Article

Subacute combined degeneration (SCD) is an acquired neurologic complication of vitamin B12 (cobalamin) or, rarely, vitamin B9 (folate) deficiency. SCD is characterized by progressive demyelination of the dorsal and lateral spinal cord, resulting in peripheral neuropathy; gait ataxia; impaired proprioception, vibration, and fine touch; optic neuropathy; and cognitive impairment.¹ In addition to SCD, other neurologic manifestations of B12 deficiency include dementia, depression, visual symptoms due to optic atrophy, and behavioral changes.² The prevalence of SCD in the US has not been well documented, but B12 deficiency is reported at 6% in those aged < 60 years and 20% in those > 60 years^.3

Causes of B12 and B9 deficiency include advanced age, low nutritional intake (eg, vegan diet), impaired absorption (eg, inflammatory bowel disease, autoimmune pernicious anemia, gastrectomy, pancreatic disease), alcohol use, tapeworm infection, medications, and high metabolic states.^2,4 Impaired B12 absorption is common in patients taking medications, such as metformin and proton pump inhibitors (PPI), due to suppression of ileal membrane transport and intrinsic factor activity.^5-7 B-vitamin deficiency can be exacerbated by states of increased cellular turnover, such as polycythemia vera, due to elevated DNA synthesis.

Patients may experience permanent neurologic damage when the diagnosis and treatment of SCD are missed or delayed. Early diagnosis of SCD can be challenging due to lack of specific hematologic markers. In addition, many other conditions such as diabetic neuropathy, malnutrition, toxic neuropathy, sarcoidosis, HIV, multiple sclerosis, polycythemia vera, and iron deficiency anemia have similar presentations and clinical findings.⁸ Anemia and/or macrocytosis are not specific to B12 deficiency.⁴ In addition, patients with B12 deficiency may have a normal complete blood count (CBC); those with concomitant iron deficiency may have minimal or no mean corpuscular volume (MCV) elevation.⁴ In patients suspected to have B12 deficiency based on clinical presentation or laboratory findings of macrocytosis, serum methylmalonic acid (MMA) can serve as a direct measure of B12 activity, with levels > 0.75 μmol/L almost always indicating cobalamin deficiency. ⁹ On the other hand, plasma total homocysteine (tHcy) is a sensitive marker for B12 deficiency. The active form of B12, holotranscobalamin, has also emerged as a specific measure of B12 deficiency.⁹ However, in patients with SCD, measurement of these markers may be unnecessary due to the severity of their clinical symptoms. 

The diagnosis of SCD is further complicated because not all individuals who develop B12 or B9 deficiency will develop SCD. It is difficult to determine which patients will develop SCD because the minimum level of serum B12 required for normal function is unknown, and recent studies indicate that SCD may occur even at low-normal B12 and B9 levels.^2,4,10 Commonly, a serum B12 level of < 200 pg/mL is considered deficient, while a level between 200 and 300 pg/mL is considered borderline.⁴ The goal level of serum B12 is > 300 pg/mL, which is considered normal.⁴ While serologic findings of B-vitamin deficiency are only moderately specific, radiographic findings are highly sensitive and specific for SCD. According to Briani and colleagues, the most consistent finding in SCD on magnetic resonance imaging (MRI) is a “symmetrical, abnormally increased T2 signal intensity, commonly confined to posterior or posterior and lateral columns in the cervical and thoracic spinal cord.”²

We present a case of SCD in a patient with low-normal vitamin B12 levels who presented with progressive sensorimotor deficits and vision loss. The patient was subsequently diagnosed with SCD by radiologic workup. His course was complicated by worsening neurologic deficits despite B12 replacement. The progression of his clinical symptoms demonstrates the need for prompt, aggressive B12 replacement in patients diagnosed with SCD.

Case Presentation

A 63-year-old man presented for neurologic evaluation of progressive gait disturbance, paresthesia, blurred vision, and increasing falls despite use of a walker. Pertinent medical history included polycythemia vera requiring phlebotomy for approximately 9 years, alcohol use disorder (18 servings weekly), type 2 diabetes mellitus, and a remote episode of transient ischemic attack (TIA). The patient reported a 5-year history of burning pain in all extremities. A prior physician diagnosis attributed the symptoms to polyneuropathy secondary to iron deficiency anemia in the setting of chronic phlebotomy for polycythemia vera and high erythrogenesis. He was prescribed gabapentin 600 mg 3 times daily for pain control. B12 deficiency was considered an unlikely etiology due to a low-normal serum level of 305 pg/mL (reference range, 190-950 pg/mL) and normocytosis, with MCV of 88 fL (reference range, 80-100 fL). The patient also reported a 3-year history of blurred vision, which was initially attributed to be secondary to diabetic retinopathy. One week prior to presenting to our clinic, he was evaluated by ophthalmology for new-onset, bilateral central visual field defects, and he was diagnosed with nutritional optic neuropathy.

Previous cardiac evaluation failed to provide a diagnosis for syncopal episodes. MRI of the brain revealed nonspecific white matter changes consistent with chronic microvascular ischemic disease. Electromyography was limited due to pain but showed severe peripheral neuropathy. Laboratory results showed megalocytosis, low-normal serum B12 levels, and low serum folate levels (Table 2). The patient was diagnosed with polyneuropathy and was given intramuscular (IM) vitamin B12 1000 mcg once and a daily multivitamin (containing 25 mcg of B12). He was counseled on alcohol abstinence and medication adherence and was scheduled for follow-up in 3 months. He continued outpatient phlebotomy every 6 weeks for polycythemia.

At 3-month follow-up, the patient reported medication adherence, continued alcohol use, and worsening of symptoms. Falls, which now occurred 2 to 3 times weekly despite proper use of a walker, were described as sudden loss of bilateral lower extremity strength without loss of consciousness, palpitations, or other prodrome. Laboratory results showed minimal changes. Physical examination of the patient demonstrated similar deficits as on initial presentation. The patient received one additional B12 1000 mcg IM. Gabapentin was replaced with pregabalin 75 mg twice daily due to persistent uncontrolled pain and paresthesia. The patient was scheduled for a 3-month followup (6 months from initial visit) and repeat serology.

At 6-month follow-up, the patient showed continued progression of disease with significant difficulty using the walker, worsening falls, and wheelchair use required. Physical examination showed decreased sensation bilaterally up to the knees, absent bilateral patellar and Achilles reflexes, and unsteady gait. Laboratory results showed persistent subclinical B12 deficiency. MRI of the brain and spine showed high T2 signaling in a pattern highly specific for SCD. A formal diagnosis of SCD was made. The patient received an additional B12 1000 mcg IM once. Follow-up phone call with the patient 1 month later revealed no progression or improvement of symptoms.

Radiographic Findings

MRI of the cervical and thoracic spine demonstrated abnormal high T2 signal starting from C2 and extending along the course of the cervical and thoracic spinal cord (Figure). MRI in SCD classically shows symmetric, bilateral high T2 signal within the dorsal columns; on axial images, there is typically an inverted “V” sign.^2,4 There can also be abnormal cerebral white matter change; however, MRI of the brain in this patient did not show any abnormalities.2 The imaging differential for this appearance includes other metabolic deficiencies/toxicities: copper deficiency; vitamin E deficiency; methotrexateinduced myelopathy, and infectious causes: HIV vacuolar myelopathy; and neurosyphilis (tabes dorsalis).⁴

Discussion

This case demonstrates the clinical and radiographic findings of SCD and underscores the need for high-intensity dosing of B12 replacement in patients with SCD to prevent progression of the disease and development of morbidities.

Symptoms of SCD may manifest even when the vitamin levels are in low-normal levels. Its presentation is often nonspecific, thus radiologic workup is beneficial to elucidate the clinical picture. We support the use of spinal MRI in patients with clinical suspicion of SCD to help rule out other causes of myelopathy. However, an MRI is not indicated in all patients with B12 deficiency, especially those without myelopathic symptoms. Additionally, follow-up spinal MRIs are useful in monitoring the progression or improvement of SCD after B12 replacement.² It is important to note that the MRI findings in SCD are not specific to B12 deficiency; other causes may present with similar radiographic findings.⁴ Therefore, radiologic findings must be correlated with a patient’s clinical presentation.

B12 replacement improves and may resolve clinical symptoms and abnormal radiographic findings of SCD. The treatment duration of B12 deficiency depends on the underlying etiology. Reversible causes, such as metformin use > 4 months, PPI use > 12 months, and dietary deficiency, require treatment until appropriate levels are reached and symptoms are resolved.^4,11 The need for chronic metformin and PPI use should also be reassessed regularly. In patients who require long-term metformin use, IM administration of B12 1000 mcg annually should be considered, which will ensure adequate storage for more than 1 year.^12,13 In patients who require long-term PPI use, the risk and benefits of continued use should be measured, and if needed, the lowest possible effective PPI dose is recommended.¹⁴ Irreversible causes of B12 deficiency, such as advanced age, prior gastrectomy, chronic pancreatitis, or autoimmune pernicious anemia, require lifelong supplementation of B12.^4,11

In general, oral vitamin B12 replacement at 1000 to 2000 mcg daily may be as effective as parenteral replacement in patients with mild to moderate deficiency or neurologic symptoms.¹¹ On the other hand, patients with SCD often require parenteral replacement of B12 due to the severity of their deficiency or neurologic symptoms, need for more rapid improvement in symptoms, and prevention of irreversible neurological deficits. ^4,11 Appropriate B12 replacement in SCD requires intensive initial therapy which may involve IM B12 1000 mcg every other day for 2 weeks and additional IM supplementation every 2 to 3 months afterward until resolution of deficiency.^4,14 IM replacement may also be considered in patients who are nonadherent to oral replacement or have an underlying gastrointestinal condition that impairs enteral absorption.^4,11

B12 deficiency is frequently undertreated and can lead to progression of disease with significant morbidity. The need for highintensity dosing of B12 replacement is crucial in patients with SCD. Failure to respond to treatment, as shown from the lack of improvement of serum markers or symptoms, likely suggests undertreatment, treatment nonadherence, iron deficiency anemia, an unidentified malabsorption syndrome, or other diagnoses. In our case, significant undertreatment, compounded by his suspected iron deficiency anemia secondary to his polycythemia vera and chronic phlebotomies, are the most likel etiologies for his lack of clinical improvement.

Multiple factors may affect the prognosis of SCD. Males aged < 50 years with absence of anemia, spinal cord atrophy, Romberg sign, Babinski sign, or sensory deficits on examination have increased likelihood of eventual recovery of signs and symptoms of SCD; those with less spinal cord involvement (< 7 cord segments), contrast enhancement, and spinal cord edema also have improved outcomes.^4,15

Conclusion

SCD is a rare but serious complication of chronic vitamin B12 deficiency that presents with a variety of neurological findings and may be easily confused with other illnesses. The condition is easily overlooked or misdiagnosed; thus, it is crucial to differentiate B12 deficiency from other common causes of neurologic symptoms. Specific findings on MRI are useful to support the clinical diagnosis of SCD and guide clinical decisions. Given the prevalence of B12 deficiency in the older adult population, clinicians should remain alert to the possibility of these conditions in patients who present with progressive neuropathy. Once a patient is diagnosed with SCD secondary to a B12 deficiency, appropriate B12 replacement is critical. Appropriate B12 replacement is aggressive and involves IM B12 1000 mcg every other day for 2 to 3 weeks, followed by additional IM administration every 2 months before transitioning to oral therapy. As seen in this case, failure to adequately replenish B12 can lead to progression or lack of resolution of SCD symptoms.

Subacute combined degeneration (SCD) is an acquired neurologic complication of vitamin B12 (cobalamin) or, rarely, vitamin B9 (folate) deficiency. SCD is characterized by progressive demyelination of the dorsal and lateral spinal cord, resulting in peripheral neuropathy; gait ataxia; impaired proprioception, vibration, and fine touch; optic neuropathy; and cognitive impairment.¹ In addition to SCD, other neurologic manifestations of B12 deficiency include dementia, depression, visual symptoms due to optic atrophy, and behavioral changes.² The prevalence of SCD in the US has not been well documented, but B12 deficiency is reported at 6% in those aged < 60 years and 20% in those > 60 years^.3

Causes of B12 and B9 deficiency include advanced age, low nutritional intake (eg, vegan diet), impaired absorption (eg, inflammatory bowel disease, autoimmune pernicious anemia, gastrectomy, pancreatic disease), alcohol use, tapeworm infection, medications, and high metabolic states.^2,4 Impaired B12 absorption is common in patients taking medications, such as metformin and proton pump inhibitors (PPI), due to suppression of ileal membrane transport and intrinsic factor activity.^5-7 B-vitamin deficiency can be exacerbated by states of increased cellular turnover, such as polycythemia vera, due to elevated DNA synthesis.

