currently no published literature explores the number of medication interventions or the impact of those interventions made by USCG pharmacists. This study aimed to quantify the number, duty status impact, and replicability of medication interventions made by one pharmacist at the USCG Base Alameda clinic over 6 months.

 

Methods

As part of a USCG quality improvement study, a pharmacist tracked all medication interventions on a spreadsheet at USCG Base Alameda clinic from July 1, 2021, to December 31, 2021. The study defined a medication intervention as a communication with the prescriber with the intention to change the medication, strength, dose, dosage form, quantity, or instructions. Each intervention was subcategorized as either a drug therapy problem (DTP) or a non-DTP intervention. Interventions were divided into 7 categories.

Each DTP intervention was evaluated in a retrospective chart review by a panel of USCG pharmacists to assess for duty status severity and replicability. For duty status severity, the panel reviewed the intervention after considering patient-specific factors and determined whether the original prescribing (had there not been an intervention) could have reasonably resulted in a change of duty status for the ADSM from a fit for full duty (FFFD) status to a different duty status (eg, fit for limited duty [FFLD]). This duty status review factored in potential impacts across multiple positions and billets, including aviators (pilots) and divers. In addition, the panel, whose members all have prior community pharmacy experience, assessed replicability by determining whether the same intervention could have reasonably been made in the absence of access to the patient EHR, as would be common in a community pharmacy setting.

Interventions without an identified DTP were considered non-DTP interventions. These interventions involved recommendations for a more cost-effective medication or a similar in stock therapeutic option to minimize delay of patient care. The spreadsheet also included the date, medication name, medication class, specific intervention made, outcome, and other descriptive comments.

Results

During the 6-month period, 1751 prescriptions were dispensed at USCG Base Alameda pharmacy with 116 interventions (7%).

Most interventions (n = 111, 96%) were accepted by the prescriber. Of the 116 interventions, 64 (55%) were DTP interventions; 21 of the DTP interventions (33%) were indication, 20 effectiveness (31%), 19 safety (30%), and 4 adherence (6%) (Table 1).

Among the DTP interventions, 26 (41%) dealt with an inappropriate dose, 13 (20%) were for medication omission, 7 (11%) for inappropriate dosage form, and 6 (9%) for excess medication (Table 2).

Fourteen interventions (22%) impacted duty status, and 18 (28%) were made because the pharmacist had EHR access. Among 51 non-DTP interventions, 34 (67%) minimized delay in patient care, and 17 (33%) cost-savings interventions were made, resulting in about $1700 in savings. Antibiotics had the most interventions (n = 28: 10 DTP and 18 non-DTP).

Discussion

This study is novel in examining the impact of a pharmacist’s medication interventions in a USCG ambulatory care practice setting. A PubMed literature search of the phrases “Coast Guard AND pharmacy” or “Coast Guard AND pharmacy AND intervention” yielded no results specific to pharmacy interventions in a USCG setting. However, the 2021 implementation of the enterprise-wide MHS GENESIS EHR may support additional tracking and analysis tools in the future.

Pharmacist interventions have been studied in diverse patient populations and practice settings, and most conclude that pharmacists make meaningful interventions at their respective organizations.^4-7 Many of these studies were conducted at open-door health care systems, whereas USCG clinics serve ADSMs nearly exclusively. The ADSM population tends to be younger and healthier due to age requirements and medical accession and retention standards.

It is important to recognize the value of a USCG pharmacist in identifying and rectifying potential medication errors, particularly those that may affect the ability to stand duty for ADSMs. An example intervention includes changing the daily starting dose of citalopram from the ordered 30 mg to the intended 10 mg. Inappropriately prescribed medication regimens may increase the incidence of adverse effects or prolong duration to therapeutic efficacy, which impairs the ability to stand duty. There were 3 circumstances where the prescriber had ordered the medication for an incorrect ADSM that were rectified by the pharmacist. If left unchanged, these errors could negatively affect the ADSM’s overall health, well-being, and duty status.

The acceptance rate for interventions in this study was 96%. The literature suggests a highly variable acceptance rate of pharmacist interventions when examined across various practice settings, health systems, and geographic locations.^8-10 This study’s comparatively high rate could be due to the pharmacist-prescriber relationships at USCG clinics. By virtue of colocatation and teamwork initiatives, the pharmacist has the opportunity to develop positive rapport with physicians, physician assistants, and other clinic staff.

Having access to EHRs allowed the pharmacist to make 18 of the DTP interventions. Chart access is not unique to the USCG and is common in other ambulatory care settings. Those 18 interventions, such as reconciling a prescription ordered as fluticasone/salmeterol but recorded in the EHR as “will prescribe montelukast,” were deemed possible because of EHR access. Such interventions could potentially be lost if ADSMs solely received their pharmaceutical care elsewhere.

USCG uses independent duty health services technicians (IDHSs) who practice in settings where a medical officer is not present, such as at smaller sickbays or aboard Coast Guard cutters. In this study, an IDHS had mistakenly created a medication order for the medical officer to sign for bupropion SR, when the ADSM had been taking and was intended to continue taking bupropion XL. This order was signed off by the medical officer, but this oversight was identified and corrected by the pharmacist before dispensing. This indicates that there is a vital educational role that the USCG pharmacist fulfills when working with health care team members within the AOR.

Equally important to consider are the non-DTP interventions. In a military setting, minimizations of delay in care are a high priority. There were 34 instances where the pharmacist made an intervention to recommend a similar therapeutic medication that was in stock to ensure that the ADSM had timely access to the medication without the need for prior authorization. In the context of short-notice, mission-critical deployments that may last for multiple months, recognizing medication shortages or other inventory constraints and recommending therapeutic alternatives ensures that the USCG can maintain a ready posture for missions in addition to providing timely and quality patient care.

Saving about $1700 over 6 months is also important. While this was not explicitly evaluated in the study, prescribers may not be acutely aware of medication pricing. There are often significant price differences between different formulations of the same medication (eg, naproxen delayed-release vs tablets). Because USCG pharmacists are responsible for ordering medications and managing their regional budget within the AOR, they are best poised to make cost-savings recommendations. These interventions suggest that USCG pharmacists must continue to remain actively involved in the patient care team alongside physicians, physician assistants, nurses, and corpsmen. Throughout this setting and in so many others, patients’ health outcomes improve when pharmacists are more engaged in the pharmacotherapy care plan.

 

Limitations

Currently, the USCG does not publish ADSM demographic or health-related data, making it difficult to evaluate these interventions in the context of age, gender, or type of disease. Accordingly, potential directions for future research include how USCG pharmacists’ interventions are stratified by duty station and initial diagnosis. Such studies may support future models where USCG pharmacists are providing targeted education to prescribers based on disease or medication classes.

This analysis may have limited applicability to other practice settings even within USCG. Most USCG clinics have a limited number of medical officers; indeed, many have only one, and clinics with pharmacies typically have 1 to 5 medical officers aboard. USCG medical officers have a multitude of other duties, which may impact prescribing patterns and pharmacist interventions. Statistical analyses were limited by the dearth of baseline data or comparative literature. Finally, the assessment of DTP interventions’ impact did not use an official measurement tool like the US Department of Veterans Affairs’ Safety Assessment Code matrix.¹¹ Instead, the study used the internal USCG pharmacist panel for the fitness for duty consideration as the main stratification of the DTP interventions’ duty status severity, because maintaining medical readiness is the top priority for a USCG clinic.

Conclusions

The multifaceted role of pharmacists in USCG clinics includes collaborating with the patient care team to make pharmacy interventions that have significant impacts on ADSMs’ wellness and the USCG mission. The ADSMs of this nation deserve quality medical care that translates into mission readiness, and the USCG pharmacy force stands ready to support that goal.

Acknowledgments

The authors acknowledge the contributions of CDR Christopher Janik, US Coast Guard Headquarters, and LCDR Darin Schneider, US Coast Guard D11 Regional Practice Manager, in the drafting of the manuscript.

The US Coast Guard (USCG) operates within the US Department of Homeland Security during times of peace and represents a force of > 55,000 active-duty service members (ADSMs), civilians, and reservists. ADSMs account for about 40,000 USCG personnel. The missions of the USCG include activities such as maritime law enforcement (drug interdiction), search and rescue, and defense readiness.¹ Akin to other US Department of Defense (DoD) services, USCG ADSMs are required to maintain medical readiness to maximize operational success.

Whereas the DoD centralizes its health care services at military treatment facilities, USCG health care tends to be dispersed to smaller clinics and sickbays across large geographic areas. The USCG operates 42 clinics of varying sizes and medical capabilities, providing outpatient, dentistry, pharmacy, laboratory, radiology, physical therapy, optometry, and other health care services. Many ADSMs are evaluated by a USCG medical officer in these outpatient clinics, and ADSMs may choose to fill prescriptions at the in-house pharmacy if present at that clinic.

The USCG has 14 field pharmacists. In addition to the standard dispensing role at their respective clinics, USCG pharmacists provide regional oversight of pharmaceutical services for USCG units within their area of responsibility (AOR). Therefore, USCG pharmacists clinically, operationally, and logistically support these regional assets within their AOR while serving the traditional pharmacist role. USCG pharmacists have access to ADSM electronic health records (EHRs) when evaluating prescription orders, similar to other ambulatory care settings.

New recruits and accessions into the USCG are first screened for disqualifying health conditions, and ADSMs are required to maintain medical readiness throughout their careers.² Therefore, this population tends to be younger and overall healthier compared with the general population. Equally important, medication errors or inappropriate prescribing in the ADSM group could negatively affect their duty status and mission readiness of the USCG in addition to exposing the ADSM to medication-related harms.

Duty status is an important and unique consideration in this population. ADSMs are expected to be deployable worldwide and physically and mentally capable of executing all duties associated with their position. Duty status implications and the perceived ability to stand watch are tied to an ADMS’s specialty, training, and unit role. Duty status is based on various frameworks like the USCG Medical Manual, Aeromedical Policy Letters, and other governing documents.³ Duty status determinations are initiated by privileged USCG medical practitioners and may be executed in consultation with relevant commands and other subject matter experts. An inappropriately dosed antibiotic prescription, for example, can extend the duration that an ADSM would be considered unfit for full duty due to prolonged illness. Accordingly, being on a limited duty status may negatively affect USCG total mission readiness as a whole. USCG pharmacists play a vital role in optimizing ADSMs’ medication therapies to ensure safety and efficacy.