Patients may experience permanent neurologic damage when the diagnosis and treatment of SCD are missed or delayed. Early diagnosis of SCD can be challenging due to lack of specific hematologic markers. In addition, many other conditions such as diabetic neuropathy, malnutrition, toxic neuropathy, sarcoidosis, HIV, multiple sclerosis, polycythemia vera, and iron deficiency anemia have similar presentations and clinical findings.⁸ Anemia and/or macrocytosis are not specific to B12 deficiency.⁴ In addition, patients with B12 deficiency may have a normal complete blood count (CBC); those with concomitant iron deficiency may have minimal or no mean corpuscular volume (MCV) elevation.⁴ In patients suspected to have B12 deficiency based on clinical presentation or laboratory findings of macrocytosis, serum methylmalonic acid (MMA) can serve as a direct measure of B12 activity, with levels > 0.75 μmol/L almost always indicating cobalamin deficiency. ⁹ On the other hand, plasma total homocysteine (tHcy) is a sensitive marker for B12 deficiency. The active form of B12, holotranscobalamin, has also emerged as a specific measure of B12 deficiency.⁹ However, in patients with SCD, measurement of these markers may be unnecessary due to the severity of their clinical symptoms. 

The diagnosis of SCD is further complicated because not all individuals who develop B12 or B9 deficiency will develop SCD. It is difficult to determine which patients will develop SCD because the minimum level of serum B12 required for normal function is unknown, and recent studies indicate that SCD may occur even at low-normal B12 and B9 levels.^2,4,10 Commonly, a serum B12 level of < 200 pg/mL is considered deficient, while a level between 200 and 300 pg/mL is considered borderline.⁴ The goal level of serum B12 is > 300 pg/mL, which is considered normal.⁴ While serologic findings of B-vitamin deficiency are only moderately specific, radiographic findings are highly sensitive and specific for SCD. According to Briani and colleagues, the most consistent finding in SCD on magnetic resonance imaging (MRI) is a “symmetrical, abnormally increased T2 signal intensity, commonly confined to posterior or posterior and lateral columns in the cervical and thoracic spinal cord.”²

We present a case of SCD in a patient with low-normal vitamin B12 levels who presented with progressive sensorimotor deficits and vision loss. The patient was subsequently diagnosed with SCD by radiologic workup. His course was complicated by worsening neurologic deficits despite B12 replacement. The progression of his clinical symptoms demonstrates the need for prompt, aggressive B12 replacement in patients diagnosed with SCD.

Case Presentation

A 63-year-old man presented for neurologic evaluation of progressive gait disturbance, paresthesia, blurred vision, and increasing falls despite use of a walker. Pertinent medical history included polycythemia vera requiring phlebotomy for approximately 9 years, alcohol use disorder (18 servings weekly), type 2 diabetes mellitus, and a remote episode of transient ischemic attack (TIA). The patient reported a 5-year history of burning pain in all extremities. A prior physician diagnosis attributed the symptoms to polyneuropathy secondary to iron deficiency anemia in the setting of chronic phlebotomy for polycythemia vera and high erythrogenesis. He was prescribed gabapentin 600 mg 3 times daily for pain control. B12 deficiency was considered an unlikely etiology due to a low-normal serum level of 305 pg/mL (reference range, 190-950 pg/mL) and normocytosis, with MCV of 88 fL (reference range, 80-100 fL). The patient also reported a 3-year history of blurred vision, which was initially attributed to be secondary to diabetic retinopathy. One week prior to presenting to our clinic, he was evaluated by ophthalmology for new-onset, bilateral central visual field defects, and he was diagnosed with nutritional optic neuropathy.

Previous cardiac evaluation failed to provide a diagnosis for syncopal episodes. MRI of the brain revealed nonspecific white matter changes consistent with chronic microvascular ischemic disease. Electromyography was limited due to pain but showed severe peripheral neuropathy. Laboratory results showed megalocytosis, low-normal serum B12 levels, and low serum folate levels (Table 2). The patient was diagnosed with polyneuropathy and was given intramuscular (IM) vitamin B12 1000 mcg once and a daily multivitamin (containing 25 mcg of B12). He was counseled on alcohol abstinence and medication adherence and was scheduled for follow-up in 3 months. He continued outpatient phlebotomy every 6 weeks for polycythemia.

At 3-month follow-up, the patient reported medication adherence, continued alcohol use, and worsening of symptoms. Falls, which now occurred 2 to 3 times weekly despite proper use of a walker, were described as sudden loss of bilateral lower extremity strength without loss of consciousness, palpitations, or other prodrome. Laboratory results showed minimal changes. Physical examination of the patient demonstrated similar deficits as on initial presentation. The patient received one additional B12 1000 mcg IM. Gabapentin was replaced with pregabalin 75 mg twice daily due to persistent uncontrolled pain and paresthesia. The patient was scheduled for a 3-month followup (6 months from initial visit) and repeat serology.

At 6-month follow-up, the patient showed continued progression of disease with significant difficulty using the walker, worsening falls, and wheelchair use required. Physical examination showed decreased sensation bilaterally up to the knees, absent bilateral patellar and Achilles reflexes, and unsteady gait. Laboratory results showed persistent subclinical B12 deficiency. MRI of the brain and spine showed high T2 signaling in a pattern highly specific for SCD. A formal diagnosis of SCD was made. The patient received an additional B12 1000 mcg IM once. Follow-up phone call with the patient 1 month later revealed no progression or improvement of symptoms.

Radiographic Findings

MRI of the cervical and thoracic spine demonstrated abnormal high T2 signal starting from C2 and extending along the course of the cervical and thoracic spinal cord (Figure). MRI in SCD classically shows symmetric, bilateral high T2 signal within the dorsal columns; on axial images, there is typically an inverted “V” sign.^2,4 There can also be abnormal cerebral white matter change; however, MRI of the brain in this patient did not show any abnormalities.2 The imaging differential for this appearance includes other metabolic deficiencies/toxicities: copper deficiency; vitamin E deficiency; methotrexateinduced myelopathy, and infectious causes: HIV vacuolar myelopathy; and neurosyphilis (tabes dorsalis).⁴

Discussion

This case demonstrates the clinical and radiographic findings of SCD and underscores the need for high-intensity dosing of B12 replacement in patients with SCD to prevent progression of the disease and development of morbidities.

Symptoms of SCD may manifest even when the vitamin levels are in low-normal levels. Its presentation is often nonspecific, thus radiologic workup is beneficial to elucidate the clinical picture. We support the use of spinal MRI in patients with clinical suspicion of SCD to help rule out other causes of myelopathy. However, an MRI is not indicated in all patients with B12 deficiency, especially those without myelopathic symptoms. Additionally, follow-up spinal MRIs are useful in monitoring the progression or improvement of SCD after B12 replacement.² It is important to note that the MRI findings in SCD are not specific to B12 deficiency; other causes may present with similar radiographic findings.⁴ Therefore, radiologic findings must be correlated with a patient’s clinical presentation.

B12 replacement improves and may resolve clinical symptoms and abnormal radiographic findings of SCD. The treatment duration of B12 deficiency depends on the underlying etiology. Reversible causes, such as metformin use > 4 months, PPI use > 12 months, and dietary deficiency, require treatment until appropriate levels are reached and symptoms are resolved.^4,11 The need for chronic metformin and PPI use should also be reassessed regularly. In patients who require long-term metformin use, IM administration of B12 1000 mcg annually should be considered, which will ensure adequate storage for more than 1 year.^12,13 In patients who require long-term PPI use, the risk and benefits of continued use should be measured, and if needed, the lowest possible effective PPI dose is recommended.¹⁴ Irreversible causes of B12 deficiency, such as advanced age, prior gastrectomy, chronic pancreatitis, or autoimmune pernicious anemia, require lifelong supplementation of B12.^4,11

In general, oral vitamin B12 replacement at 1000 to 2000 mcg daily may be as effective as parenteral replacement in patients with mild to moderate deficiency or neurologic symptoms.¹¹ On the other hand, patients with SCD often require parenteral replacement of B12 due to the severity of their deficiency or neurologic symptoms, need for more rapid improvement in symptoms, and prevention of irreversible neurological deficits. ^4,11 Appropriate B12 replacement in SCD requires intensive initial therapy which may involve IM B12 1000 mcg every other day for 2 weeks and additional IM supplementation every 2 to 3 months afterward until resolution of deficiency.^4,14 IM replacement may also be considered in patients who are nonadherent to oral replacement or have an underlying gastrointestinal condition that impairs enteral absorption.^4,11

B12 deficiency is frequently undertreated and can lead to progression of disease with significant morbidity. The need for highintensity dosing of B12 replacement is crucial in patients with SCD. Failure to respond to treatment, as shown from the lack of improvement of serum markers or symptoms, likely suggests undertreatment, treatment nonadherence, iron deficiency anemia, an unidentified malabsorption syndrome, or other diagnoses. In our case, significant undertreatment, compounded by his suspected iron deficiency anemia secondary to his polycythemia vera and chronic phlebotomies, are the most likel etiologies for his lack of clinical improvement.

Multiple factors may affect the prognosis of SCD. Males aged < 50 years with absence of anemia, spinal cord atrophy, Romberg sign, Babinski sign, or sensory deficits on examination have increased likelihood of eventual recovery of signs and symptoms of SCD; those with less spinal cord involvement (< 7 cord segments), contrast enhancement, and spinal cord edema also have improved outcomes.^4,15

Conclusion

SCD is a rare but serious complication of chronic vitamin B12 deficiency that presents with a variety of neurological findings and may be easily confused with other illnesses. The condition is easily overlooked or misdiagnosed; thus, it is crucial to differentiate B12 deficiency from other common causes of neurologic symptoms. Specific findings on MRI are useful to support the clinical diagnosis of SCD and guide clinical decisions. Given the prevalence of B12 deficiency in the older adult population, clinicians should remain alert to the possibility of these conditions in patients who present with progressive neuropathy. Once a patient is diagnosed with SCD secondary to a B12 deficiency, appropriate B12 replacement is critical. Appropriate B12 replacement is aggressive and involves IM B12 1000 mcg every other day for 2 to 3 weeks, followed by additional IM administration every 2 months before transitioning to oral therapy. As seen in this case, failure to adequately replenish B12 can lead to progression or lack of resolution of SCD symptoms.

Subacute combined degeneration (SCD) is an acquired neurologic complication of vitamin B12 (cobalamin) or, rarely, vitamin B9 (folate) deficiency. SCD is characterized by progressive demyelination of the dorsal and lateral spinal cord, resulting in peripheral neuropathy; gait ataxia; impaired proprioception, vibration, and fine touch; optic neuropathy; and cognitive impairment.¹ In addition to SCD, other neurologic manifestations of B12 deficiency include dementia, depression, visual symptoms due to optic atrophy, and behavioral changes.² The prevalence of SCD in the US has not been well documented, but B12 deficiency is reported at 6% in those aged < 60 years and 20% in those > 60 years^.3

Causes of B12 and B9 deficiency include advanced age, low nutritional intake (eg, vegan diet), impaired absorption (eg, inflammatory bowel disease, autoimmune pernicious anemia, gastrectomy, pancreatic disease), alcohol use, tapeworm infection, medications, and high metabolic states.^2,4 Impaired B12 absorption is common in patients taking medications, such as metformin and proton pump inhibitors (PPI), due to suppression of ileal membrane transport and intrinsic factor activity.^5-7 B-vitamin deficiency can be exacerbated by states of increased cellular turnover, such as polycythemia vera, due to elevated DNA synthesis.

Patients may experience permanent neurologic damage when the diagnosis and treatment of SCD are missed or delayed. Early diagnosis of SCD can be challenging due to lack of specific hematologic markers. In addition, many other conditions such as diabetic neuropathy, malnutrition, toxic neuropathy, sarcoidosis, HIV, multiple sclerosis, polycythemia vera, and iron deficiency anemia have similar presentations and clinical findings.⁸ Anemia and/or macrocytosis are not specific to B12 deficiency.⁴ In addition, patients with B12 deficiency may have a normal complete blood count (CBC); those with concomitant iron deficiency may have minimal or no mean corpuscular volume (MCV) elevation.⁴ In patients suspected to have B12 deficiency based on clinical presentation or laboratory findings of macrocytosis, serum methylmalonic acid (MMA) can serve as a direct measure of B12 activity, with levels > 0.75 μmol/L almost always indicating cobalamin deficiency. ⁹ On the other hand, plasma total homocysteine (tHcy) is a sensitive marker for B12 deficiency. The active form of B12, holotranscobalamin, has also emerged as a specific measure of B12 deficiency.⁹ However, in patients with SCD, measurement of these markers may be unnecessary due to the severity of their clinical symptoms. 