Currently no published literature explores the number of medication interventions or the impact of those interventions made by USCG pharmacists. This study aimed to quantify the number, duty status impact, and replicability of medication interventions made by one pharmacist at the USCG Base Alameda clinic over 6 months.

 

Methods

As part of a USCG quality improvement study, a pharmacist tracked all medication interventions on a spreadsheet at USCG Base Alameda clinic from July 1, 2021, to December 31, 2021. The study defined a medication intervention as a communication with the prescriber with the intention to change the medication, strength, dose, dosage form, quantity, or instructions. Each intervention was subcategorized as either a drug therapy problem (DTP) or a non-DTP intervention. Interventions were divided into 7 categories.

Each DTP intervention was evaluated in a retrospective chart review by a panel of USCG pharmacists to assess for duty status severity and replicability. For duty status severity, the panel reviewed the intervention after considering patient-specific factors and determined whether the original prescribing (had there not been an intervention) could have reasonably resulted in a change of duty status for the ADSM from a fit for full duty (FFFD) status to a different duty status (eg, fit for limited duty [FFLD]). This duty status review factored in potential impacts across multiple positions and billets, including aviators (pilots) and divers. In addition, the panel, whose members all have prior community pharmacy experience, assessed replicability by determining whether the same intervention could have reasonably been made in the absence of access to the patient EHR, as would be common in a community pharmacy setting.

Interventions without an identified DTP were considered non-DTP interventions. These interventions involved recommendations for a more cost-effective medication or a similar in stock therapeutic option to minimize delay of patient care. The spreadsheet also included the date, medication name, medication class, specific intervention made, outcome, and other descriptive comments.

Results

During the 6-month period, 1751 prescriptions were dispensed at USCG Base Alameda pharmacy with 116 interventions (7%).

Most interventions (n = 111, 96%) were accepted by the prescriber. Of the 116 interventions, 64 (55%) were DTP interventions; 21 of the DTP interventions (33%) were indication, 20 effectiveness (31%), 19 safety (30%), and 4 adherence (6%) (Table 1).

Among the DTP interventions, 26 (41%) dealt with an inappropriate dose, 13 (20%) were for medication omission, 7 (11%) for inappropriate dosage form, and 6 (9%) for excess medication (Table 2).

Fourteen interventions (22%) impacted duty status, and 18 (28%) were made because the pharmacist had EHR access. Among 51 non-DTP interventions, 34 (67%) minimized delay in patient care, and 17 (33%) cost-savings interventions were made, resulting in about $1700 in savings. Antibiotics had the most interventions (n = 28: 10 DTP and 18 non-DTP).

Discussion

This study is novel in examining the impact of a pharmacist’s medication interventions in a USCG ambulatory care practice setting. A PubMed literature search of the phrases “Coast Guard AND pharmacy” or “Coast Guard AND pharmacy AND intervention” yielded no results specific to pharmacy interventions in a USCG setting. However, the 2021 implementation of the enterprise-wide MHS GENESIS EHR may support additional tracking and analysis tools in the future.

Pharmacist interventions have been studied in diverse patient populations and practice settings, and most conclude that pharmacists make meaningful interventions at their respective organizations.^4-7 Many of these studies were conducted at open-door health care systems, whereas USCG clinics serve ADSMs nearly exclusively. The ADSM population tends to be younger and healthier due to age requirements and medical accession and retention standards.

It is important to recognize the value of a USCG pharmacist in identifying and rectifying potential medication errors, particularly those that may affect the ability to stand duty for ADSMs. An example intervention includes changing the daily starting dose of citalopram from the ordered 30 mg to the intended 10 mg. Inappropriately prescribed medication regimens may increase the incidence of adverse effects or prolong duration to therapeutic efficacy, which impairs the ability to stand duty. There were 3 circumstances where the prescriber had ordered the medication for an incorrect ADSM that were rectified by the pharmacist. If left unchanged, these errors could negatively affect the ADSM’s overall health, well-being, and duty status.

The acceptance rate for interventions in this study was 96%. The literature suggests a highly variable acceptance rate of pharmacist interventions when examined across various practice settings, health systems, and geographic locations.^8-10 This study’s comparatively high rate could be due to the pharmacist-prescriber relationships at USCG clinics. By virtue of colocatation and teamwork initiatives, the pharmacist has the opportunity to develop positive rapport with physicians, physician assistants, and other clinic staff.

Having access to EHRs allowed the pharmacist to make 18 of the DTP interventions. Chart access is not unique to the USCG and is common in other ambulatory care settings. Those 18 interventions, such as reconciling a prescription ordered as fluticasone/salmeterol but recorded in the EHR as “will prescribe montelukast,” were deemed possible because of EHR access. Such interventions could potentially be lost if ADSMs solely received their pharmaceutical care elsewhere.

USCG uses independent duty health services technicians (IDHSs) who practice in settings where a medical officer is not present, such as at smaller sickbays or aboard Coast Guard cutters. In this study, an IDHS had mistakenly created a medication order for the medical officer to sign for bupropion SR, when the ADSM had been taking and was intended to continue taking bupropion XL. This order was signed off by the medical officer, but this oversight was identified and corrected by the pharmacist before dispensing. This indicates that there is a vital educational role that the USCG pharmacist fulfills when working with health care team members within the AOR.

Equally important to consider are the non-DTP interventions. In a military setting, minimizations of delay in care are a high priority. There were 34 instances where the pharmacist made an intervention to recommend a similar therapeutic medication that was in stock to ensure that the ADSM had timely access to the medication without the need for prior authorization. In the context of short-notice, mission-critical deployments that may last for multiple months, recognizing medication shortages or other inventory constraints and recommending therapeutic alternatives ensures that the USCG can maintain a ready posture for missions in addition to providing timely and quality patient care.

Saving about $1700 over 6 months is also important. While this was not explicitly evaluated in the study, prescribers may not be acutely aware of medication pricing. There are often significant price differences between different formulations of the same medication (eg, naproxen delayed-release vs tablets). Because USCG pharmacists are responsible for ordering medications and managing their regional budget within the AOR, they are best poised to make cost-savings recommendations. These interventions suggest that USCG pharmacists must continue to remain actively involved in the patient care team alongside physicians, physician assistants, nurses, and corpsmen. Throughout this setting and in so many others, patients’ health outcomes improve when pharmacists are more engaged in the pharmacotherapy care plan.

 

Limitations

Currently, the USCG does not publish ADSM demographic or health-related data, making it difficult to evaluate these interventions in the context of age, gender, or type of disease. Accordingly, potential directions for future research include how USCG pharmacists’ interventions are stratified by duty station and initial diagnosis. Such studies may support future models where USCG pharmacists are providing targeted education to prescribers based on disease or medication classes.

This analysis may have limited applicability to other practice settings even within USCG. Most USCG clinics have a limited number of medical officers; indeed, many have only one, and clinics with pharmacies typically have 1 to 5 medical officers aboard. USCG medical officers have a multitude of other duties, which may impact prescribing patterns and pharmacist interventions. Statistical analyses were limited by the dearth of baseline data or comparative literature. Finally, the assessment of DTP interventions’ impact did not use an official measurement tool like the US Department of Veterans Affairs’ Safety Assessment Code matrix.¹¹ Instead, the study used the internal USCG pharmacist panel for the fitness for duty consideration as the main stratification of the DTP interventions’ duty status severity, because maintaining medical readiness is the top priority for a USCG clinic.

Conclusions

The multifaceted role of pharmacists in USCG clinics includes collaborating with the patient care team to make pharmacy interventions that have significant impacts on ADSMs’ wellness and the USCG mission. The ADSMs of this nation deserve quality medical care that translates into mission readiness, and the USCG pharmacy force stands ready to support that goal.

Acknowledgments

The authors acknowledge the contributions of CDR Christopher Janik, US Coast Guard Headquarters, and LCDR Darin Schneider, US Coast Guard D11 Regional Practice Manager, in the drafting of the manuscript.

The US Coast Guard (USCG) operates within the US Department of Homeland Security during times of peace and represents a force of > 55,000 active-duty service members (ADSMs), civilians, and reservists. ADSMs account for about 40,000 USCG personnel. The missions of the USCG include activities such as maritime law enforcement (drug interdiction), search and rescue, and defense readiness.¹ Akin to other US Department of Defense (DoD) services, USCG ADSMs are required to maintain medical readiness to maximize operational success.

Whereas the DoD centralizes its health care services at military treatment facilities, USCG health care tends to be dispersed to smaller clinics and sickbays across large geographic areas. The USCG operates 42 clinics of varying sizes and medical capabilities, providing outpatient, dentistry, pharmacy, laboratory, radiology, physical therapy, optometry, and other health care services. Many ADSMs are evaluated by a USCG medical officer in these outpatient clinics, and ADSMs may choose to fill prescriptions at the in-house pharmacy if present at that clinic.

The USCG has 14 field pharmacists. In addition to the standard dispensing role at their respective clinics, USCG pharmacists provide regional oversight of pharmaceutical services for USCG units within their area of responsibility (AOR). Therefore, USCG pharmacists clinically, operationally, and logistically support these regional assets within their AOR while serving the traditional pharmacist role. USCG pharmacists have access to ADSM electronic health records (EHRs) when evaluating prescription orders, similar to other ambulatory care settings.

New recruits and accessions into the USCG are first screened for disqualifying health conditions, and ADSMs are required to maintain medical readiness throughout their careers.² Therefore, this population tends to be younger and overall healthier compared with the general population. Equally important, medication errors or inappropriate prescribing in the ADSM group could negatively affect their duty status and mission readiness of the USCG in addition to exposing the ADSM to medication-related harms.

Duty status is an important and unique consideration in this population. ADSMs are expected to be deployable worldwide and physically and mentally capable of executing all duties associated with their position. Duty status implications and the perceived ability to stand watch are tied to an ADMS’s specialty, training, and unit role. Duty status is based on various frameworks like the USCG Medical Manual, Aeromedical Policy Letters, and other governing documents.³ Duty status determinations are initiated by privileged USCG medical practitioners and may be executed in consultation with relevant commands and other subject matter experts. An inappropriately dosed antibiotic prescription, for example, can extend the duration that an ADSM would be considered unfit for full duty due to prolonged illness. Accordingly, being on a limited duty status may negatively affect USCG total mission readiness as a whole. USCG pharmacists play a vital role in optimizing ADSMs’ medication therapies to ensure safety and efficacy.