The diagnosis of SCD is further complicated because not all individuals who develop B12 or B9 deficiency will develop SCD. It is difficult to determine which patients will develop SCD because the minimum level of serum B12 required for normal function is unknown, and recent studies indicate that SCD may occur even at low-normal B12 and B9 levels.^2,4,10 Commonly, a serum B12 level of < 200 pg/mL is considered deficient, while a level between 200 and 300 pg/mL is considered borderline.⁴ The goal level of serum B12 is > 300 pg/mL, which is considered normal.⁴ While serologic findings of B-vitamin deficiency are only moderately specific, radiographic findings are highly sensitive and specific for SCD. According to Briani and colleagues, the most consistent finding in SCD on magnetic resonance imaging (MRI) is a “symmetrical, abnormally increased T2 signal intensity, commonly confined to posterior or posterior and lateral columns in the cervical and thoracic spinal cord.”²

We present a case of SCD in a patient with low-normal vitamin B12 levels who presented with progressive sensorimotor deficits and vision loss. The patient was subsequently diagnosed with SCD by radiologic workup. His course was complicated by worsening neurologic deficits despite B12 replacement. The progression of his clinical symptoms demonstrates the need for prompt, aggressive B12 replacement in patients diagnosed with SCD.

Case Presentation

A 63-year-old man presented for neurologic evaluation of progressive gait disturbance, paresthesia, blurred vision, and increasing falls despite use of a walker. Pertinent medical history included polycythemia vera requiring phlebotomy for approximately 9 years, alcohol use disorder (18 servings weekly), type 2 diabetes mellitus, and a remote episode of transient ischemic attack (TIA). The patient reported a 5-year history of burning pain in all extremities. A prior physician diagnosis attributed the symptoms to polyneuropathy secondary to iron deficiency anemia in the setting of chronic phlebotomy for polycythemia vera and high erythrogenesis. He was prescribed gabapentin 600 mg 3 times daily for pain control. B12 deficiency was considered an unlikely etiology due to a low-normal serum level of 305 pg/mL (reference range, 190-950 pg/mL) and normocytosis, with MCV of 88 fL (reference range, 80-100 fL). The patient also reported a 3-year history of blurred vision, which was initially attributed to be secondary to diabetic retinopathy. One week prior to presenting to our clinic, he was evaluated by ophthalmology for new-onset, bilateral central visual field defects, and he was diagnosed with nutritional optic neuropathy.

Previous cardiac evaluation failed to provide a diagnosis for syncopal episodes. MRI of the brain revealed nonspecific white matter changes consistent with chronic microvascular ischemic disease. Electromyography was limited due to pain but showed severe peripheral neuropathy. Laboratory results showed megalocytosis, low-normal serum B12 levels, and low serum folate levels (Table 2). The patient was diagnosed with polyneuropathy and was given intramuscular (IM) vitamin B12 1000 mcg once and a daily multivitamin (containing 25 mcg of B12). He was counseled on alcohol abstinence and medication adherence and was scheduled for follow-up in 3 months. He continued outpatient phlebotomy every 6 weeks for polycythemia.

At 3-month follow-up, the patient reported medication adherence, continued alcohol use, and worsening of symptoms. Falls, which now occurred 2 to 3 times weekly despite proper use of a walker, were described as sudden loss of bilateral lower extremity strength without loss of consciousness, palpitations, or other prodrome. Laboratory results showed minimal changes. Physical examination of the patient demonstrated similar deficits as on initial presentation. The patient received one additional B12 1000 mcg IM. Gabapentin was replaced with pregabalin 75 mg twice daily due to persistent uncontrolled pain and paresthesia. The patient was scheduled for a 3-month followup (6 months from initial visit) and repeat serology.

At 6-month follow-up, the patient showed continued progression of disease with significant difficulty using the walker, worsening falls, and wheelchair use required. Physical examination showed decreased sensation bilaterally up to the knees, absent bilateral patellar and Achilles reflexes, and unsteady gait. Laboratory results showed persistent subclinical B12 deficiency. MRI of the brain and spine showed high T2 signaling in a pattern highly specific for SCD. A formal diagnosis of SCD was made. The patient received an additional B12 1000 mcg IM once. Follow-up phone call with the patient 1 month later revealed no progression or improvement of symptoms.

Radiographic Findings

MRI of the cervical and thoracic spine demonstrated abnormal high T2 signal starting from C2 and extending along the course of the cervical and thoracic spinal cord (Figure). MRI in SCD classically shows symmetric, bilateral high T2 signal within the dorsal columns; on axial images, there is typically an inverted “V” sign.^2,4 There can also be abnormal cerebral white matter change; however, MRI of the brain in this patient did not show any abnormalities.2 The imaging differential for this appearance includes other metabolic deficiencies/toxicities: copper deficiency; vitamin E deficiency; methotrexateinduced myelopathy, and infectious causes: HIV vacuolar myelopathy; and neurosyphilis (tabes dorsalis).⁴

Discussion

This case demonstrates the clinical and radiographic findings of SCD and underscores the need for high-intensity dosing of B12 replacement in patients with SCD to prevent progression of the disease and development of morbidities.

Symptoms of SCD may manifest even when the vitamin levels are in low-normal levels. Its presentation is often nonspecific, thus radiologic workup is beneficial to elucidate the clinical picture. We support the use of spinal MRI in patients with clinical suspicion of SCD to help rule out other causes of myelopathy. However, an MRI is not indicated in all patients with B12 deficiency, especially those without myelopathic symptoms. Additionally, follow-up spinal MRIs are useful in monitoring the progression or improvement of SCD after B12 replacement.² It is important to note that the MRI findings in SCD are not specific to B12 deficiency; other causes may present with similar radiographic findings.⁴ Therefore, radiologic findings must be correlated with a patient’s clinical presentation.

B12 replacement improves and may resolve clinical symptoms and abnormal radiographic findings of SCD. The treatment duration of B12 deficiency depends on the underlying etiology. Reversible causes, such as metformin use > 4 months, PPI use > 12 months, and dietary deficiency, require treatment until appropriate levels are reached and symptoms are resolved.^4,11 The need for chronic metformin and PPI use should also be reassessed regularly. In patients who require long-term metformin use, IM administration of B12 1000 mcg annually should be considered, which will ensure adequate storage for more than 1 year.^12,13 In patients who require long-term PPI use, the risk and benefits of continued use should be measured, and if needed, the lowest possible effective PPI dose is recommended.¹⁴ Irreversible causes of B12 deficiency, such as advanced age, prior gastrectomy, chronic pancreatitis, or autoimmune pernicious anemia, require lifelong supplementation of B12.^4,11

In general, oral vitamin B12 replacement at 1000 to 2000 mcg daily may be as effective as parenteral replacement in patients with mild to moderate deficiency or neurologic symptoms.¹¹ On the other hand, patients with SCD often require parenteral replacement of B12 due to the severity of their deficiency or neurologic symptoms, need for more rapid improvement in symptoms, and prevention of irreversible neurological deficits. ^4,11 Appropriate B12 replacement in SCD requires intensive initial therapy which may involve IM B12 1000 mcg every other day for 2 weeks and additional IM supplementation every 2 to 3 months afterward until resolution of deficiency.^4,14 IM replacement may also be considered in patients who are nonadherent to oral replacement or have an underlying gastrointestinal condition that impairs enteral absorption.^4,11

B12 deficiency is frequently undertreated and can lead to progression of disease with significant morbidity. The need for highintensity dosing of B12 replacement is crucial in patients with SCD. Failure to respond to treatment, as shown from the lack of improvement of serum markers or symptoms, likely suggests undertreatment, treatment nonadherence, iron deficiency anemia, an unidentified malabsorption syndrome, or other diagnoses. In our case, significant undertreatment, compounded by his suspected iron deficiency anemia secondary to his polycythemia vera and chronic phlebotomies, are the most likel etiologies for his lack of clinical improvement.

Multiple factors may affect the prognosis of SCD. Males aged < 50 years with absence of anemia, spinal cord atrophy, Romberg sign, Babinski sign, or sensory deficits on examination have increased likelihood of eventual recovery of signs and symptoms of SCD; those with less spinal cord involvement (< 7 cord segments), contrast enhancement, and spinal cord edema also have improved outcomes.^4,15

Conclusion

SCD is a rare but serious complication of chronic vitamin B12 deficiency that presents with a variety of neurological findings and may be easily confused with other illnesses. The condition is easily overlooked or misdiagnosed; thus, it is crucial to differentiate B12 deficiency from other common causes of neurologic symptoms. Specific findings on MRI are useful to support the clinical diagnosis of SCD and guide clinical decisions. Given the prevalence of B12 deficiency in the older adult population, clinicians should remain alert to the possibility of these conditions in patients who present with progressive neuropathy. Once a patient is diagnosed with SCD secondary to a B12 deficiency, appropriate B12 replacement is critical. Appropriate B12 replacement is aggressive and involves IM B12 1000 mcg every other day for 2 to 3 weeks, followed by additional IM administration every 2 months before transitioning to oral therapy. As seen in this case, failure to adequately replenish B12 can lead to progression or lack of resolution of SCD symptoms.

Dr Michael Wilson, associate professor at the University of California, San Francisco, School of Medicine, shares updates on disease-modifying therapies (DMTs) and health economics that were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2022 meeting.  

First, Dr Wilson reports on a holistic review of the US economic burdens associated with MS and DMT use. The total burden of MS was estimated to be $85 billion in both direct and indirect costs, with the average annual DMT cost ranging between $57,000 and $90,000. 

Another study looked at long-term outcomes for patients who were treated with autologous hematopoietic stem cell transplantation (aHSCT). With follow-up periods ranging from 8 months to 20 years, there were no reported relapses after aHSCT. In contrast, there were 1.1 relapses per patient year before aHSCT. Patients also saw improvement in Expanded Disability Status Scale scores during follow-up.  

Finally, Dr Wilson reviews the 18-month results from a long-term extension study of tolebrutinib, which looked at MRI activity, efficacy, and safety. Investigators reported a significant decrease in the number of new or enhancing lesions and in annual relapse rates, while T2 lesion burden remained stable.  

--

Michael Wilson, MD, Associate Professor, Department of Neurology, University of California, San Francisco, School of Medicine; Director, UCSF Center for Encephalitis and Meningitis, San Francisco, California 

Michael Wilson, MD, has disclosed the following relevant financial relationships: 

Received research grant from: Roche/Genentech 

Received income in an amount equal to or greater than $250 from: Takeda; Genentech; Novartis 

Dr Michael Wilson, associate professor at the University of California, San Francisco, School of Medicine, shares updates on disease-modifying therapies (DMTs) and health economics that were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2022 meeting.  

First, Dr Wilson reports on a holistic review of the US economic burdens associated with MS and DMT use. The total burden of MS was estimated to be $85 billion in both direct and indirect costs, with the average annual DMT cost ranging between $57,000 and $90,000. 

Another study looked at long-term outcomes for patients who were treated with autologous hematopoietic stem cell transplantation (aHSCT). With follow-up periods ranging from 8 months to 20 years, there were no reported relapses after aHSCT. In contrast, there were 1.1 relapses per patient year before aHSCT. Patients also saw improvement in Expanded Disability Status Scale scores during follow-up.  

Finally, Dr Wilson reviews the 18-month results from a long-term extension study of tolebrutinib, which looked at MRI activity, efficacy, and safety. Investigators reported a significant decrease in the number of new or enhancing lesions and in annual relapse rates, while T2 lesion burden remained stable.  

--

Michael Wilson, MD, Associate Professor, Department of Neurology, University of California, San Francisco, School of Medicine; Director, UCSF Center for Encephalitis and Meningitis, San Francisco, California 

Michael Wilson, MD, has disclosed the following relevant financial relationships: 

Received research grant from: Roche/Genentech 

Received income in an amount equal to or greater than $250 from: Takeda; Genentech; Novartis 

Dr Michael Wilson, associate professor at the University of California, San Francisco, School of Medicine, shares updates on disease-modifying therapies (DMTs) and health economics that were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2022 meeting.  

First, Dr Wilson reports on a holistic review of the US economic burdens associated with MS and DMT use. The total burden of MS was estimated to be $85 billion in both direct and indirect costs, with the average annual DMT cost ranging between $57,000 and $90,000. 

Another study looked at long-term outcomes for patients who were treated with autologous hematopoietic stem cell transplantation (aHSCT). With follow-up periods ranging from 8 months to 20 years, there were no reported relapses after aHSCT. In contrast, there were 1.1 relapses per patient year before aHSCT. Patients also saw improvement in Expanded Disability Status Scale scores during follow-up.  