Currently no published literature explores the number of medication interventions or the impact of those interventions made by USCG pharmacists. This study aimed to quantify the number, duty status impact, and replicability of medication interventions made by one pharmacist at the USCG Base Alameda clinic over 6 months.

 

Methods

As part of a USCG quality improvement study, a pharmacist tracked all medication interventions on a spreadsheet at USCG Base Alameda clinic from July 1, 2021, to December 31, 2021. The study defined a medication intervention as a communication with the prescriber with the intention to change the medication, strength, dose, dosage form, quantity, or instructions. Each intervention was subcategorized as either a drug therapy problem (DTP) or a non-DTP intervention. Interventions were divided into 7 categories.

Each DTP intervention was evaluated in a retrospective chart review by a panel of USCG pharmacists to assess for duty status severity and replicability. For duty status severity, the panel reviewed the intervention after considering patient-specific factors and determined whether the original prescribing (had there not been an intervention) could have reasonably resulted in a change of duty status for the ADSM from a fit for full duty (FFFD) status to a different duty status (eg, fit for limited duty [FFLD]). This duty status review factored in potential impacts across multiple positions and billets, including aviators (pilots) and divers. In addition, the panel, whose members all have prior community pharmacy experience, assessed replicability by determining whether the same intervention could have reasonably been made in the absence of access to the patient EHR, as would be common in a community pharmacy setting.

Interventions without an identified DTP were considered non-DTP interventions. These interventions involved recommendations for a more cost-effective medication or a similar in stock therapeutic option to minimize delay of patient care. The spreadsheet also included the date, medication name, medication class, specific intervention made, outcome, and other descriptive comments.

Results

During the 6-month period, 1751 prescriptions were dispensed at USCG Base Alameda pharmacy with 116 interventions (7%).

Most interventions (n = 111, 96%) were accepted by the prescriber. Of the 116 interventions, 64 (55%) were DTP interventions; 21 of the DTP interventions (33%) were indication, 20 effectiveness (31%), 19 safety (30%), and 4 adherence (6%) (Table 1).

Among the DTP interventions, 26 (41%) dealt with an inappropriate dose, 13 (20%) were for medication omission, 7 (11%) for inappropriate dosage form, and 6 (9%) for excess medication (Table 2).

Fourteen interventions (22%) impacted duty status, and 18 (28%) were made because the pharmacist had EHR access. Among 51 non-DTP interventions, 34 (67%) minimized delay in patient care, and 17 (33%) cost-savings interventions were made, resulting in about $1700 in savings. Antibiotics had the most interventions (n = 28: 10 DTP and 18 non-DTP).

Discussion

This study is novel in examining the impact of a pharmacist’s medication interventions in a USCG ambulatory care practice setting. A PubMed literature search of the phrases “Coast Guard AND pharmacy” or “Coast Guard AND pharmacy AND intervention” yielded no results specific to pharmacy interventions in a USCG setting. However, the 2021 implementation of the enterprise-wide MHS GENESIS EHR may support additional tracking and analysis tools in the future.

Pharmacist interventions have been studied in diverse patient populations and practice settings, and most conclude that pharmacists make meaningful interventions at their respective organizations.^4-7 Many of these studies were conducted at open-door health care systems, whereas USCG clinics serve ADSMs nearly exclusively. The ADSM population tends to be younger and healthier due to age requirements and medical accession and retention standards.

It is important to recognize the value of a USCG pharmacist in identifying and rectifying potential medication errors, particularly those that may affect the ability to stand duty for ADSMs. An example intervention includes changing the daily starting dose of citalopram from the ordered 30 mg to the intended 10 mg. Inappropriately prescribed medication regimens may increase the incidence of adverse effects or prolong duration to therapeutic efficacy, which impairs the ability to stand duty. There were 3 circumstances where the prescriber had ordered the medication for an incorrect ADSM that were rectified by the pharmacist. If left unchanged, these errors could negatively affect the ADSM’s overall health, well-being, and duty status.

The acceptance rate for interventions in this study was 96%. The literature suggests a highly variable acceptance rate of pharmacist interventions when examined across various practice settings, health systems, and geographic locations.^8-10 This study’s comparatively high rate could be due to the pharmacist-prescriber relationships at USCG clinics. By virtue of colocatation and teamwork initiatives, the pharmacist has the opportunity to develop positive rapport with physicians, physician assistants, and other clinic staff.

Having access to EHRs allowed the pharmacist to make 18 of the DTP interventions. Chart access is not unique to the USCG and is common in other ambulatory care settings. Those 18 interventions, such as reconciling a prescription ordered as fluticasone/salmeterol but recorded in the EHR as “will prescribe montelukast,” were deemed possible because of EHR access. Such interventions could potentially be lost if ADSMs solely received their pharmaceutical care elsewhere.

USCG uses independent duty health services technicians (IDHSs) who practice in settings where a medical officer is not present, such as at smaller sickbays or aboard Coast Guard cutters. In this study, an IDHS had mistakenly created a medication order for the medical officer to sign for bupropion SR, when the ADSM had been taking and was intended to continue taking bupropion XL. This order was signed off by the medical officer, but this oversight was identified and corrected by the pharmacist before dispensing. This indicates that there is a vital educational role that the USCG pharmacist fulfills when working with health care team members within the AOR.

Equally important to consider are the non-DTP interventions. In a military setting, minimizations of delay in care are a high priority. There were 34 instances where the pharmacist made an intervention to recommend a similar therapeutic medication that was in stock to ensure that the ADSM had timely access to the medication without the need for prior authorization. In the context of short-notice, mission-critical deployments that may last for multiple months, recognizing medication shortages or other inventory constraints and recommending therapeutic alternatives ensures that the USCG can maintain a ready posture for missions in addition to providing timely and quality patient care.

Saving about $1700 over 6 months is also important. While this was not explicitly evaluated in the study, prescribers may not be acutely aware of medication pricing. There are often significant price differences between different formulations of the same medication (eg, naproxen delayed-release vs tablets). Because USCG pharmacists are responsible for ordering medications and managing their regional budget within the AOR, they are best poised to make cost-savings recommendations. These interventions suggest that USCG pharmacists must continue to remain actively involved in the patient care team alongside physicians, physician assistants, nurses, and corpsmen. Throughout this setting and in so many others, patients’ health outcomes improve when pharmacists are more engaged in the pharmacotherapy care plan.

 

Limitations

Currently, the USCG does not publish ADSM demographic or health-related data, making it difficult to evaluate these interventions in the context of age, gender, or type of disease. Accordingly, potential directions for future research include how USCG pharmacists’ interventions are stratified by duty station and initial diagnosis. Such studies may support future models where USCG pharmacists are providing targeted education to prescribers based on disease or medication classes.

This analysis may have limited applicability to other practice settings even within USCG. Most USCG clinics have a limited number of medical officers; indeed, many have only one, and clinics with pharmacies typically have 1 to 5 medical officers aboard. USCG medical officers have a multitude of other duties, which may impact prescribing patterns and pharmacist interventions. Statistical analyses were limited by the dearth of baseline data or comparative literature. Finally, the assessment of DTP interventions’ impact did not use an official measurement tool like the US Department of Veterans Affairs’ Safety Assessment Code matrix.¹¹ Instead, the study used the internal USCG pharmacist panel for the fitness for duty consideration as the main stratification of the DTP interventions’ duty status severity, because maintaining medical readiness is the top priority for a USCG clinic.

Conclusions

The multifaceted role of pharmacists in USCG clinics includes collaborating with the patient care team to make pharmacy interventions that have significant impacts on ADSMs’ wellness and the USCG mission. The ADSMs of this nation deserve quality medical care that translates into mission readiness, and the USCG pharmacy force stands ready to support that goal.

Acknowledgments

The authors acknowledge the contributions of CDR Christopher Janik, US Coast Guard Headquarters, and LCDR Darin Schneider, US Coast Guard D11 Regional Practice Manager, in the drafting of the manuscript.

Advances in technology, including ubiquitous access to the internet and the capacity to transfer high-resolution representative images, have facilitated the adoption of telepathology by laboratories worldwide.^1-5 Telepathology includes the use of telecommunication links that enable transmission of digital pathology images for primary diagnosis, quality assurance (QA), education, research, or second opinion diagnoses.³ This improvement has culminated in approvals by the US Food and Drug Administration (FDA) of whole slide imaging (WSI) systems for surgical pathology slides: specifically, the Philips IntelliSite Digital Pathology Solution in 2017 and the Leica Aperio AT2 DX in 2020.^6-8 However, the approvals do not include telecytology due to lack of whole slide multiplanar scanning at different planes of focus or z-stacking capabilities.⁷

Long-term trends in pathology, specifically the slow reduction in the number of practicing pathologists available in the workforce compared with the total served population, along with the social distancing imperatives and disruptions brought about by the COVID-19 pandemic have made telepathology implementation pertinent to continue and improve pathology practice.^8-10

Despite the initial capital equipment costs, telepathology has several advantages, including increasing productivity, saving costs, improving access to pathologist care, improving quality of care, and ease of second opinions (Figures 1 and 2; Table 1).^2-5,6-8  

This review will cover aspects of telepathology implementation for laboratories in light of the recent COVID-19 pandemic and its potential to improve pathology practice.

Description and Definitions

The primary modes of telepathology (static image telepathology, robotic telepathology, video microscopy, WSI, and multimodality telepathology) have been defined by the American Telemedicine Association (ATA).² WSI has been particularly suited for telepathology due to the ability to view digital slides in high resolution at various magnifications. These image files can also be viewed and shared with ease with other observers. Also, they take a shorter time to view compared with the use of a robotic microscope.³

Selection, Validation, and Implementation

WSI platforms vary in their characteristics and have several parameters, including but not limited to batch scanning vs continuous or random-access processing, throughput volume capacities, scan speed, cost, manual vs automatic loading of slides, image quality, slide capacity, flexibility for different slide sizes/features, telepathology capabilities once slide scanned, z-stacking, and regulatory approval status.⁸ Selection of the WSI device is dependent on need and cost considerations. For example, use for frozen section requires faster scanning speed and does not generally require a high throughput scanner.

 

Validation of telepathology by the testing site demonstrates that the new system performs as expected for its intended clinical use before being put into service and that the digital slides produced are acceptable for clinical diagnostic interpretation.¹¹ The College of American Pathologists (CAP) established WSI validation guidelines are part of the published laboratory standard of care.^11-13 An appropriate validation enables the benefits of telepathology while mitigating the risks.