Finally, Dr Wilson reviews the 18-month results from a long-term extension study of tolebrutinib, which looked at MRI activity, efficacy, and safety. Investigators reported a significant decrease in the number of new or enhancing lesions and in annual relapse rates, while T2 lesion burden remained stable.  

--

Michael Wilson, MD, Associate Professor, Department of Neurology, University of California, San Francisco, School of Medicine; Director, UCSF Center for Encephalitis and Meningitis, San Francisco, California 

Michael Wilson, MD, has disclosed the following relevant financial relationships: 

Received research grant from: Roche/Genentech 

Received income in an amount equal to or greater than $250 from: Takeda; Genentech; Novartis 

Should a postpartum patient with chronic hepatitis C infection be discouraged from breastfeeding her infant?

Continue to the answer...

Hepatitis C is not a contraindication to breastfeeding. Although the virus has been identified in breast milk, the risk of transmission to the infant is exceedingly low.

Should a postpartum patient with chronic hepatitis C infection be discouraged from breastfeeding her infant?

Continue to the answer...

Hepatitis C is not a contraindication to breastfeeding. Although the virus has been identified in breast milk, the risk of transmission to the infant is exceedingly low.

Should a postpartum patient with chronic hepatitis C infection be discouraged from breastfeeding her infant?

Continue to the answer...

Hepatitis C is not a contraindication to breastfeeding. Although the virus has been identified in breast milk, the risk of transmission to the infant is exceedingly low.

Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.^1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.² Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.^2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.^4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.^3,8-10

Blood Cell Counts and Thrombotic Events in PV

Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.¹¹ Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.¹² Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).¹²

Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.^13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 10⁹/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.¹³ In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 10⁹/L vs reference level of < 7 × 10⁹/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).¹⁴ Likewise, WBC count ≥ 11 × 10⁹/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.⁸

Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.^12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.

The Veteran Population with PV

Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.^16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.

In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.¹⁷ The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).

Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 10⁹/L) compared with those reported in CYTO-PV (≥ 11 × 10⁹/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.^14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).^6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.^18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.

Current PV Management and Future Implications

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.¹¹ Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.^11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).

Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.²¹ In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.²² The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.^21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.²⁴

However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.²⁵

Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.^11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.

Acknowledgments

Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).

Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.^1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.² Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.^2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.^4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.^3,8-10

Blood Cell Counts and Thrombotic Events in PV

Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.¹¹ Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.¹² Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).¹²

Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.^13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 10⁹/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.¹³ In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 10⁹/L vs reference level of < 7 × 10⁹/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).¹⁴ Likewise, WBC count ≥ 11 × 10⁹/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.⁸

Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.^12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.

The Veteran Population with PV

Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.^16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.

In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.¹⁷ The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).

Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 10⁹/L) compared with those reported in CYTO-PV (≥ 11 × 10⁹/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.^14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).^6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.^18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.

Current PV Management and Future Implications

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.¹¹ Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.^11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).

Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.²¹ In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.²² The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.^21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.²⁴

However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.²⁵

Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.^11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.

Acknowledgments

Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).

Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.^1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.² Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.^2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.^4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.^3,8-10

Blood Cell Counts and Thrombotic Events in PV

Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.¹¹ Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.¹² Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).¹²

Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.^13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 10⁹/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.¹³ In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 10⁹/L vs reference level of < 7 × 10⁹/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).¹⁴ Likewise, WBC count ≥ 11 × 10⁹/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.⁸

Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.^12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.

The Veteran Population with PV

Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.^16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.

In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.¹⁷ The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).

Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 10⁹/L) compared with those reported in CYTO-PV (≥ 11 × 10⁹/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.^14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).^6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.^18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.

Current PV Management and Future Implications

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.¹¹ Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.^11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).

Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.²¹ In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.²² The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.^21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.²⁴

However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.²⁵

Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.^11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.

Acknowledgments

Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).

Older adults admitted to post-acute settings frequently have complex rehabilitation needs and multimorbidity, which predisposes them to pain management challenges.^1,2 The prevalence of pain in post-acute and long-term care is as high as 65%, and opioid use is common among this population with 1 in 7 residents receiving long-term opioids.^3,4

Opioids that do not adequately control pain represent a missed opportunity for deprescribing. There is limited evidence regarding efficacy of long-term opioid use (> 90 days) for improving pain and physical functioning.⁵ In addition, long-term opioid use carries significant risks, including overdose-related death, dependence, and increased emergency department visits.⁵ These risks are likely to be pronounced among veterans receiving post-acute care (PAC) who are older, have comorbid psychiatric disorders, are prescribed several centrally acting medications, and experience substance use disorder (SUD).⁶

Older adults are at increased risk for opioid toxicity because of reduced drug clearance and smaller therapeutic window.⁵ Centers for Disease Control and Prevention (CDC) guidelines recommend frequently assessing patients for benefit in terms of sustained improvement in pain as well as physical function.⁵ If pain and functional improvements are minimal, opioid use and nonopioid pain management strategies should be considered. Some patients will struggle with this approach. Directly asking patients about the effectiveness of opioids is challenging. Opioid users with chronic pain frequently report problems with opioids even as they describe them as indispensable for pain management.^7,8

Earlier studies have assessed patient perspectives regarding opioid difficulties as well as their helpfulness, which could introduce recall bias. Patient-level factors that contribute to a global sense of distress, in addition to the presence of painful physical conditions, also could contribute to patients requesting opioids without experiencing adequate pain relief. One study in veterans residing in PAC facilities found that individuals with depression, posttraumatic stress disorder (PTSD), and SUD were more likely to report pain and receive scheduled analgesics; this effect persisted in individuals with PTSD even after adjusting for demographic and functional status variables.⁹ The study looked only at analgesics as a class and did not examine opioids specifically. It is possible that distressed individuals, such as those with uncontrolled depression, PTSD, and SUD, might be more likely to report high pain levels and receive opioids with inadequate benefit and increased risk. Identifying the primary condition causing distress and targeting treatment to that condition (ie, depression) is preferable to escalating opioids in an attempt to treat pain in the context of nonresponse. Assessing an individual’s aggregate response to opioids rather than relying on a single self-report is a useful addition to current pain management strategies.

The goal of this study was to pilot a method of identifying opioid-nonresponsive pain using administrative data, measure its prevalence in a PAC population of veterans, and explore clinical and demographic correlates with particular attention to variates that could indicate high levels of psychological and physical distress. Identifying pain that is poorly responsive to opioids would give clinicians the opportunity to avoid or minimize opioid use and prioritize treatments that are likely to improve the resident’s pain, quality of life, and physical function while minimizing recall bias. We hypothesized that pain that responds poorly to opioids would be prevalent among veterans residing in a PAC unit. We considered that veterans with pain poorly responsive to opioids would be more likely to have factors that would place them at increased risk of adverse effects, such as comorbid psychiatric conditions, history of SUD, and multimorbidity, providing further rationale for clinical equipoise in that population.⁶

Methods

This was a small, retrospective cross-sectional study using administrative data and chart review. The study included veterans who were administered opioids while residing in a single US Department of Veterans Affairs (VA) community living center PAC (CLC-PAC) unit during at least 1 of 4 nonconsecutive, random days in 2016 and 2017. The study was approved by the institutional review board of the Ann Arbor VA Health System (#2017-1034) as part of a larger project involving models of care in vulnerable older veterans.

Inclusion criteria were the presence of at least moderate pain (≥ 4 on a 0 to 10 scale); receiving ≥ 2 opioids ordered as needed over the prespecified 24-hour observation period; and having ≥ 2 pre-and postopioid administration pain scores during the observation period. Veterans who did not meet these criteria were excluded. At the time of initial sample selection, we did not capture information related to coprescribed analgesics, including a standing order of opioids. To obtain the sample, we initially characterized all veterans on the 4 days residing in the CLC-PAC unit as those reporting at least moderate pain (≥ 4) and those who reported no or mild pain (< 4). The cut point of 4 of 10 is consistent with moderate pain based on earlier work showing higher likelihood of pain that interferes with physical function.¹⁰ We then restricted the sample to veterans who received ≥ 2 opioids ordered as needed for pain and had ≥ 2 pre- and postopioid administration numeric pain rating scores during the 24-hour observation period. This methodology was chosen to enrich our sample for those who received opioids regularly for ongoing pain. Opioids were defined as full µ-opioid receptor agonists and included hydrocodone, oxycodone, morphine, hydromorphone, fentanyl, tramadol, and methadone.

Outcome of Interest

The primary outcome of interest was an individual’s response to as-needed opioids, which we defined as change in the pain score after opioid administration. The pre-opioid pain score was the score that immediately preceded administration of an as-needed opioid. The postopioid administration pain score was the first score after opioid administration if obtained within 3 hours of administration. Scores collected > 3 hours after opioid administration were excluded because they no longer accurately reflected the impact of the opioid due to the short half-lives. Observations were excluded if an opioid was administered without a recorded pain score; this occurred once for 6 individuals. Observations also were excluded if an opioid was administered but the data were captured on the following day (outside of the 24-hour window); this occurred once for 3 individuals.

We calculated a ∆ score by subtracting the postopioid pain rating score from the pre-opioid score. Individual ∆ scores were then averaged over the 24-hour period (range, 2-5 opioid doses). For example, if an individual reported a pre-opioid pain score of 10, and a postopioid pain score of 2, the ∆ was recorded as 8. If the individual’s next pre-opioid score was 10, and post-opioid score was 6, the ∆ was recorded as 4. ∆ scores over the 24-hour period were averaged together to determine that individual’s response to as-needed opioids. In the previous example, the mean ∆ score is 6. Lower mean ∆ scores reflect decreased responsiveness to opioids’ analgesic effect.

Demographic and clinical data were obtained from electronic health record review using a standardized assessment form. These data included information about medical and psychiatric comorbidities, specialist consultations, and CLC-PAC unit admission indications and diagnoses. Medications of interest were categorized as antidepressants, antipsychotics, benzodiazepines, muscle relaxants, hypnotics, stimulants, antiepileptic drugs/mood stabilizers (including gabapentin and pregabalin), and all adjuvant analgesics. Adjuvant analgesics were defined as medications administered for pain as documented by chart notes or those ordered as needed for pain, and analyzed as a composite variable. Antidepressants with analgesic properties (serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants) were considered adjuvant analgesics. Psychiatric information collected included presence of mood, anxiety, and psychotic disorders, and PTSD. SUD information was collected separately from other psychiatric disorders.

Analyses

The study population was described using tabulations for categorical data and means and standard deviations for continuous data. Responsiveness to opioids was analyzed as a continuous variable. Those with higher mean ∆ scores were considered to have pain relatively more responsive to opioids, while lower mean ∆ scores indicated pain less responsive to opioids. We constructed linear regression models controlling for average pre-opioid pain rating scores to explore associations between opioid responsiveness and variables of interest. All analyses were completed using Stata version 15. This study was not adequately powered to detect differences across the spectrum of opioid responsiveness, although the authors have reported differences in this article.

Results

Over the 4-day observational period there were 146 resident-days. Of these, 88 (60.3%) reported at least 1 pain score of ≥ 4. Of those, 61 (41.8%) received ≥ 1 as-needed opioid for pain. We identified 46 resident-days meeting study criteria of ≥ 2 pre- and postanalgesic scores. We identified 41 unique individuals (Figure 1). Two individuals were admitted to the CLC-PAC unit on 2 of the 4 observation days, and 1 individual was admitted to the CLC-PAC unit on 3 of the 4 observation days. For individuals admitted several days, we included data only from the initial observation day.

Response to opioids varied greatly in this sample. The mean (SD) ∆ pain score was 3.4 (1.6) and ranged from 0.5 to 6.3. Using linear regression, we found no relationship between admission indication, medical comorbidities (including active cancer), and opioid responsiveness (Table).

A poorer response to opioids was associated with a significantly higher as-needed opioid dosage (β = −0.02; 95% CI, −0.04 to −0.01; P = .002) as well as a trend toward higher total opioid dosage (β = −0.005; 95% CI, −0.01 to 0.0003; P = .06) (Figure 4). Thirty-eight (92.7%) participants received nonopioid adjuvant analgesics for pain. More than half (56.1%) received antidepressants or gabapentinoids (51.2%), although we did not assess whether they were prescribed for pain or another indication. We did not identify a relationship between any specific psychoactive drug class and opioid responsiveness in this sample.

Discussion

This exploratory study used readily available administrative data in a CLC-PAC unit to assess responsiveness to opioids via a numeric mean ∆ score, with higher values indicating more pain relief in response to opioids. We then constructed linear regression models to characterize the relationship between the mean ∆ score and factors known to be associated with difficult-to-control pain and psychosocial distress. As expected, opioid responsiveness was highly variable among residents; some residents experienced essentially no reduction in pain, on average, despite receiving opioids. Psychiatric comorbidity, higher dosage in OMEs, and the presence of a pain service consult significantly correlated with poorer response to opioids. To our knowledge, this is the first study to quantify opioid responsiveness and describe the relationship with clinical correlates in the understudied PAC population.