There are 3 major CAP recommendations for validation. First, ≥ 60 cases should be included for each use case being validated with 20 additional cases for relevant ancillary applications not included in the 60 cases. Second, diagnostic concordance (ideally ≥ 95%) should be established between digital and glass slides for the same observer. Third, there should be a 2-week washout period between the viewing of digital and glass slides (Table 2).^12,13

Neither glass nor digital slides are viewed during the washout period. In addition, there are 9 CAP good practice statements, including that all pathology laboratories implementing WSI technology should carry out appropriate validations, have adequately trained pathologists, and be able to address changes in the WSI system that could impact clinical results.^12,13 This CAP guideline is an effective reference for medical laboratories validating WSI systems.^2,11-13 Telepathology involves many technical, privacy/security, and facility-based specifications.² Therefore, involvement of the relevant departments is warranted.²

Guidelines from the ATA establish that telepathology systems should be validated for clinical use, including non-WSI platforms.² Published validations of other non-WSI platforms (such as by robotic or multimodality telepathology) have followed the structure proposed in the guidelines by CAP for validating WSI.^14,15

Ensuring that all relevant responsibilities (clinical, facility, technical, training, documentation/archiving, quality management, and operations related) for the use of telepathology are met is another aspect of validation and implementation.² Clinical responsibilities include an agreement between the sending (referring) and receiving (consulting) parties on the information to accompany the digital material.² From ATA clinical guidelines, this includes identification information, provision to the consulting pathologist of all relevant clinical data, provision to retrieve for access any needed and/or relevant diagnostic material, and responsibility by referrer that the correct image/metadata was sent.² Involved parties should be trained to manage the materials being transmitted.²

Facility responsibilities include maintaining the standard of care defined by the facility and regulatory agencies.² The maintenance of accreditation, adherence to licensure requirements, and proper management of privileges to practice telepathology are also important.² Technical responsibilities include ensuring a proper validation that meets the standard of care and covers use cases.^2,11-13

All processes, training, and competencies should be followed and documented per standard facility operating procedures.² ATA recommends that telepathology should result in a formal report for diagnostic consultations, maintain logs of telepathology interactions or disclaimer statements, and have an appropriate retention policy.² The CAP recommends digital images used for primary diagnosis should be kept for 10 years if the original glass slides are not available.¹⁶ Once implemented, telepathology reports must be incorporated into the pathology and laboratory medicine department’s quality management plan for both the technical performance of the telepathology system and diagnostic performance of the pathologists using the system.² Operations responsibilities include ensuring that the telepathology system is maintained according to vendor recommendations and regulatory standards. Appropriate provisions for space and associated needs should be developed in conjunction with the information technology team of the facility to ensure appropriate security, privacy, and regulatory compliance.²

 

Applications and Uses

Telecytology. Rapid real-time telecytology has been documented to be useful in rapid on-site evaluations (ROSE) of the adequacy of fine needle aspirations (FNA).^17-21 Nevertheless, current Medicare reimbursement is limited given that ROSE is cost prohibitive, time consuming, and affects productivity in cytology laboratories.^17,22,23 Estimates of the time to provide ROSE for 1 procedure without telecytology range from 48.7 to 56.2 minutes.^17,23 The use of telecytology significantly reduces pathologist ROSE time without losing quality to about 12 minutes, of which only an average of 7.5 minutes was spent by the cytopathologist for the ROSE diagnosis.^17-21 ROSE also can be used for distant and remote locations to improve patient care.^17-21 Multiple vendors provide real-time telecytology service. Innovations using smartphone adapters, digital cameras that could work as their own IP addresses, and connection with high-speed dedicated connections with viewing platforms on high-sensitivity monitors can facilitate ROSE to improve patient management.^24,25 The successful accurate use of ROSE has been described; however, there are currently no FDA-approved telepathology ROSE platforms.^17-19,21-25

To date, the FDA has not approved any telecytology whole slide scanner due to a lack of z-stacking capability in submitted scanners.^7,21 Not all whole slide scanners offer z-stacking, though even in those that do offer it, the time necessary to scan the entire slide with adequate z-stacking takes too long to be clinically acceptable for many situations involving ROSE.²¹ WSI has also been used to develop international consensus for cytologic samples.²⁶ Published recommendations for the validation of these other modalities before usage follow the spirit of the CAP guidelines (as far as multiple cases with high concordance rates) for validation of WSI for diagnostic purposes but vary on the exact number of slides and acceptable concordance rate.^21,27 For ROSE with a robotic microscope without any on-site cytology personnel, documented standardized training of nonpathology staff members, such as the radiologist or other physician performing the FNA procedure, may be needed to enable the performance of ROSE telecytology and ensure compliance with regulations.^2,21 Besides ROSE, there are published validations for telecytology in primary diagnosis and QA, indicating a role for telecytology for diagnosis for laboratories that have properly validated and implemented the laboratory-developed test.^28-30

Frozen section. Telepathology has significant potential to improve access to frozen section consultation.^5,31-33 Benefits to improving access to frozen section include providing frozen section consultation at remote or off-site locations, increasing access to subspecialty consultation, improving workflow by eliminating the need to travel off-site to the frozen section case, cost savings in staff work time, and providing educational opportunities for pathology trainees.^5,31-33 In our experience, WSI with real-time viewing of frozen section allows for the assessment of transplant tissues, which is an evaluation that generally occurs at night. Discrepancies from frozen section telepathology using WSI to the final diagnosis may occur and those specific to WSI could result from slide or image quality, internet connectivity, and lack of training in using the telepathology system.³² Other issues that may lead to discrepancies between the frozen section diagnosis and the final diagnosis may occur with the review of glass slides by light microscopy.³⁴ Appropriate performance of validation, training, implementation, and quality control for telepathology can help in reaping the benefits while mitigating the risks.² In a large study comparing frozen section evaluation by telepathology with light microscopy, the sensitivity and specificity of frozen section were comparable between telepathology and light microscopy with a trend toward greater sensitivity by telepathology (0.92 and 0.99 for telepathology vs 0.90 and 0.99 by light microscopy alone, sensitivity and specificity, respectively).³³

Other applications. Evidence for efficacy in surgical pathology diagnosis led to FDA approval of the Philips IntelliSite Digital Pathology in 2017 and the Leica Aperio AT2 DX in 2020 WSI platforms.^6-8 The use of WSI in surgical pathology has been successfully validated or used in clinical practice at several pathology laboratory settings with documented benefits in the literature for primary and secondary diagnoses, QA, research, and education.^6-8,35-45 Benefits of telepathology include improved ergonomics and access to real-time pathologic services in remote areas or during on-site pathologist absence and expert second opinions. Telepathology also may reduce risk of slide loss during transport, shortened turnaround time, reduced costs of operation through workflow efficiencies, better load balancing, improve virtual collaboration, and digital storage of slides that may be irreplaceable.^3-8,35-45 Telepathology also has been shown to be useful for education, improving access to learning materials and increasing quality instructional materials at a lower cost.⁴⁵ The increased ease of collaboration with remote experts and access to slide material for other pathologists improves QA capabilities.^3-8,35-45 The availability of virtual slides is expected to promote further research in telepathology and pathology due to the increased availability of virtual material to researchers.^1,5,46

Telehematology. Published validations have shown effectiveness for hematopathology specimens, such as the peripheral smear. Telehematology also has demonstrated potential in a laboratory after proper validation and implementation as a laboratory-developed test.^37,47-49

Telemicrobiology and Computer-Assisted Pathologic Diagnosis. Telemicrobiology also has been successfully used for clinical, educational, and QA purposes.⁵⁰ The digitalization of slides involved with telepathology enables further innovation in machine learning for computer-assisted pathologic diagnosis (CAPD), which is already being used clinically for cervical Pap smears.²⁰ An artificial intelligence (AI)–based algorithm analyzes the slides to identify cells of interest, which are presented to the cytopathologist for confirmation.²⁰ However, the expansion of CAPD to include a variety of specimen types or diagnostic situations as well as safely and effectively take initiative in completing an accurate automated diagnosis requires additional development.^20,51,52 One of the key factors for machine learning to develop AI is the provision of a corpus of data.^51,52 Public, open-source data sources have been limited in size while private proprietary sources have highly restricted and expensive access; to address this, there is a current effort to build the world’s largest public open-source digital pathology corpus at Temple University Hospital, which may help enable innovations in the future.⁵²

 

Long-Term Trends/Applications

The COVID-19 pandemic has been unprecedented not only in its widespread morbidity and mortality, but also for the significant socioeconomic, health, lifestyle, societal, and workspace changes.^53-57 Specifically, the pandemic has introduced not only a need for social distancing and staff quarantines to prevent the spread of infection, but also a reduction in the workforce due to the stresses of COVID-19 (also known as the Great Resignation).⁵⁵ Before the pandemic, there was an existing downtrend in the number of pathologists in the US workforce.^9-10,58,59 From 2007 to 2017, the number of active pathologists in the US declined by 17.5% despite the increasing national population, resulting in not only an absolute decrease in the number of pathologists, but also an increasing population served per pathologist ratio.⁵⁹ Since 2017, this downtrend has continued; given the increasing loss of active pathologists from the workforce and the decreasing training of new pathologists, this decrease shows no signs of reversing even as the impact of the COVID-19 pandemic has begun to wane.^9,10,58-60

The advantages of telepathology in enabling social distancing and reducing travel to remote sites are known.^3-7,17 Given these advantages, some medical centers in the US have previously successfully validated and implemented telepathology operations earlier during the COVID-19 pandemic to ease workflow and ensure continued operations.^56,57 The use of telepathology also helps in balancing workload and continuing pathology operations even in light of the workforce reduction as cases no longer need to be signed out on site with glass slides but instead can be signed out at a remote laboratory. Although the impact of the COVID-19 pandemic on operations is decreasing, the capabilities for social distancing and reducing travel remain important to both improve operations and ensure resiliency in response to similar potential events.^3-7,17,60

Considering the long-term trends, the lessons of the COVID-19 pandemic, and the potential for future pandemics or other disasters, telepathology’s validation and implementation remains a reasonable choice for pathology practices looking to improve. A variety of practices not just in the general population, but also among US Department of Veterans Affairs medical centers (VAMCs) and the US Department of Defense Military Health System treating a veteran population can benefit from telepathology where it has previously been reported to have been reliable or successfully implemented.^61-63 Although the veteran population differs from the general population in several characteristics, such as the severity of disease, coexisting morbidities, and other history, given proper validation and implementation, telepathology’s usefulness extends across different pathology practice settings.^35-43,61-66