Earlier research has demonstrated a relationship between the presence of psychiatric disorders and increased likelihood of receiving any analgesics among veterans residing in PAC.⁹ Our study adds to the literature by quantifying opioid response using readily available administrative data and examining associations with psychiatric diagnoses. These findings highlight the possibility that attempting to treat high levels of pain by escalating the opioid dosage in patients with a comorbid psychiatric diagnosis should be re-addressed, particularly if there is no meaningful pain reduction at lower opioid dosages. Our sample had a variety of admission diagnoses and medical comorbidities, however, we did not identify a relationship with opioid responsiveness, including an active cancer diagnosis. Although SUDs were highly prevalent in our sample, there was no relationship with opioid responsiveness. This suggests that lack of response to opioids is not merely a matter of drug tolerance or an indication of drug-seeking behavior.

Factors Impacting Response

Many factors could affect whether an individual obtains an adequate analgesic response to opioids or other pain medications, including variations in genes encoding opioid receptors and hepatic enzymes involved in drug metabolism and an individual’s opioid exposure history.¹³ The phenomenon of requiring more drug to produce the same relief after repeated exposures (ie, tolerance) is well known.¹⁴ Opioid-induced hyperalgesia is a phenomenon whereby a patient’s overall pain increases while receiving opioids, but each opioid dose might be perceived as beneficial.¹⁵ Increasingly, psychosocial distress is an important factor in opioid response. Adverse selection is the process culminating in those with psychosocial distress and/or SUDs being prescribed more opioids for longer durations.¹⁶ Our data suggests that this process could play a role in PAC settings. In addition, exaggerating pain to obtain additional opioids for nonmedical purposes, such as euphoria or relaxation, also is possible.¹⁷

When clinically assessing an individual whose pain is not well controlled despite escalating opioid dosages, prescribers must consider which of these factors likely is predominant. However, the first step of determining who has a poor opioid response is not straightforward. Directly asking patients is challenging; many individuals perceive opioids to be helpful while simultaneously reporting inadequately controlled pain.^7,8 The primary value of this study is the possibility of providing prescribers a quick, simple method of assessing a patient’s response to opioids. Using this method, individuals who are responding poorly to opioids, including those who might exaggerate pain for secondary gain, could be identified. Health care professionals could consider revisiting pain management strategies, assess for the presence of OUD, or evaluate other contributors to inadequately controlled pain. Although we only collected data regarding response to opioids in this study, any pain medication administered as needed (ie, nonsteroidal anti-inflammatory drugs, acetaminophen) could be analyzed using this methodology, allowing identification of other helpful pain management strategies. We began the validation process with extensive chart review, but further validation is required before this method can be applied to routine clinical practice.

Patients who report uncontrolled pain despite receiving opioids are a clinically challenging population. The traditional strategy has been to escalate opioids, which is recommended by the World Health Organization stepladder approach for patients with cancer pain and limited life expectancy.¹⁸ Applying this approach to a general population of patients with chronic pain is ineffective and dangerous.¹⁹ The CDC and the VA/US Department of Defense (VA/DoD) guidelines both recommend carefully reassessing risks and benefits at total daily dosages > 50 OME and avoid increasing dosages to > 90 OME daily in most circumstances.^5,20 Our finding that participants taking higher dosages of opioids were not more likely to have better control over their pain supports this recommendation.

Limitations

This study has several limitations, the most significant is its small sample size because of the exploratory nature of the project. Results are based on a small pilot sample enriched to include individuals with at least moderate pain who receive opioids frequently at 1 VA CLC-PAC unit; therefore, the results might not be representative of all veterans or a more general population. Our small sample size limits power to detect small differences. Data collected should be used to inform formal power calculations before subsequent larger studies to select adequate sample size. Validation studies, including samples from the same population using different dates, which reproduce findings are an important step. Moreover, we only had data on a single dimension of pain (intensity/severity), as measured by the pain scale, which nursing staff used to make a real-time clinical decision of whether to administer an as-needed opioid. Future studies should consider using pain measures that provide multidimensional assessment (ie, severity, functional interference) and/or were developed specifically for veterans, such as the Defense and Veterans Pain Rating Scale.²¹

Our study was cross-sectional in nature and addressed a single 24-hour period of data per participant. The years of data collection (2016 and 2017) followed a decline in overall opioid prescribing that has continued, likely influenced by CDC and VA/DoD guidelines.²² It is unclear whether our observations are an accurate reflection of individuals’ response over time or whether prescribing practices in PAC have shifted.

We did not consider the type of pain being treated or explore clinicians’ reasons for prescribing opioids, therefore limiting our ability to know whether opioids were indicated. Information regarding OUD and other SUDs was limited to what was documented in the chart during the CLC-PAC unit admission. We did not have information on length of exposure to opioids. It is possible that opioid tolerance could play a role in reducing opioid responsiveness. However, simple tolerance would not be expected to explain robust correlations with psychiatric comorbidities. Also, simple tolerance would be expected to be overcome with higher opioid dosages, whereas our study demonstrates less responsiveness. These data suggests that some individuals’ pain might be poorly opioid responsive, and psychiatric factors could increase this risk. We used a novel data source in combination with chart review; to our knowledge, barcode medication administration data have not been used in this manner previously. Future work needs to validate this method, using larger sample sizes and several clinical sites. Finally, we used regression models that controlled for average pre-opioid pain rating scores, which is only 1 covariate important for examining effects. Larger studies with adequate power should control for multiple covariates known to be associated with pain and opioid response.

Conclusions

Opioid responsiveness is important clinically yet challenging to assess. This pilot study identifies a way of classifying pain as relatively opioid nonresponsive using administrative data but requires further validation before considering scaling for more general use. The possibility that a substantial percentage of residents in a CLC-PAC unit could be receiving increasing dosages of opioids without adequate benefit justifies the need for more research and underscores the need for prescribers to assess individuals frequently for ongoing benefit of opioids regardless of diagnosis or mechanism of pain.

Acknowledgments

The authors thank Andrzej Galecki, Corey Powell, and the University of Michigan Consulting for Statistics, Computing and Analytics Research Center for assistance with statistical analysis.

Older adults admitted to post-acute settings frequently have complex rehabilitation needs and multimorbidity, which predisposes them to pain management challenges.^1,2 The prevalence of pain in post-acute and long-term care is as high as 65%, and opioid use is common among this population with 1 in 7 residents receiving long-term opioids.^3,4

Opioids that do not adequately control pain represent a missed opportunity for deprescribing. There is limited evidence regarding efficacy of long-term opioid use (> 90 days) for improving pain and physical functioning.⁵ In addition, long-term opioid use carries significant risks, including overdose-related death, dependence, and increased emergency department visits.⁵ These risks are likely to be pronounced among veterans receiving post-acute care (PAC) who are older, have comorbid psychiatric disorders, are prescribed several centrally acting medications, and experience substance use disorder (SUD).⁶

Older adults are at increased risk for opioid toxicity because of reduced drug clearance and smaller therapeutic window.⁵ Centers for Disease Control and Prevention (CDC) guidelines recommend frequently assessing patients for benefit in terms of sustained improvement in pain as well as physical function.⁵ If pain and functional improvements are minimal, opioid use and nonopioid pain management strategies should be considered. Some patients will struggle with this approach. Directly asking patients about the effectiveness of opioids is challenging. Opioid users with chronic pain frequently report problems with opioids even as they describe them as indispensable for pain management.^7,8

Earlier studies have assessed patient perspectives regarding opioid difficulties as well as their helpfulness, which could introduce recall bias. Patient-level factors that contribute to a global sense of distress, in addition to the presence of painful physical conditions, also could contribute to patients requesting opioids without experiencing adequate pain relief. One study in veterans residing in PAC facilities found that individuals with depression, posttraumatic stress disorder (PTSD), and SUD were more likely to report pain and receive scheduled analgesics; this effect persisted in individuals with PTSD even after adjusting for demographic and functional status variables.⁹ The study looked only at analgesics as a class and did not examine opioids specifically. It is possible that distressed individuals, such as those with uncontrolled depression, PTSD, and SUD, might be more likely to report high pain levels and receive opioids with inadequate benefit and increased risk. Identifying the primary condition causing distress and targeting treatment to that condition (ie, depression) is preferable to escalating opioids in an attempt to treat pain in the context of nonresponse. Assessing an individual’s aggregate response to opioids rather than relying on a single self-report is a useful addition to current pain management strategies.

The goal of this study was to pilot a method of identifying opioid-nonresponsive pain using administrative data, measure its prevalence in a PAC population of veterans, and explore clinical and demographic correlates with particular attention to variates that could indicate high levels of psychological and physical distress. Identifying pain that is poorly responsive to opioids would give clinicians the opportunity to avoid or minimize opioid use and prioritize treatments that are likely to improve the resident’s pain, quality of life, and physical function while minimizing recall bias. We hypothesized that pain that responds poorly to opioids would be prevalent among veterans residing in a PAC unit. We considered that veterans with pain poorly responsive to opioids would be more likely to have factors that would place them at increased risk of adverse effects, such as comorbid psychiatric conditions, history of SUD, and multimorbidity, providing further rationale for clinical equipoise in that population.⁶

Methods

This was a small, retrospective cross-sectional study using administrative data and chart review. The study included veterans who were administered opioids while residing in a single US Department of Veterans Affairs (VA) community living center PAC (CLC-PAC) unit during at least 1 of 4 nonconsecutive, random days in 2016 and 2017. The study was approved by the institutional review board of the Ann Arbor VA Health System (#2017-1034) as part of a larger project involving models of care in vulnerable older veterans.

Inclusion criteria were the presence of at least moderate pain (≥ 4 on a 0 to 10 scale); receiving ≥ 2 opioids ordered as needed over the prespecified 24-hour observation period; and having ≥ 2 pre-and postopioid administration pain scores during the observation period. Veterans who did not meet these criteria were excluded. At the time of initial sample selection, we did not capture information related to coprescribed analgesics, including a standing order of opioids. To obtain the sample, we initially characterized all veterans on the 4 days residing in the CLC-PAC unit as those reporting at least moderate pain (≥ 4) and those who reported no or mild pain (< 4). The cut point of 4 of 10 is consistent with moderate pain based on earlier work showing higher likelihood of pain that interferes with physical function.¹⁰ We then restricted the sample to veterans who received ≥ 2 opioids ordered as needed for pain and had ≥ 2 pre- and postopioid administration numeric pain rating scores during the 24-hour observation period. This methodology was chosen to enrich our sample for those who received opioids regularly for ongoing pain. Opioids were defined as full µ-opioid receptor agonists and included hydrocodone, oxycodone, morphine, hydromorphone, fentanyl, tramadol, and methadone.

Outcome of Interest

The primary outcome of interest was an individual’s response to as-needed opioids, which we defined as change in the pain score after opioid administration. The pre-opioid pain score was the score that immediately preceded administration of an as-needed opioid. The postopioid administration pain score was the first score after opioid administration if obtained within 3 hours of administration. Scores collected > 3 hours after opioid administration were excluded because they no longer accurately reflected the impact of the opioid due to the short half-lives. Observations were excluded if an opioid was administered without a recorded pain score; this occurred once for 6 individuals. Observations also were excluded if an opioid was administered but the data were captured on the following day (outside of the 24-hour window); this occurred once for 3 individuals.

We calculated a ∆ score by subtracting the postopioid pain rating score from the pre-opioid score. Individual ∆ scores were then averaged over the 24-hour period (range, 2-5 opioid doses). For example, if an individual reported a pre-opioid pain score of 10, and a postopioid pain score of 2, the ∆ was recorded as 8. If the individual’s next pre-opioid score was 10, and post-opioid score was 6, the ∆ was recorded as 4. ∆ scores over the 24-hour period were averaged together to determine that individual’s response to as-needed opioids. In the previous example, the mean ∆ score is 6. Lower mean ∆ scores reflect decreased responsiveness to opioids’ analgesic effect.

Demographic and clinical data were obtained from electronic health record review using a standardized assessment form. These data included information about medical and psychiatric comorbidities, specialist consultations, and CLC-PAC unit admission indications and diagnoses. Medications of interest were categorized as antidepressants, antipsychotics, benzodiazepines, muscle relaxants, hypnotics, stimulants, antiepileptic drugs/mood stabilizers (including gabapentin and pregabalin), and all adjuvant analgesics. Adjuvant analgesics were defined as medications administered for pain as documented by chart notes or those ordered as needed for pain, and analyzed as a composite variable. Antidepressants with analgesic properties (serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants) were considered adjuvant analgesics. Psychiatric information collected included presence of mood, anxiety, and psychotic disorders, and PTSD. SUD information was collected separately from other psychiatric disorders.