Limitations of Telepathology

In telepathology’s current state, there are limitations despite its immense promise.^6,35 These include initial capital costs, the additional training requirement, the additional time necessary to scan slides, technical challenges (ie, laboratory information system integration, color calibration, display artifacts, potential for small particle scanner omissions, and information technology dependence), the potential for slower evaluation per slide compared with optical microscopes, limitations of slide imaging (ie, z-stacking or lack of polarization on digital pathology), and occupational concerns regarding eye strain with increased computer monitor usage (ie, computer vision syndrome).^6,35 In addition, there are few telepathology scanners with FDA approval for WSI.^6-8

The improving technology of telepathology has made these limitations surmountable, including faster slide scanning and increasing digital storage capacity for large WSI files. Due to this improvement in technology, an increasing number of laboratory settings, have adopted telepathology as its advantages have begun to outweigh the limitations.^2-5 Additionally, the proper validation performed before implementing telepathology can help laboratories identify their unique challenges, troubleshoot, and resolve the limitations before use in clinical care.^11-13 Continuing QA during its use and implementation is important to ensure that telepathology performs as expected for clinical purposes despite its limitations.²

Conclusions

Telepathology is a promising technology that may improve pathology practice once properly validated and implemented.^1-8 Though there are barriers to this validation and implementation, particularly the capital costs and training, there are several potential benefits, including increased productivity, cost savings, improvement in the workflow, enhanced access to pathologic consultation, and adaptability of the pathology laboratory in an era of a decreased workforce and social distancing due to the COVID-19 pandemic.^1-8,55-56 This potential applies across the wide spectrum of potential telepathology uses from frozen section, telecytology (including ROSE) to primary and second opinion diagnoses.^1-8,17-33 The benefits also extends to QA, education, and research, as diagnoses can not only be rereviewed by specialty or second opinion consultation with ease, but also digital slides can be produced for educational and research purposes.^3-8,35-45 Settings that treat the general population and those focused on the care of veterans or members of the armed forces have reported similar reliability or successful implementation.^35-44,61-63 All in all, the use of telepathology represents an innovation that may transform the practice of pathology tomorrow.

Advances in technology, including ubiquitous access to the internet and the capacity to transfer high-resolution representative images, have facilitated the adoption of telepathology by laboratories worldwide.^1-5 Telepathology includes the use of telecommunication links that enable transmission of digital pathology images for primary diagnosis, quality assurance (QA), education, research, or second opinion diagnoses.³ This improvement has culminated in approvals by the US Food and Drug Administration (FDA) of whole slide imaging (WSI) systems for surgical pathology slides: specifically, the Philips IntelliSite Digital Pathology Solution in 2017 and the Leica Aperio AT2 DX in 2020.^6-8 However, the approvals do not include telecytology due to lack of whole slide multiplanar scanning at different planes of focus or z-stacking capabilities.⁷

Long-term trends in pathology, specifically the slow reduction in the number of practicing pathologists available in the workforce compared with the total served population, along with the social distancing imperatives and disruptions brought about by the COVID-19 pandemic have made telepathology implementation pertinent to continue and improve pathology practice.^8-10

Despite the initial capital equipment costs, telepathology has several advantages, including increasing productivity, saving costs, improving access to pathologist care, improving quality of care, and ease of second opinions (Figures 1 and 2; Table 1).^2-5,6-8  

This review will cover aspects of telepathology implementation for laboratories in light of the recent COVID-19 pandemic and its potential to improve pathology practice.

Description and Definitions

The primary modes of telepathology (static image telepathology, robotic telepathology, video microscopy, WSI, and multimodality telepathology) have been defined by the American Telemedicine Association (ATA).² WSI has been particularly suited for telepathology due to the ability to view digital slides in high resolution at various magnifications. These image files can also be viewed and shared with ease with other observers. Also, they take a shorter time to view compared with the use of a robotic microscope.³

Selection, Validation, and Implementation

WSI platforms vary in their characteristics and have several parameters, including but not limited to batch scanning vs continuous or random-access processing, throughput volume capacities, scan speed, cost, manual vs automatic loading of slides, image quality, slide capacity, flexibility for different slide sizes/features, telepathology capabilities once slide scanned, z-stacking, and regulatory approval status.⁸ Selection of the WSI device is dependent on need and cost considerations. For example, use for frozen section requires faster scanning speed and does not generally require a high throughput scanner.

 

Validation of telepathology by the testing site demonstrates that the new system performs as expected for its intended clinical use before being put into service and that the digital slides produced are acceptable for clinical diagnostic interpretation.¹¹ The College of American Pathologists (CAP) established WSI validation guidelines are part of the published laboratory standard of care.^11-13 An appropriate validation enables the benefits of telepathology while mitigating the risks.

There are 3 major CAP recommendations for validation. First, ≥ 60 cases should be included for each use case being validated with 20 additional cases for relevant ancillary applications not included in the 60 cases. Second, diagnostic concordance (ideally ≥ 95%) should be established between digital and glass slides for the same observer. Third, there should be a 2-week washout period between the viewing of digital and glass slides (Table 2).^12,13

Neither glass nor digital slides are viewed during the washout period. In addition, there are 9 CAP good practice statements, including that all pathology laboratories implementing WSI technology should carry out appropriate validations, have adequately trained pathologists, and be able to address changes in the WSI system that could impact clinical results.^12,13 This CAP guideline is an effective reference for medical laboratories validating WSI systems.^2,11-13 Telepathology involves many technical, privacy/security, and facility-based specifications.² Therefore, involvement of the relevant departments is warranted.²

Guidelines from the ATA establish that telepathology systems should be validated for clinical use, including non-WSI platforms.² Published validations of other non-WSI platforms (such as by robotic or multimodality telepathology) have followed the structure proposed in the guidelines by CAP for validating WSI.^14,15

Ensuring that all relevant responsibilities (clinical, facility, technical, training, documentation/archiving, quality management, and operations related) for the use of telepathology are met is another aspect of validation and implementation.² Clinical responsibilities include an agreement between the sending (referring) and receiving (consulting) parties on the information to accompany the digital material.² From ATA clinical guidelines, this includes identification information, provision to the consulting pathologist of all relevant clinical data, provision to retrieve for access any needed and/or relevant diagnostic material, and responsibility by referrer that the correct image/metadata was sent.² Involved parties should be trained to manage the materials being transmitted.²

Facility responsibilities include maintaining the standard of care defined by the facility and regulatory agencies.² The maintenance of accreditation, adherence to licensure requirements, and proper management of privileges to practice telepathology are also important.² Technical responsibilities include ensuring a proper validation that meets the standard of care and covers use cases.^2,11-13

All processes, training, and competencies should be followed and documented per standard facility operating procedures.² ATA recommends that telepathology should result in a formal report for diagnostic consultations, maintain logs of telepathology interactions or disclaimer statements, and have an appropriate retention policy.² The CAP recommends digital images used for primary diagnosis should be kept for 10 years if the original glass slides are not available.¹⁶ Once implemented, telepathology reports must be incorporated into the pathology and laboratory medicine department’s quality management plan for both the technical performance of the telepathology system and diagnostic performance of the pathologists using the system.² Operations responsibilities include ensuring that the telepathology system is maintained according to vendor recommendations and regulatory standards. Appropriate provisions for space and associated needs should be developed in conjunction with the information technology team of the facility to ensure appropriate security, privacy, and regulatory compliance.²

 

Applications and Uses

Telecytology. Rapid real-time telecytology has been documented to be useful in rapid on-site evaluations (ROSE) of the adequacy of fine needle aspirations (FNA).^17-21 Nevertheless, current Medicare reimbursement is limited given that ROSE is cost prohibitive, time consuming, and affects productivity in cytology laboratories.^17,22,23 Estimates of the time to provide ROSE for 1 procedure without telecytology range from 48.7 to 56.2 minutes.^17,23 The use of telecytology significantly reduces pathologist ROSE time without losing quality to about 12 minutes, of which only an average of 7.5 minutes was spent by the cytopathologist for the ROSE diagnosis.^17-21 ROSE also can be used for distant and remote locations to improve patient care.^17-21 Multiple vendors provide real-time telecytology service. Innovations using smartphone adapters, digital cameras that could work as their own IP addresses, and connection with high-speed dedicated connections with viewing platforms on high-sensitivity monitors can facilitate ROSE to improve patient management.^24,25 The successful accurate use of ROSE has been described; however, there are currently no FDA-approved telepathology ROSE platforms.^17-19,21-25

To date, the FDA has not approved any telecytology whole slide scanner due to a lack of z-stacking capability in submitted scanners.^7,21 Not all whole slide scanners offer z-stacking, though even in those that do offer it, the time necessary to scan the entire slide with adequate z-stacking takes too long to be clinically acceptable for many situations involving ROSE.²¹ WSI has also been used to develop international consensus for cytologic samples.²⁶ Published recommendations for the validation of these other modalities before usage follow the spirit of the CAP guidelines (as far as multiple cases with high concordance rates) for validation of WSI for diagnostic purposes but vary on the exact number of slides and acceptable concordance rate.^21,27 For ROSE with a robotic microscope without any on-site cytology personnel, documented standardized training of nonpathology staff members, such as the radiologist or other physician performing the FNA procedure, may be needed to enable the performance of ROSE telecytology and ensure compliance with regulations.^2,21 Besides ROSE, there are published validations for telecytology in primary diagnosis and QA, indicating a role for telecytology for diagnosis for laboratories that have properly validated and implemented the laboratory-developed test.^28-30

Frozen section. Telepathology has significant potential to improve access to frozen section consultation.^5,31-33 Benefits to improving access to frozen section include providing frozen section consultation at remote or off-site locations, increasing access to subspecialty consultation, improving workflow by eliminating the need to travel off-site to the frozen section case, cost savings in staff work time, and providing educational opportunities for pathology trainees.^5,31-33 In our experience, WSI with real-time viewing of frozen section allows for the assessment of transplant tissues, which is an evaluation that generally occurs at night. Discrepancies from frozen section telepathology using WSI to the final diagnosis may occur and those specific to WSI could result from slide or image quality, internet connectivity, and lack of training in using the telepathology system.³² Other issues that may lead to discrepancies between the frozen section diagnosis and the final diagnosis may occur with the review of glass slides by light microscopy.³⁴ Appropriate performance of validation, training, implementation, and quality control for telepathology can help in reaping the benefits while mitigating the risks.² In a large study comparing frozen section evaluation by telepathology with light microscopy, the sensitivity and specificity of frozen section were comparable between telepathology and light microscopy with a trend toward greater sensitivity by telepathology (0.92 and 0.99 for telepathology vs 0.90 and 0.99 by light microscopy alone, sensitivity and specificity, respectively).³³

Other applications. Evidence for efficacy in surgical pathology diagnosis led to FDA approval of the Philips IntelliSite Digital Pathology in 2017 and the Leica Aperio AT2 DX in 2020 WSI platforms.^6-8 The use of WSI in surgical pathology has been successfully validated or used in clinical practice at several pathology laboratory settings with documented benefits in the literature for primary and secondary diagnoses, QA, research, and education.^6-8,35-45 Benefits of telepathology include improved ergonomics and access to real-time pathologic services in remote areas or during on-site pathologist absence and expert second opinions. Telepathology also may reduce risk of slide loss during transport, shortened turnaround time, reduced costs of operation through workflow efficiencies, better load balancing, improve virtual collaboration, and digital storage of slides that may be irreplaceable.^3-8,35-45 Telepathology also has been shown to be useful for education, improving access to learning materials and increasing quality instructional materials at a lower cost.⁴⁵ The increased ease of collaboration with remote experts and access to slide material for other pathologists improves QA capabilities.^3-8,35-45 The availability of virtual slides is expected to promote further research in telepathology and pathology due to the increased availability of virtual material to researchers.^1,5,46

Telehematology. Published validations have shown effectiveness for hematopathology specimens, such as the peripheral smear. Telehematology also has demonstrated potential in a laboratory after proper validation and implementation as a laboratory-developed test.^37,47-49

Telemicrobiology and Computer-Assisted Pathologic Diagnosis. Telemicrobiology also has been successfully used for clinical, educational, and QA purposes.⁵⁰ The digitalization of slides involved with telepathology enables further innovation in machine learning for computer-assisted pathologic diagnosis (CAPD), which is already being used clinically for cervical Pap smears.²⁰ An artificial intelligence (AI)–based algorithm analyzes the slides to identify cells of interest, which are presented to the cytopathologist for confirmation.²⁰ However, the expansion of CAPD to include a variety of specimen types or diagnostic situations as well as safely and effectively take initiative in completing an accurate automated diagnosis requires additional development.^20,51,52 One of the key factors for machine learning to develop AI is the provision of a corpus of data.^51,52 Public, open-source data sources have been limited in size while private proprietary sources have highly restricted and expensive access; to address this, there is a current effort to build the world’s largest public open-source digital pathology corpus at Temple University Hospital, which may help enable innovations in the future.⁵²

 

Long-Term Trends/Applications

The COVID-19 pandemic has been unprecedented not only in its widespread morbidity and mortality, but also for the significant socioeconomic, health, lifestyle, societal, and workspace changes.^53-57 Specifically, the pandemic has introduced not only a need for social distancing and staff quarantines to prevent the spread of infection, but also a reduction in the workforce due to the stresses of COVID-19 (also known as the Great Resignation).⁵⁵ Before the pandemic, there was an existing downtrend in the number of pathologists in the US workforce.^9-10,58,59 From 2007 to 2017, the number of active pathologists in the US declined by 17.5% despite the increasing national population, resulting in not only an absolute decrease in the number of pathologists, but also an increasing population served per pathologist ratio.⁵⁹ Since 2017, this downtrend has continued; given the increasing loss of active pathologists from the workforce and the decreasing training of new pathologists, this decrease shows no signs of reversing even as the impact of the COVID-19 pandemic has begun to wane.^9,10,58-60

The advantages of telepathology in enabling social distancing and reducing travel to remote sites are known.^3-7,17 Given these advantages, some medical centers in the US have previously successfully validated and implemented telepathology operations earlier during the COVID-19 pandemic to ease workflow and ensure continued operations.^56,57 The use of telepathology also helps in balancing workload and continuing pathology operations even in light of the workforce reduction as cases no longer need to be signed out on site with glass slides but instead can be signed out at a remote laboratory. Although the impact of the COVID-19 pandemic on operations is decreasing, the capabilities for social distancing and reducing travel remain important to both improve operations and ensure resiliency in response to similar potential events.^3-7,17,60

Considering the long-term trends, the lessons of the COVID-19 pandemic, and the potential for future pandemics or other disasters, telepathology’s validation and implementation remains a reasonable choice for pathology practices looking to improve. A variety of practices not just in the general population, but also among US Department of Veterans Affairs medical centers (VAMCs) and the US Department of Defense Military Health System treating a veteran population can benefit from telepathology where it has previously been reported to have been reliable or successfully implemented.^61-63 Although the veteran population differs from the general population in several characteristics, such as the severity of disease, coexisting morbidities, and other history, given proper validation and implementation, telepathology’s usefulness extends across different pathology practice settings.^35-43,61-66

Limitations of Telepathology

In telepathology’s current state, there are limitations despite its immense promise.^6,35 These include initial capital costs, the additional training requirement, the additional time necessary to scan slides, technical challenges (ie, laboratory information system integration, color calibration, display artifacts, potential for small particle scanner omissions, and information technology dependence), the potential for slower evaluation per slide compared with optical microscopes, limitations of slide imaging (ie, z-stacking or lack of polarization on digital pathology), and occupational concerns regarding eye strain with increased computer monitor usage (ie, computer vision syndrome).^6,35 In addition, there are few telepathology scanners with FDA approval for WSI.^6-8

The improving technology of telepathology has made these limitations surmountable, including faster slide scanning and increasing digital storage capacity for large WSI files. Due to this improvement in technology, an increasing number of laboratory settings, have adopted telepathology as its advantages have begun to outweigh the limitations.^2-5 Additionally, the proper validation performed before implementing telepathology can help laboratories identify their unique challenges, troubleshoot, and resolve the limitations before use in clinical care.^11-13 Continuing QA during its use and implementation is important to ensure that telepathology performs as expected for clinical purposes despite its limitations.²

Conclusions

Telepathology is a promising technology that may improve pathology practice once properly validated and implemented.^1-8 Though there are barriers to this validation and implementation, particularly the capital costs and training, there are several potential benefits, including increased productivity, cost savings, improvement in the workflow, enhanced access to pathologic consultation, and adaptability of the pathology laboratory in an era of a decreased workforce and social distancing due to the COVID-19 pandemic.^1-8,55-56 This potential applies across the wide spectrum of potential telepathology uses from frozen section, telecytology (including ROSE) to primary and second opinion diagnoses.^1-8,17-33 The benefits also extends to QA, education, and research, as diagnoses can not only be rereviewed by specialty or second opinion consultation with ease, but also digital slides can be produced for educational and research purposes.^3-8,35-45 Settings that treat the general population and those focused on the care of veterans or members of the armed forces have reported similar reliability or successful implementation.^35-44,61-63 All in all, the use of telepathology represents an innovation that may transform the practice of pathology tomorrow.

Advances in technology, including ubiquitous access to the internet and the capacity to transfer high-resolution representative images, have facilitated the adoption of telepathology by laboratories worldwide.^1-5 Telepathology includes the use of telecommunication links that enable transmission of digital pathology images for primary diagnosis, quality assurance (QA), education, research, or second opinion diagnoses.³ This improvement has culminated in approvals by the US Food and Drug Administration (FDA) of whole slide imaging (WSI) systems for surgical pathology slides: specifically, the Philips IntelliSite Digital Pathology Solution in 2017 and the Leica Aperio AT2 DX in 2020.^6-8 However, the approvals do not include telecytology due to lack of whole slide multiplanar scanning at different planes of focus or z-stacking capabilities.⁷

Long-term trends in pathology, specifically the slow reduction in the number of practicing pathologists available in the workforce compared with the total served population, along with the social distancing imperatives and disruptions brought about by the COVID-19 pandemic have made telepathology implementation pertinent to continue and improve pathology practice.^8-10

Despite the initial capital equipment costs, telepathology has several advantages, including increasing productivity, saving costs, improving access to pathologist care, improving quality of care, and ease of second opinions (Figures 1 and 2; Table 1).^2-5,6-8  

This review will cover aspects of telepathology implementation for laboratories in light of the recent COVID-19 pandemic and its potential to improve pathology practice.

Description and Definitions

The primary modes of telepathology (static image telepathology, robotic telepathology, video microscopy, WSI, and multimodality telepathology) have been defined by the American Telemedicine Association (ATA).² WSI has been particularly suited for telepathology due to the ability to view digital slides in high resolution at various magnifications. These image files can also be viewed and shared with ease with other observers. Also, they take a shorter time to view compared with the use of a robotic microscope.³

Selection, Validation, and Implementation

WSI platforms vary in their characteristics and have several parameters, including but not limited to batch scanning vs continuous or random-access processing, throughput volume capacities, scan speed, cost, manual vs automatic loading of slides, image quality, slide capacity, flexibility for different slide sizes/features, telepathology capabilities once slide scanned, z-stacking, and regulatory approval status.⁸ Selection of the WSI device is dependent on need and cost considerations. For example, use for frozen section requires faster scanning speed and does not generally require a high throughput scanner.

 

Validation of telepathology by the testing site demonstrates that the new system performs as expected for its intended clinical use before being put into service and that the digital slides produced are acceptable for clinical diagnostic interpretation.¹¹ The College of American Pathologists (CAP) established WSI validation guidelines are part of the published laboratory standard of care.^11-13 An appropriate validation enables the benefits of telepathology while mitigating the risks.