Analyses

The study population was described using tabulations for categorical data and means and standard deviations for continuous data. Responsiveness to opioids was analyzed as a continuous variable. Those with higher mean ∆ scores were considered to have pain relatively more responsive to opioids, while lower mean ∆ scores indicated pain less responsive to opioids. We constructed linear regression models controlling for average pre-opioid pain rating scores to explore associations between opioid responsiveness and variables of interest. All analyses were completed using Stata version 15. This study was not adequately powered to detect differences across the spectrum of opioid responsiveness, although the authors have reported differences in this article.

Results

Over the 4-day observational period there were 146 resident-days. Of these, 88 (60.3%) reported at least 1 pain score of ≥ 4. Of those, 61 (41.8%) received ≥ 1 as-needed opioid for pain. We identified 46 resident-days meeting study criteria of ≥ 2 pre- and postanalgesic scores. We identified 41 unique individuals (Figure 1). Two individuals were admitted to the CLC-PAC unit on 2 of the 4 observation days, and 1 individual was admitted to the CLC-PAC unit on 3 of the 4 observation days. For individuals admitted several days, we included data only from the initial observation day.

Response to opioids varied greatly in this sample. The mean (SD) ∆ pain score was 3.4 (1.6) and ranged from 0.5 to 6.3. Using linear regression, we found no relationship between admission indication, medical comorbidities (including active cancer), and opioid responsiveness (Table).

A poorer response to opioids was associated with a significantly higher as-needed opioid dosage (β = −0.02; 95% CI, −0.04 to −0.01; P = .002) as well as a trend toward higher total opioid dosage (β = −0.005; 95% CI, −0.01 to 0.0003; P = .06) (Figure 4). Thirty-eight (92.7%) participants received nonopioid adjuvant analgesics for pain. More than half (56.1%) received antidepressants or gabapentinoids (51.2%), although we did not assess whether they were prescribed for pain or another indication. We did not identify a relationship between any specific psychoactive drug class and opioid responsiveness in this sample.

Discussion

This exploratory study used readily available administrative data in a CLC-PAC unit to assess responsiveness to opioids via a numeric mean ∆ score, with higher values indicating more pain relief in response to opioids. We then constructed linear regression models to characterize the relationship between the mean ∆ score and factors known to be associated with difficult-to-control pain and psychosocial distress. As expected, opioid responsiveness was highly variable among residents; some residents experienced essentially no reduction in pain, on average, despite receiving opioids. Psychiatric comorbidity, higher dosage in OMEs, and the presence of a pain service consult significantly correlated with poorer response to opioids. To our knowledge, this is the first study to quantify opioid responsiveness and describe the relationship with clinical correlates in the understudied PAC population.

Earlier research has demonstrated a relationship between the presence of psychiatric disorders and increased likelihood of receiving any analgesics among veterans residing in PAC.⁹ Our study adds to the literature by quantifying opioid response using readily available administrative data and examining associations with psychiatric diagnoses. These findings highlight the possibility that attempting to treat high levels of pain by escalating the opioid dosage in patients with a comorbid psychiatric diagnosis should be re-addressed, particularly if there is no meaningful pain reduction at lower opioid dosages. Our sample had a variety of admission diagnoses and medical comorbidities, however, we did not identify a relationship with opioid responsiveness, including an active cancer diagnosis. Although SUDs were highly prevalent in our sample, there was no relationship with opioid responsiveness. This suggests that lack of response to opioids is not merely a matter of drug tolerance or an indication of drug-seeking behavior.

Factors Impacting Response

Many factors could affect whether an individual obtains an adequate analgesic response to opioids or other pain medications, including variations in genes encoding opioid receptors and hepatic enzymes involved in drug metabolism and an individual’s opioid exposure history.¹³ The phenomenon of requiring more drug to produce the same relief after repeated exposures (ie, tolerance) is well known.¹⁴ Opioid-induced hyperalgesia is a phenomenon whereby a patient’s overall pain increases while receiving opioids, but each opioid dose might be perceived as beneficial.¹⁵ Increasingly, psychosocial distress is an important factor in opioid response. Adverse selection is the process culminating in those with psychosocial distress and/or SUDs being prescribed more opioids for longer durations.¹⁶ Our data suggests that this process could play a role in PAC settings. In addition, exaggerating pain to obtain additional opioids for nonmedical purposes, such as euphoria or relaxation, also is possible.¹⁷

When clinically assessing an individual whose pain is not well controlled despite escalating opioid dosages, prescribers must consider which of these factors likely is predominant. However, the first step of determining who has a poor opioid response is not straightforward. Directly asking patients is challenging; many individuals perceive opioids to be helpful while simultaneously reporting inadequately controlled pain.^7,8 The primary value of this study is the possibility of providing prescribers a quick, simple method of assessing a patient’s response to opioids. Using this method, individuals who are responding poorly to opioids, including those who might exaggerate pain for secondary gain, could be identified. Health care professionals could consider revisiting pain management strategies, assess for the presence of OUD, or evaluate other contributors to inadequately controlled pain. Although we only collected data regarding response to opioids in this study, any pain medication administered as needed (ie, nonsteroidal anti-inflammatory drugs, acetaminophen) could be analyzed using this methodology, allowing identification of other helpful pain management strategies. We began the validation process with extensive chart review, but further validation is required before this method can be applied to routine clinical practice.

Patients who report uncontrolled pain despite receiving opioids are a clinically challenging population. The traditional strategy has been to escalate opioids, which is recommended by the World Health Organization stepladder approach for patients with cancer pain and limited life expectancy.¹⁸ Applying this approach to a general population of patients with chronic pain is ineffective and dangerous.¹⁹ The CDC and the VA/US Department of Defense (VA/DoD) guidelines both recommend carefully reassessing risks and benefits at total daily dosages > 50 OME and avoid increasing dosages to > 90 OME daily in most circumstances.^5,20 Our finding that participants taking higher dosages of opioids were not more likely to have better control over their pain supports this recommendation.

Limitations

This study has several limitations, the most significant is its small sample size because of the exploratory nature of the project. Results are based on a small pilot sample enriched to include individuals with at least moderate pain who receive opioids frequently at 1 VA CLC-PAC unit; therefore, the results might not be representative of all veterans or a more general population. Our small sample size limits power to detect small differences. Data collected should be used to inform formal power calculations before subsequent larger studies to select adequate sample size. Validation studies, including samples from the same population using different dates, which reproduce findings are an important step. Moreover, we only had data on a single dimension of pain (intensity/severity), as measured by the pain scale, which nursing staff used to make a real-time clinical decision of whether to administer an as-needed opioid. Future studies should consider using pain measures that provide multidimensional assessment (ie, severity, functional interference) and/or were developed specifically for veterans, such as the Defense and Veterans Pain Rating Scale.²¹

Our study was cross-sectional in nature and addressed a single 24-hour period of data per participant. The years of data collection (2016 and 2017) followed a decline in overall opioid prescribing that has continued, likely influenced by CDC and VA/DoD guidelines.²² It is unclear whether our observations are an accurate reflection of individuals’ response over time or whether prescribing practices in PAC have shifted.

We did not consider the type of pain being treated or explore clinicians’ reasons for prescribing opioids, therefore limiting our ability to know whether opioids were indicated. Information regarding OUD and other SUDs was limited to what was documented in the chart during the CLC-PAC unit admission. We did not have information on length of exposure to opioids. It is possible that opioid tolerance could play a role in reducing opioid responsiveness. However, simple tolerance would not be expected to explain robust correlations with psychiatric comorbidities. Also, simple tolerance would be expected to be overcome with higher opioid dosages, whereas our study demonstrates less responsiveness. These data suggests that some individuals’ pain might be poorly opioid responsive, and psychiatric factors could increase this risk. We used a novel data source in combination with chart review; to our knowledge, barcode medication administration data have not been used in this manner previously. Future work needs to validate this method, using larger sample sizes and several clinical sites. Finally, we used regression models that controlled for average pre-opioid pain rating scores, which is only 1 covariate important for examining effects. Larger studies with adequate power should control for multiple covariates known to be associated with pain and opioid response.

Conclusions

Opioid responsiveness is important clinically yet challenging to assess. This pilot study identifies a way of classifying pain as relatively opioid nonresponsive using administrative data but requires further validation before considering scaling for more general use. The possibility that a substantial percentage of residents in a CLC-PAC unit could be receiving increasing dosages of opioids without adequate benefit justifies the need for more research and underscores the need for prescribers to assess individuals frequently for ongoing benefit of opioids regardless of diagnosis or mechanism of pain.

Acknowledgments

The authors thank Andrzej Galecki, Corey Powell, and the University of Michigan Consulting for Statistics, Computing and Analytics Research Center for assistance with statistical analysis.

Older adults admitted to post-acute settings frequently have complex rehabilitation needs and multimorbidity, which predisposes them to pain management challenges.^1,2 The prevalence of pain in post-acute and long-term care is as high as 65%, and opioid use is common among this population with 1 in 7 residents receiving long-term opioids.^3,4

Opioids that do not adequately control pain represent a missed opportunity for deprescribing. There is limited evidence regarding efficacy of long-term opioid use (> 90 days) for improving pain and physical functioning.⁵ In addition, long-term opioid use carries significant risks, including overdose-related death, dependence, and increased emergency department visits.⁵ These risks are likely to be pronounced among veterans receiving post-acute care (PAC) who are older, have comorbid psychiatric disorders, are prescribed several centrally acting medications, and experience substance use disorder (SUD).⁶

Older adults are at increased risk for opioid toxicity because of reduced drug clearance and smaller therapeutic window.⁵ Centers for Disease Control and Prevention (CDC) guidelines recommend frequently assessing patients for benefit in terms of sustained improvement in pain as well as physical function.⁵ If pain and functional improvements are minimal, opioid use and nonopioid pain management strategies should be considered. Some patients will struggle with this approach. Directly asking patients about the effectiveness of opioids is challenging. Opioid users with chronic pain frequently report problems with opioids even as they describe them as indispensable for pain management.^7,8

Earlier studies have assessed patient perspectives regarding opioid difficulties as well as their helpfulness, which could introduce recall bias. Patient-level factors that contribute to a global sense of distress, in addition to the presence of painful physical conditions, also could contribute to patients requesting opioids without experiencing adequate pain relief. One study in veterans residing in PAC facilities found that individuals with depression, posttraumatic stress disorder (PTSD), and SUD were more likely to report pain and receive scheduled analgesics; this effect persisted in individuals with PTSD even after adjusting for demographic and functional status variables.⁹ The study looked only at analgesics as a class and did not examine opioids specifically. It is possible that distressed individuals, such as those with uncontrolled depression, PTSD, and SUD, might be more likely to report high pain levels and receive opioids with inadequate benefit and increased risk. Identifying the primary condition causing distress and targeting treatment to that condition (ie, depression) is preferable to escalating opioids in an attempt to treat pain in the context of nonresponse. Assessing an individual’s aggregate response to opioids rather than relying on a single self-report is a useful addition to current pain management strategies.

The goal of this study was to pilot a method of identifying opioid-nonresponsive pain using administrative data, measure its prevalence in a PAC population of veterans, and explore clinical and demographic correlates with particular attention to variates that could indicate high levels of psychological and physical distress. Identifying pain that is poorly responsive to opioids would give clinicians the opportunity to avoid or minimize opioid use and prioritize treatments that are likely to improve the resident’s pain, quality of life, and physical function while minimizing recall bias. We hypothesized that pain that responds poorly to opioids would be prevalent among veterans residing in a PAC unit. We considered that veterans with pain poorly responsive to opioids would be more likely to have factors that would place them at increased risk of adverse effects, such as comorbid psychiatric conditions, history of SUD, and multimorbidity, providing further rationale for clinical equipoise in that population.⁶

Methods

This was a small, retrospective cross-sectional study using administrative data and chart review. The study included veterans who were administered opioids while residing in a single US Department of Veterans Affairs (VA) community living center PAC (CLC-PAC) unit during at least 1 of 4 nonconsecutive, random days in 2016 and 2017. The study was approved by the institutional review board of the Ann Arbor VA Health System (#2017-1034) as part of a larger project involving models of care in vulnerable older veterans.