There are 3 major CAP recommendations for validation. First, ≥ 60 cases should be included for each use case being validated with 20 additional cases for relevant ancillary applications not included in the 60 cases. Second, diagnostic concordance (ideally ≥ 95%) should be established between digital and glass slides for the same observer. Third, there should be a 2-week washout period between the viewing of digital and glass slides (Table 2).^12,13

Neither glass nor digital slides are viewed during the washout period. In addition, there are 9 CAP good practice statements, including that all pathology laboratories implementing WSI technology should carry out appropriate validations, have adequately trained pathologists, and be able to address changes in the WSI system that could impact clinical results.^12,13 This CAP guideline is an effective reference for medical laboratories validating WSI systems.^2,11-13 Telepathology involves many technical, privacy/security, and facility-based specifications.² Therefore, involvement of the relevant departments is warranted.²

Guidelines from the ATA establish that telepathology systems should be validated for clinical use, including non-WSI platforms.² Published validations of other non-WSI platforms (such as by robotic or multimodality telepathology) have followed the structure proposed in the guidelines by CAP for validating WSI.^14,15

Ensuring that all relevant responsibilities (clinical, facility, technical, training, documentation/archiving, quality management, and operations related) for the use of telepathology are met is another aspect of validation and implementation.² Clinical responsibilities include an agreement between the sending (referring) and receiving (consulting) parties on the information to accompany the digital material.² From ATA clinical guidelines, this includes identification information, provision to the consulting pathologist of all relevant clinical data, provision to retrieve for access any needed and/or relevant diagnostic material, and responsibility by referrer that the correct image/metadata was sent.² Involved parties should be trained to manage the materials being transmitted.²

Facility responsibilities include maintaining the standard of care defined by the facility and regulatory agencies.² The maintenance of accreditation, adherence to licensure requirements, and proper management of privileges to practice telepathology are also important.² Technical responsibilities include ensuring a proper validation that meets the standard of care and covers use cases.^2,11-13

All processes, training, and competencies should be followed and documented per standard facility operating procedures.² ATA recommends that telepathology should result in a formal report for diagnostic consultations, maintain logs of telepathology interactions or disclaimer statements, and have an appropriate retention policy.² The CAP recommends digital images used for primary diagnosis should be kept for 10 years if the original glass slides are not available.¹⁶ Once implemented, telepathology reports must be incorporated into the pathology and laboratory medicine department’s quality management plan for both the technical performance of the telepathology system and diagnostic performance of the pathologists using the system.² Operations responsibilities include ensuring that the telepathology system is maintained according to vendor recommendations and regulatory standards. Appropriate provisions for space and associated needs should be developed in conjunction with the information technology team of the facility to ensure appropriate security, privacy, and regulatory compliance.²

 

Applications and Uses

Telecytology. Rapid real-time telecytology has been documented to be useful in rapid on-site evaluations (ROSE) of the adequacy of fine needle aspirations (FNA).^17-21 Nevertheless, current Medicare reimbursement is limited given that ROSE is cost prohibitive, time consuming, and affects productivity in cytology laboratories.^17,22,23 Estimates of the time to provide ROSE for 1 procedure without telecytology range from 48.7 to 56.2 minutes.^17,23 The use of telecytology significantly reduces pathologist ROSE time without losing quality to about 12 minutes, of which only an average of 7.5 minutes was spent by the cytopathologist for the ROSE diagnosis.^17-21 ROSE also can be used for distant and remote locations to improve patient care.^17-21 Multiple vendors provide real-time telecytology service. Innovations using smartphone adapters, digital cameras that could work as their own IP addresses, and connection with high-speed dedicated connections with viewing platforms on high-sensitivity monitors can facilitate ROSE to improve patient management.^24,25 The successful accurate use of ROSE has been described; however, there are currently no FDA-approved telepathology ROSE platforms.^17-19,21-25

To date, the FDA has not approved any telecytology whole slide scanner due to a lack of z-stacking capability in submitted scanners.^7,21 Not all whole slide scanners offer z-stacking, though even in those that do offer it, the time necessary to scan the entire slide with adequate z-stacking takes too long to be clinically acceptable for many situations involving ROSE.²¹ WSI has also been used to develop international consensus for cytologic samples.²⁶ Published recommendations for the validation of these other modalities before usage follow the spirit of the CAP guidelines (as far as multiple cases with high concordance rates) for validation of WSI for diagnostic purposes but vary on the exact number of slides and acceptable concordance rate.^21,27 For ROSE with a robotic microscope without any on-site cytology personnel, documented standardized training of nonpathology staff members, such as the radiologist or other physician performing the FNA procedure, may be needed to enable the performance of ROSE telecytology and ensure compliance with regulations.^2,21 Besides ROSE, there are published validations for telecytology in primary diagnosis and QA, indicating a role for telecytology for diagnosis for laboratories that have properly validated and implemented the laboratory-developed test.^28-30

Frozen section. Telepathology has significant potential to improve access to frozen section consultation.^5,31-33 Benefits to improving access to frozen section include providing frozen section consultation at remote or off-site locations, increasing access to subspecialty consultation, improving workflow by eliminating the need to travel off-site to the frozen section case, cost savings in staff work time, and providing educational opportunities for pathology trainees.^5,31-33 In our experience, WSI with real-time viewing of frozen section allows for the assessment of transplant tissues, which is an evaluation that generally occurs at night. Discrepancies from frozen section telepathology using WSI to the final diagnosis may occur and those specific to WSI could result from slide or image quality, internet connectivity, and lack of training in using the telepathology system.³² Other issues that may lead to discrepancies between the frozen section diagnosis and the final diagnosis may occur with the review of glass slides by light microscopy.³⁴ Appropriate performance of validation, training, implementation, and quality control for telepathology can help in reaping the benefits while mitigating the risks.² In a large study comparing frozen section evaluation by telepathology with light microscopy, the sensitivity and specificity of frozen section were comparable between telepathology and light microscopy with a trend toward greater sensitivity by telepathology (0.92 and 0.99 for telepathology vs 0.90 and 0.99 by light microscopy alone, sensitivity and specificity, respectively).³³

Other applications. Evidence for efficacy in surgical pathology diagnosis led to FDA approval of the Philips IntelliSite Digital Pathology in 2017 and the Leica Aperio AT2 DX in 2020 WSI platforms.^6-8 The use of WSI in surgical pathology has been successfully validated or used in clinical practice at several pathology laboratory settings with documented benefits in the literature for primary and secondary diagnoses, QA, research, and education.^6-8,35-45 Benefits of telepathology include improved ergonomics and access to real-time pathologic services in remote areas or during on-site pathologist absence and expert second opinions. Telepathology also may reduce risk of slide loss during transport, shortened turnaround time, reduced costs of operation through workflow efficiencies, better load balancing, improve virtual collaboration, and digital storage of slides that may be irreplaceable.^3-8,35-45 Telepathology also has been shown to be useful for education, improving access to learning materials and increasing quality instructional materials at a lower cost.⁴⁵ The increased ease of collaboration with remote experts and access to slide material for other pathologists improves QA capabilities.^3-8,35-45 The availability of virtual slides is expected to promote further research in telepathology and pathology due to the increased availability of virtual material to researchers.^1,5,46

Telehematology. Published validations have shown effectiveness for hematopathology specimens, such as the peripheral smear. Telehematology also has demonstrated potential in a laboratory after proper validation and implementation as a laboratory-developed test.^37,47-49

Telemicrobiology and Computer-Assisted Pathologic Diagnosis. Telemicrobiology also has been successfully used for clinical, educational, and QA purposes.⁵⁰ The digitalization of slides involved with telepathology enables further innovation in machine learning for computer-assisted pathologic diagnosis (CAPD), which is already being used clinically for cervical Pap smears.²⁰ An artificial intelligence (AI)–based algorithm analyzes the slides to identify cells of interest, which are presented to the cytopathologist for confirmation.²⁰ However, the expansion of CAPD to include a variety of specimen types or diagnostic situations as well as safely and effectively take initiative in completing an accurate automated diagnosis requires additional development.^20,51,52 One of the key factors for machine learning to develop AI is the provision of a corpus of data.^51,52 Public, open-source data sources have been limited in size while private proprietary sources have highly restricted and expensive access; to address this, there is a current effort to build the world’s largest public open-source digital pathology corpus at Temple University Hospital, which may help enable innovations in the future.⁵²

 

Long-Term Trends/Applications

The COVID-19 pandemic has been unprecedented not only in its widespread morbidity and mortality, but also for the significant socioeconomic, health, lifestyle, societal, and workspace changes.^53-57 Specifically, the pandemic has introduced not only a need for social distancing and staff quarantines to prevent the spread of infection, but also a reduction in the workforce due to the stresses of COVID-19 (also known as the Great Resignation).⁵⁵ Before the pandemic, there was an existing downtrend in the number of pathologists in the US workforce.^9-10,58,59 From 2007 to 2017, the number of active pathologists in the US declined by 17.5% despite the increasing national population, resulting in not only an absolute decrease in the number of pathologists, but also an increasing population served per pathologist ratio.⁵⁹ Since 2017, this downtrend has continued; given the increasing loss of active pathologists from the workforce and the decreasing training of new pathologists, this decrease shows no signs of reversing even as the impact of the COVID-19 pandemic has begun to wane.^9,10,58-60

The advantages of telepathology in enabling social distancing and reducing travel to remote sites are known.^3-7,17 Given these advantages, some medical centers in the US have previously successfully validated and implemented telepathology operations earlier during the COVID-19 pandemic to ease workflow and ensure continued operations.^56,57 The use of telepathology also helps in balancing workload and continuing pathology operations even in light of the workforce reduction as cases no longer need to be signed out on site with glass slides but instead can be signed out at a remote laboratory. Although the impact of the COVID-19 pandemic on operations is decreasing, the capabilities for social distancing and reducing travel remain important to both improve operations and ensure resiliency in response to similar potential events.^3-7,17,60

Considering the long-term trends, the lessons of the COVID-19 pandemic, and the potential for future pandemics or other disasters, telepathology’s validation and implementation remains a reasonable choice for pathology practices looking to improve. A variety of practices not just in the general population, but also among US Department of Veterans Affairs medical centers (VAMCs) and the US Department of Defense Military Health System treating a veteran population can benefit from telepathology where it has previously been reported to have been reliable or successfully implemented.^61-63 Although the veteran population differs from the general population in several characteristics, such as the severity of disease, coexisting morbidities, and other history, given proper validation and implementation, telepathology’s usefulness extends across different pathology practice settings.^35-43,61-66

Limitations of Telepathology

In telepathology’s current state, there are limitations despite its immense promise.^6,35 These include initial capital costs, the additional training requirement, the additional time necessary to scan slides, technical challenges (ie, laboratory information system integration, color calibration, display artifacts, potential for small particle scanner omissions, and information technology dependence), the potential for slower evaluation per slide compared with optical microscopes, limitations of slide imaging (ie, z-stacking or lack of polarization on digital pathology), and occupational concerns regarding eye strain with increased computer monitor usage (ie, computer vision syndrome).^6,35 In addition, there are few telepathology scanners with FDA approval for WSI.^6-8

The improving technology of telepathology has made these limitations surmountable, including faster slide scanning and increasing digital storage capacity for large WSI files. Due to this improvement in technology, an increasing number of laboratory settings, have adopted telepathology as its advantages have begun to outweigh the limitations.^2-5 Additionally, the proper validation performed before implementing telepathology can help laboratories identify their unique challenges, troubleshoot, and resolve the limitations before use in clinical care.^11-13 Continuing QA during its use and implementation is important to ensure that telepathology performs as expected for clinical purposes despite its limitations.²

Conclusions

Telepathology is a promising technology that may improve pathology practice once properly validated and implemented.^1-8 Though there are barriers to this validation and implementation, particularly the capital costs and training, there are several potential benefits, including increased productivity, cost savings, improvement in the workflow, enhanced access to pathologic consultation, and adaptability of the pathology laboratory in an era of a decreased workforce and social distancing due to the COVID-19 pandemic.^1-8,55-56 This potential applies across the wide spectrum of potential telepathology uses from frozen section, telecytology (including ROSE) to primary and second opinion diagnoses.^1-8,17-33 The benefits also extends to QA, education, and research, as diagnoses can not only be rereviewed by specialty or second opinion consultation with ease, but also digital slides can be produced for educational and research purposes.^3-8,35-45 Settings that treat the general population and those focused on the care of veterans or members of the armed forces have reported similar reliability or successful implementation.^35-44,61-63 All in all, the use of telepathology represents an innovation that may transform the practice of pathology tomorrow.

Therapeutic hypothermia (TH) for moderate and severe neonatal encephalopathy has been shown to reduce the risk of newborn death, major neurodevelopmental disability, developmental delay, and cerebral palsy.¹ It is estimated that 8 newborns with moderate or severe neonatal encephalopathy need to be treated with TH to prevent 1 case of cerebral palsy.¹ The key elements of TH include:

• initiate hypothermia within 6 hoursof birth
• cool the newborn to a core temperature of 33.5˚ C to 34.5˚ C (92.3˚ F to 94.1˚ F) for 72 hours
• obtain brain ultrasonography to assess for intracranial hemorrhage
• obtain sequential MRI studies to assess brain structure and function
• initiate EEG monitoring for seizure activity.

During hypothermia the newborn is sedated, and oral feedings are reduced. During TH, important physiological goals are to maintain normal oxygenation, blood pressure, fluid balance, and glucose levels.^1,2

TH: The basics

Most of the major published randomized clinical trials used the following inclusion criteria to initiate TH²:

• gestational age at birth of ≥ 35 weeks
• neonate is within 6 hours of birth
• an Apgar score ≤ 5 at 10 minutes of life or prolonged resuscitation at birth or umbilical artery cord pH < 7.1 or neonatal blood gas within 60 minutes of life < 7.1
• moderate to severe encephalopathy or the presence of seizures
• absence of recognizable congenital abnormalities at birth.

However, in some institutions, expert neonatologists have developed more liberal criteria for the initiation of TH, to be considered on a case-by-case basis. These more inclusive criteria, which will result in more newborns being treated with TH, include^3:

• gestational age at birth of ≥ 34 weeks
• neonate is within 12 hours of birth
• a sentinel event at birth or Apgar score ≤ 5 at 10 minutes of life or prolonged resuscitation or umbilical artery cord pH < 7.1 or neonatal blood gas within 60 minutes of life < 7.1 or postnatal cardiopulmonary failure
• moderate to severe encephalopathy or concern for the presence of seizures.

Birth at a gestational age ≤ 34 weeks is a contraindication to TH. Relative contraindications to initiation of TH include: birth weight < 1,750 g, severe congenital anomaly, major genetic disorders, known severe metabolic disorders, major intracranial hemorrhage, severe septicemia, and uncorrectable coagulopathy.³ Adverse outcomes of TH include thrombocytopenia, cardiac arrythmia, and fat necrosis.⁴

Diagnosing neonatal encephalopathy

Neonatal encephalopathy is a clinical diagnosis, defined as abnormal neurologic function in the first few days of life in an infant born at ≥ 35 weeks’ gestation. It is divided into 3 categories: mild (Stage 1), moderate (Stage 2), and severe (Stage 3).^5,6 Institutions vary in the criteria used to differentiate mild from moderate neonatal encephalopathy, the two most frequent forms of encephalopathy. Newborns with mild encephalopathy are not routinely treated with TH because TH has not been shown to be helpful in this setting. Institutions with liberal criteria for diagnosing moderate encephalopathy will initiate TH in more cases. Involvement of a pediatric neurologist in the diagnosis of moderate encephalopathy may help confirm the diagnosis made by the primary neonatologist and provide an independent, second opinion about whether the newborn should be diagnosed with mild or moderate encephalopathy, a clinically important distinction. Physical examination and EEG findings associated with cases of mild, moderate, and severe encephalopathy are presented in TABLE 1.⁷

Continue: Obstetric factors that may be associated with neonatal encephalopathy...

 

Obstetric factors that may be associated with neonatal encephalopathy

In a retrospective case-control study that included 405 newborns at ≥ 35 weeks’ gestational age with neonatal encephalopathy thought to be due to hypoxia, 8 obstetric factors were identified as being associated with an increased risk of neonatal encephalopathy, including (TABLE 2)⁸:

1. an obstetric sentinel event (uterine rupture, placental abruption, umbilical cord prolapse, maternal collapse, or severe fetal bleeding)

2. shoulder dystocia

3. abnormal cardiotocogram (persistent late or variable decelerations, fetal bradycardia, and/or absent or minimal fetal heart variability)

4. failed vacuum delivery

5. prolonged rupture of the membranes (> 24 hours)

6. tight nuchal cord

7. gestational age at birth > 41 weeks

8. thick meconium. 

 

Similar findings have been reported by other investigators analyzing the obstetric risk factors for neonatal encephalopathy.^7,9

Genetic causes of neonatal seizures and neonatal encephalopathy

Many neonatologists practice with the belief that for a newborn with encephalopathy in the setting of a sentinel labor event, a low Apgar score at 5 minutes, an umbilical cord artery pH < 7.00, and/or an elevated lactate level, the diagnosis of hypoxic ischemic encephalopathy is warranted. However, there are many causes of neonatal encephalopathy not related to intrapartum events. For example, neonatal encephalopathy and seizures may be caused by infectious, vascular, metabolic, medications, or congenital problems.¹⁰

There are genetic disorders that can be associated with both neonatal seizures and encephalopathy, suggesting that in some cases the primary cause of the encephalopathy is a genetic problem, not management of labor. Mutations in the potassium channel and sodium channel genes are well recognized causes of neonatal seizures.^11,12 Cerebral palsy, a childhood outcome that may follow neonatal encephalopathy, also has numerous etiologies, including genetic causes. Among 1,345 children with cerebral palsy referred for exome sequencing, investigators reported that a genetic abnormality was identified in 33% of the cases.¹³ Mutations in 86 genes were identified in multiple children. Similar results have been reported in other cohorts.^14-16 Maintaining an open mind about the causes of a case of neonatal encephalopathy and not jumping to a conclusion before completing an evaluation is an optimal approach.

Parent’s evolving emotional and intellectual reaction to the initiation of TH

Initiation of TH for a newborn with encephalopathy catalyzes parents to wonder, “How did my baby develop an encephalopathy?”, “Did my obstetrician’s management of labor and delivery contribute to the outcome?” and “What is the prognosis for my baby?” These are difficult questions with high emotional valence for both patients and clinicians. Obstetricians and neonatologists should collaborate to provide consistent responses to these questions.

The presence of a low umbilical cord artery pH and high lactate in combination with a low Apgar score at 5 minutes may lead the neonatologist to diagnose hypoxic-ischemic encephalopathy in the medical record. The diagnosis of brain hypoxia and ischemia in a newborn may be interpreted by parents as meaning that labor events caused or contributed to the encephalopathy. During the 72 hours of TH, the newborn is sedated and separated from the parents, causing additional emotional stress and uncertainty. When a baby is transferred from a community hospital to a neonatal intensive care unit (NICU) at a tertiary center, the parents may be geographically separated from their baby during a critical period of time, adding to their anxiety. At some point during the care process most newborns treated with TH will have an EEG, brain ultrasound, and brain magnetic resonance imaging (MRI). These data will be discussed with the parent(s) and may cause confusion and additional stress.

The optimal approach to communicating with parents whose newborn is treated with TH continues to evolve. Best practices may include^17-20:

• in-person, regular multidisciplinary family meetings with the parents, including neonatologists, obstetricians, social service specialists and mental health experts when possible
• providing emotional support to parents, recognizing the psychological trauma of the clinical events
• encouraging parents to have physical contact with the newborn during TH
• elevating the role of the parents in the care process by having them participate in care events such as diapering the newborn
• ensuring that clinicians do not blame other clinicians for the clinical outcome
• communicating the results and interpretation of advanced physiological monitoring and imaging studies, with an emphasis on clarity, recognizing the limitations of the studies
• providing educational materials for parents about TH, early intervention programs, and support resources.

Coordinated and consistent communication with the parents is often difficult to facilitate due to many factors, including the unique perspectives and vocabularies of clinicians from different specialties and the difficulty of coordinating communications with all those involved over multiple shifts and sites of care. In terms of vocabulary, neonatologists are comfortable with making a diagnosis of hypoxic-ischemic encephalopathy in a newborn, but obstetricians would prefer that neonatologists use the more generic diagnosis of encephalopathy, holding judgment on the cause until additional data are available. In terms of coordinating communication over multiple shifts and sites of care, interactions between an obstetrician and their patient typically occurs in the postpartum unit, while interactions between neonatologists and parents occur in the NICU.

Parents of a baby with neonatal encephalopathy undergoing TH may have numerous traumatic experiences during the care process. For weeks or months after birth, they may recall or dream about the absence of sounds from their newborn at birth, the resuscitation events including chest compressions and intubation, the shivering of the baby during TH, and the jarring pivot from the expectation of holding and bonding with a healthy newborn to the reality of a sick newborn requiring intensive care. Obstetricians are also traumatized by these events and support from peers and mental health experts may help them recognize, explore, and adapt to the trauma. Neonatologists believe that TH can help improve the childhood outcomes of newborns with encephalopathy, a goal endorsed by all clinicians and family members. ●