Inclusion criteria were the presence of at least moderate pain (≥ 4 on a 0 to 10 scale); receiving ≥ 2 opioids ordered as needed over the prespecified 24-hour observation period; and having ≥ 2 pre-and postopioid administration pain scores during the observation period. Veterans who did not meet these criteria were excluded. At the time of initial sample selection, we did not capture information related to coprescribed analgesics, including a standing order of opioids. To obtain the sample, we initially characterized all veterans on the 4 days residing in the CLC-PAC unit as those reporting at least moderate pain (≥ 4) and those who reported no or mild pain (< 4). The cut point of 4 of 10 is consistent with moderate pain based on earlier work showing higher likelihood of pain that interferes with physical function.¹⁰ We then restricted the sample to veterans who received ≥ 2 opioids ordered as needed for pain and had ≥ 2 pre- and postopioid administration numeric pain rating scores during the 24-hour observation period. This methodology was chosen to enrich our sample for those who received opioids regularly for ongoing pain. Opioids were defined as full µ-opioid receptor agonists and included hydrocodone, oxycodone, morphine, hydromorphone, fentanyl, tramadol, and methadone.

Outcome of Interest

The primary outcome of interest was an individual’s response to as-needed opioids, which we defined as change in the pain score after opioid administration. The pre-opioid pain score was the score that immediately preceded administration of an as-needed opioid. The postopioid administration pain score was the first score after opioid administration if obtained within 3 hours of administration. Scores collected > 3 hours after opioid administration were excluded because they no longer accurately reflected the impact of the opioid due to the short half-lives. Observations were excluded if an opioid was administered without a recorded pain score; this occurred once for 6 individuals. Observations also were excluded if an opioid was administered but the data were captured on the following day (outside of the 24-hour window); this occurred once for 3 individuals.

We calculated a ∆ score by subtracting the postopioid pain rating score from the pre-opioid score. Individual ∆ scores were then averaged over the 24-hour period (range, 2-5 opioid doses). For example, if an individual reported a pre-opioid pain score of 10, and a postopioid pain score of 2, the ∆ was recorded as 8. If the individual’s next pre-opioid score was 10, and post-opioid score was 6, the ∆ was recorded as 4. ∆ scores over the 24-hour period were averaged together to determine that individual’s response to as-needed opioids. In the previous example, the mean ∆ score is 6. Lower mean ∆ scores reflect decreased responsiveness to opioids’ analgesic effect.

Demographic and clinical data were obtained from electronic health record review using a standardized assessment form. These data included information about medical and psychiatric comorbidities, specialist consultations, and CLC-PAC unit admission indications and diagnoses. Medications of interest were categorized as antidepressants, antipsychotics, benzodiazepines, muscle relaxants, hypnotics, stimulants, antiepileptic drugs/mood stabilizers (including gabapentin and pregabalin), and all adjuvant analgesics. Adjuvant analgesics were defined as medications administered for pain as documented by chart notes or those ordered as needed for pain, and analyzed as a composite variable. Antidepressants with analgesic properties (serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants) were considered adjuvant analgesics. Psychiatric information collected included presence of mood, anxiety, and psychotic disorders, and PTSD. SUD information was collected separately from other psychiatric disorders.

Analyses

The study population was described using tabulations for categorical data and means and standard deviations for continuous data. Responsiveness to opioids was analyzed as a continuous variable. Those with higher mean ∆ scores were considered to have pain relatively more responsive to opioids, while lower mean ∆ scores indicated pain less responsive to opioids. We constructed linear regression models controlling for average pre-opioid pain rating scores to explore associations between opioid responsiveness and variables of interest. All analyses were completed using Stata version 15. This study was not adequately powered to detect differences across the spectrum of opioid responsiveness, although the authors have reported differences in this article.

Results

Over the 4-day observational period there were 146 resident-days. Of these, 88 (60.3%) reported at least 1 pain score of ≥ 4. Of those, 61 (41.8%) received ≥ 1 as-needed opioid for pain. We identified 46 resident-days meeting study criteria of ≥ 2 pre- and postanalgesic scores. We identified 41 unique individuals (Figure 1). Two individuals were admitted to the CLC-PAC unit on 2 of the 4 observation days, and 1 individual was admitted to the CLC-PAC unit on 3 of the 4 observation days. For individuals admitted several days, we included data only from the initial observation day.

Response to opioids varied greatly in this sample. The mean (SD) ∆ pain score was 3.4 (1.6) and ranged from 0.5 to 6.3. Using linear regression, we found no relationship between admission indication, medical comorbidities (including active cancer), and opioid responsiveness (Table).

A poorer response to opioids was associated with a significantly higher as-needed opioid dosage (β = −0.02; 95% CI, −0.04 to −0.01; P = .002) as well as a trend toward higher total opioid dosage (β = −0.005; 95% CI, −0.01 to 0.0003; P = .06) (Figure 4). Thirty-eight (92.7%) participants received nonopioid adjuvant analgesics for pain. More than half (56.1%) received antidepressants or gabapentinoids (51.2%), although we did not assess whether they were prescribed for pain or another indication. We did not identify a relationship between any specific psychoactive drug class and opioid responsiveness in this sample.

Discussion

This exploratory study used readily available administrative data in a CLC-PAC unit to assess responsiveness to opioids via a numeric mean ∆ score, with higher values indicating more pain relief in response to opioids. We then constructed linear regression models to characterize the relationship between the mean ∆ score and factors known to be associated with difficult-to-control pain and psychosocial distress. As expected, opioid responsiveness was highly variable among residents; some residents experienced essentially no reduction in pain, on average, despite receiving opioids. Psychiatric comorbidity, higher dosage in OMEs, and the presence of a pain service consult significantly correlated with poorer response to opioids. To our knowledge, this is the first study to quantify opioid responsiveness and describe the relationship with clinical correlates in the understudied PAC population.

Earlier research has demonstrated a relationship between the presence of psychiatric disorders and increased likelihood of receiving any analgesics among veterans residing in PAC.⁹ Our study adds to the literature by quantifying opioid response using readily available administrative data and examining associations with psychiatric diagnoses. These findings highlight the possibility that attempting to treat high levels of pain by escalating the opioid dosage in patients with a comorbid psychiatric diagnosis should be re-addressed, particularly if there is no meaningful pain reduction at lower opioid dosages. Our sample had a variety of admission diagnoses and medical comorbidities, however, we did not identify a relationship with opioid responsiveness, including an active cancer diagnosis. Although SUDs were highly prevalent in our sample, there was no relationship with opioid responsiveness. This suggests that lack of response to opioids is not merely a matter of drug tolerance or an indication of drug-seeking behavior.

Factors Impacting Response

Many factors could affect whether an individual obtains an adequate analgesic response to opioids or other pain medications, including variations in genes encoding opioid receptors and hepatic enzymes involved in drug metabolism and an individual’s opioid exposure history.¹³ The phenomenon of requiring more drug to produce the same relief after repeated exposures (ie, tolerance) is well known.¹⁴ Opioid-induced hyperalgesia is a phenomenon whereby a patient’s overall pain increases while receiving opioids, but each opioid dose might be perceived as beneficial.¹⁵ Increasingly, psychosocial distress is an important factor in opioid response. Adverse selection is the process culminating in those with psychosocial distress and/or SUDs being prescribed more opioids for longer durations.¹⁶ Our data suggests that this process could play a role in PAC settings. In addition, exaggerating pain to obtain additional opioids for nonmedical purposes, such as euphoria or relaxation, also is possible.¹⁷

When clinically assessing an individual whose pain is not well controlled despite escalating opioid dosages, prescribers must consider which of these factors likely is predominant. However, the first step of determining who has a poor opioid response is not straightforward. Directly asking patients is challenging; many individuals perceive opioids to be helpful while simultaneously reporting inadequately controlled pain.^7,8 The primary value of this study is the possibility of providing prescribers a quick, simple method of assessing a patient’s response to opioids. Using this method, individuals who are responding poorly to opioids, including those who might exaggerate pain for secondary gain, could be identified. Health care professionals could consider revisiting pain management strategies, assess for the presence of OUD, or evaluate other contributors to inadequately controlled pain. Although we only collected data regarding response to opioids in this study, any pain medication administered as needed (ie, nonsteroidal anti-inflammatory drugs, acetaminophen) could be analyzed using this methodology, allowing identification of other helpful pain management strategies. We began the validation process with extensive chart review, but further validation is required before this method can be applied to routine clinical practice.

Patients who report uncontrolled pain despite receiving opioids are a clinically challenging population. The traditional strategy has been to escalate opioids, which is recommended by the World Health Organization stepladder approach for patients with cancer pain and limited life expectancy.¹⁸ Applying this approach to a general population of patients with chronic pain is ineffective and dangerous.¹⁹ The CDC and the VA/US Department of Defense (VA/DoD) guidelines both recommend carefully reassessing risks and benefits at total daily dosages > 50 OME and avoid increasing dosages to > 90 OME daily in most circumstances.^5,20 Our finding that participants taking higher dosages of opioids were not more likely to have better control over their pain supports this recommendation.

Limitations

This study has several limitations, the most significant is its small sample size because of the exploratory nature of the project. Results are based on a small pilot sample enriched to include individuals with at least moderate pain who receive opioids frequently at 1 VA CLC-PAC unit; therefore, the results might not be representative of all veterans or a more general population. Our small sample size limits power to detect small differences. Data collected should be used to inform formal power calculations before subsequent larger studies to select adequate sample size. Validation studies, including samples from the same population using different dates, which reproduce findings are an important step. Moreover, we only had data on a single dimension of pain (intensity/severity), as measured by the pain scale, which nursing staff used to make a real-time clinical decision of whether to administer an as-needed opioid. Future studies should consider using pain measures that provide multidimensional assessment (ie, severity, functional interference) and/or were developed specifically for veterans, such as the Defense and Veterans Pain Rating Scale.²¹

Our study was cross-sectional in nature and addressed a single 24-hour period of data per participant. The years of data collection (2016 and 2017) followed a decline in overall opioid prescribing that has continued, likely influenced by CDC and VA/DoD guidelines.²² It is unclear whether our observations are an accurate reflection of individuals’ response over time or whether prescribing practices in PAC have shifted.

We did not consider the type of pain being treated or explore clinicians’ reasons for prescribing opioids, therefore limiting our ability to know whether opioids were indicated. Information regarding OUD and other SUDs was limited to what was documented in the chart during the CLC-PAC unit admission. We did not have information on length of exposure to opioids. It is possible that opioid tolerance could play a role in reducing opioid responsiveness. However, simple tolerance would not be expected to explain robust correlations with psychiatric comorbidities. Also, simple tolerance would be expected to be overcome with higher opioid dosages, whereas our study demonstrates less responsiveness. These data suggests that some individuals’ pain might be poorly opioid responsive, and psychiatric factors could increase this risk. We used a novel data source in combination with chart review; to our knowledge, barcode medication administration data have not been used in this manner previously. Future work needs to validate this method, using larger sample sizes and several clinical sites. Finally, we used regression models that controlled for average pre-opioid pain rating scores, which is only 1 covariate important for examining effects. Larger studies with adequate power should control for multiple covariates known to be associated with pain and opioid response.

Conclusions

Opioid responsiveness is important clinically yet challenging to assess. This pilot study identifies a way of classifying pain as relatively opioid nonresponsive using administrative data but requires further validation before considering scaling for more general use. The possibility that a substantial percentage of residents in a CLC-PAC unit could be receiving increasing dosages of opioids without adequate benefit justifies the need for more research and underscores the need for prescribers to assess individuals frequently for ongoing benefit of opioids regardless of diagnosis or mechanism of pain.

Acknowledgments

The authors thank Andrzej Galecki, Corey Powell, and the University of Michigan Consulting for Statistics, Computing and Analytics Research Center for assistance with statistical analysis.

A biopsy was performed to exclude squamous cell carcinoma and an additional biopsy was sent for tissue culture for aerobic and acid-fast bacteria. The culture revealed a surprising diagnosis: cutaneous mycobacterium marinum.

Mycobacterium marinum is one of many nontuberculosis mycobacteria that may rarely cause infections in immunocompetent patients. M marinum is found worldwide in saltwater and freshwater. Infections may occur in individuals working in fisheries or fish markets, natural marine environments, or with aquariums. The infection may gain access through small, even unnoticed breaks in the skin. Papules, pustules, or abscesses caused by M marinum develop a few weeks after exposure and share many features with other common skin infections, including Staphylococcus aureus. Lymphatic involvement and sporotrichoid spread may occur. Immunocompromised patients can experience deeper involvement into tendons. Patients with significant soft tissue pain should undergo computed tomography, or preferably magnetic resonance imaging, to determine the extent of disease.

For immunocompetent patients and those with limited disease, as in this case, spontaneous resolution can occur after a year or more. However, because of the potential risk of more severe disease, treatment is recommended. M marinum is resistant to multiple antibiotics and there are no standardized treatment guidelines. Minocycline 100 mg bid for 3 weeks to 3 months is 1 accepted regimen for limited disease; treatment should be continued for 3 to 4 weeks following clinical resolution.¹ Patients with more widespread disease benefit from evaluation by Infectious Diseases. Patients exposed to atypical mycobacteria may have false positive QuantiFERON-TB Gold tests that are commonly performed prior to biologic therapies.²

This patient achieved complete resolution of his signs and symptoms after receiving minocycline 100 mg bid for 6 weeks. He continues to fish recreationally.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

A biopsy was performed to exclude squamous cell carcinoma and an additional biopsy was sent for tissue culture for aerobic and acid-fast bacteria. The culture revealed a surprising diagnosis: cutaneous mycobacterium marinum.

Mycobacterium marinum is one of many nontuberculosis mycobacteria that may rarely cause infections in immunocompetent patients. M marinum is found worldwide in saltwater and freshwater. Infections may occur in individuals working in fisheries or fish markets, natural marine environments, or with aquariums. The infection may gain access through small, even unnoticed breaks in the skin. Papules, pustules, or abscesses caused by M marinum develop a few weeks after exposure and share many features with other common skin infections, including Staphylococcus aureus. Lymphatic involvement and sporotrichoid spread may occur. Immunocompromised patients can experience deeper involvement into tendons. Patients with significant soft tissue pain should undergo computed tomography, or preferably magnetic resonance imaging, to determine the extent of disease.

For immunocompetent patients and those with limited disease, as in this case, spontaneous resolution can occur after a year or more. However, because of the potential risk of more severe disease, treatment is recommended. M marinum is resistant to multiple antibiotics and there are no standardized treatment guidelines. Minocycline 100 mg bid for 3 weeks to 3 months is 1 accepted regimen for limited disease; treatment should be continued for 3 to 4 weeks following clinical resolution.¹ Patients with more widespread disease benefit from evaluation by Infectious Diseases. Patients exposed to atypical mycobacteria may have false positive QuantiFERON-TB Gold tests that are commonly performed prior to biologic therapies.²

This patient achieved complete resolution of his signs and symptoms after receiving minocycline 100 mg bid for 6 weeks. He continues to fish recreationally.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

A biopsy was performed to exclude squamous cell carcinoma and an additional biopsy was sent for tissue culture for aerobic and acid-fast bacteria. The culture revealed a surprising diagnosis: cutaneous mycobacterium marinum.

Mycobacterium marinum is one of many nontuberculosis mycobacteria that may rarely cause infections in immunocompetent patients. M marinum is found worldwide in saltwater and freshwater. Infections may occur in individuals working in fisheries or fish markets, natural marine environments, or with aquariums. The infection may gain access through small, even unnoticed breaks in the skin. Papules, pustules, or abscesses caused by M marinum develop a few weeks after exposure and share many features with other common skin infections, including Staphylococcus aureus. Lymphatic involvement and sporotrichoid spread may occur. Immunocompromised patients can experience deeper involvement into tendons. Patients with significant soft tissue pain should undergo computed tomography, or preferably magnetic resonance imaging, to determine the extent of disease.

For immunocompetent patients and those with limited disease, as in this case, spontaneous resolution can occur after a year or more. However, because of the potential risk of more severe disease, treatment is recommended. M marinum is resistant to multiple antibiotics and there are no standardized treatment guidelines. Minocycline 100 mg bid for 3 weeks to 3 months is 1 accepted regimen for limited disease; treatment should be continued for 3 to 4 weeks following clinical resolution.¹ Patients with more widespread disease benefit from evaluation by Infectious Diseases. Patients exposed to atypical mycobacteria may have false positive QuantiFERON-TB Gold tests that are commonly performed prior to biologic therapies.²

This patient achieved complete resolution of his signs and symptoms after receiving minocycline 100 mg bid for 6 weeks. He continues to fish recreationally.

‌

Text courtesy of Jonathan Karnes, MD, medical director, MDFMR Dermatology Services, Augusta, ME. Photos courtesy of Jonathan Karnes, MD (copyright retained).

Mycosis fungoides (MF) and Sézary syndrome (SS) are non-Hodgkin T-cell lymphomas that make up the majority of cutaneous T-cell lymphomas. These conditions commonly affect Black patients, with an incidence rate of 12.6 cases of cutaneous T-cell lymphomas per million individuals vs 9.8 per million individuals in non–skin of color (SoC) patients.¹ However, educational resources tend to focus on the clinical manifestations of MF/SS in lighter skin types, describing MF as erythematous patches, plaques, or tumors presenting in non–sun-exposed areas of the skin and SS as generalized erythroderma.² Skin of color, comprised of Fitzpatrick skin types (FSTs) IV to VI,³ is poorly represented across dermatology textbooks,^4,5 medical student resources,⁶ and peer-reviewed publications,⁷ raising awareness for the need to address this disparity.

Skin of color patients with MF/SS display variable morphologies, including features such as hyperpigmentation and hypopigmentation,⁸ the latter being exceedingly rare in non-SoC patients.⁹ Familiarity with these differences among providers is essential to allow for equitable diagnosis and treatment across all skin types, especially in light of data predicting that by 2044 more than 50% of the US population will be people of color.¹⁰ Patients with SoC are of many ethnic and racial backgrounds, including Black, Hispanic, American Indian, Pacific Islander, and Asian.¹¹

Along with morphologic differences, there also are several racial disparities in the prognosis and survival of patients with MF/SS. Black patients diagnosed with MF present with greater body surface area affected, and Black women with MF have reduced survival rates compared to their White counterparts.¹² Given these racial disparities in survival and representation in educational resources, we aimed to quantify the frequency of various morphologic characteristics of MF/SS in patients with SoC vs non-SoC patients to facilitate better recognition of early MF/SS in SoC patients by medical providers.

Methods

We performed a retrospective chart review following approval from the institutional review board at Northwestern University (Chicago, Illinois). We identified all patients with FSTs IV to VI and biopsy-proven MF/SS who had been clinically photographed in our clinic from January 1998 to December 2019. Only photographs that were high quality enough to review morphologic features were included in our review. Fitzpatrick skin type was determined based on electronic medical record documentation. If photographs were available from multiple visits for the same patient, only those showing posttreatment nonactive lesions were included. Additionally, 36 patients with FSTs I to III (non-SoC) and biopsy-proven MF/SS were included in our review as a comparison with the SoC cohort. The primary outcomes for this study included the presence of scale, erythema, hyperpigmentation, hypopigmentation, violaceous color, lichenification, silver hue, dyschromia, alopecia, poikiloderma, atrophy, and ulceration in active lesions. Dyschromia was defined by the presence of both hypopigmentation and hyperpigmentation. Poikiloderma was defined by hypopigmentation and hyperpigmentation, telangiectasia, and atrophy. Secondary outcomes included evaluation of those same characteristics in posttreatment nonactive lesions. All photographs were independently assessed by 3 authors (M.L.E., C.J.W., J.M.M.), and discrepancies were resolved by further review of the photograph in question and discussion.

Statistical Analysis—Summary statistics were applied to describe demographic and clinical characteristics. The χ² test was used for categorical variables. Results achieving P<.05 were considered statistically significant.

Results

We reviewed photographs of 111 patients across all skin types (8, FST I; 12, FST II; 16, FST III; 17, FST IV; 44, FST V; 14, FST VI). The cohort was 47% female, and the mean age was 49.7 years (range, 15–86 years). The majority of the cohort had early-stage MF (stage IA or IB). There were more cases of SS in the SoC cohort than the non-SoC cohort (Table). Only 5 photographs had discrepancies and required discussion among the reviewers to achieve consensus.

Regarding morphologic characteristics in active lesions (Figure 1), scale was present in almost all patients (99% in SoC, 94% in non-SoC). Erythema was present in nearly all non-SoC patients (94%) but only in 69% of SoC patients (P=.003). Poikiloderma also was found to be present at higher frequencies in non-SoC patients compared with SoC patients (19% and 4%, respectively [P=.008]). However, hyperpigmentation (80% vs 39%), lichenification (43% vs 17%), and silver hue (25% vs 3%) were more common in SoC patients than non-SoC patients (P<.05). There were no significant differences in the remaining features, including hypopigmentation (39% vs 25%), dyschromia (24% vs 19%), violaceous color (44% vs 25%), atrophy (11% vs 22%), alopecia (23% vs 31%), and ulceration (16% vs 8%) between SoC and non-SoC patients (P>.05). Photographs of MF in patients with SoC can be seen in Figure 2.

Posttreatment (nonactive) photographs were available for 26 patients (6 non-SoC, 20 SoC). We found that across all FST groups, hyperpigmentation was more common than hypopigmentation in areas of previously active disease. Statistical analysis was not completed given that few non-SoC photographs were available for comparison.

Comment

This qualitative review demonstrates the heterogeneity of MF/SS in SoC patients and that these conditions do not present in this population with the classic erythematous patches and plaques found in non-SoC patients. We found that hyperpigmentation, lichenification, and silver hue were present at higher rates in patients with FSTs IV to VI compared to those with FSTs I to III, which had higher rates of erythema and poikiloderma. Familiarity with these morphologic features along with increased exposure to clinical photographs of MF/SS in SoC patients will aid in the visual recognition required for this diagnosis, since erythema is harder to identify in darker skin types. Recognizing the unique findings of MF in patients with SoC as well as in patients with lighter skin types will enable earlier diagnosis and treatment of MF/SS across all skin types. If MF is diagnosed and treated early, life expectancy is similar to that of patients without MF.¹³ However, the 5-year survival rate for advanced-stage MF/SS is 52% across all skin types, and studies have found that Black patients with advanced-stage disease have worse outcomes despite accounting for demographic factors and tumor stage.^14,15 Given the worse outcomes in SoC patients with advanced-stage MF/SS, earlier diagnosis could help address this disparity.^8,13,14 Similar morphologic features could be used in diagnosing other inflammatory conditions; studies have shown that the lack of recognition of erythema in Black children has led to delayed diagnosis of atopic dermatitis and subsequent inadequate treatment.^16,17

The morphologic presentation of MF/SS in SoC patients also can influence an optimal treatment plan for this population. Hypopigmented MF responds better to phototherapy than hyperpigmented MF, as phototherapy has been shown to have decreased efficacy with increasing FST.¹⁸ Therefore, for patients with FSTs IV to VI, topical agents such as nitrogen mustard or bexarotene may be more suitable treatment options, as the efficacy of these treatments is independent of skin color.⁸ However, nitrogen mustard commonly leads to postinflammatory hyperpigmentation, and topical bexarotene may lead to erythema or irritation; therefore, providers must counsel patients on these possible side effects. For refractory disease, adjunct systemic treatments such as oral bexarotene, subcutaneous interferon, methotrexate, or radiation therapy may be considered.⁸

In addition to aiding in the prompt diagnosis and treatment of MF/SS in SoC patients, our findings may be used to better assess the extent of disease and distinguish between active MF/SS lesions vs xerosis cutis or residual dyschromia from previously treated lesions. It is important to note that these morphologic features must be taken into account with a complete history and work-up. The differential diagnosis of MF/SS includes conditions such as atopic dermatitis, psoriasis, tinea corporis, and drug reactions, which may have similar morphology in SoC.¹⁹

Limitations of our study include the single-center design and the use of photographs instead of in-person examination; however, our cutaneous lymphoma clinic serves a diverse patient population, and our 3 reviewers rated the photographs independently. Discussion amongst the reviewers to address discrepancies was only required for 5 photographs, indicating the high inter-reviewer reliability. Additionally, the original purpose of FST was to assess for the propensity of the skin to burn when undergoing phototherapy, not to serve as a marker for skin color. We recommend trainees and clinicians be mindful about the purpose of FST and to use inclusive language (eg, using the terms skin irritation, skin tenderness, or skin becoming darker from the sun instead of tanning) when determining FST in darker-skinned individuals.²⁰ Future directions include examining if certain treatments are associated with prolonged dyschromia.

Conclusion

In our single-institution retrospective study, we found differences in the morphologic presentation of MF/SS in SoC patients vs non-SoC patients. While erythema is a common feature in non-SoC patients, clinical features of hyperpigmentation, lichenification, and silver hue should be carefully evaluated in the diagnosis of MF/SS in SoC patients. Knowledge of the heterogenous presentation of MF/SS in patients with SoC allows for expedited diagnosis and treatment, leading to better clinical outcomes. Valuable resources, including Taylor and Kelly’s Dermatology for Skin of Color, the Skin of Color Society, and VisualDx educate providers on how dermatologic conditions present in darker skin types. However, there is still work to be done to enhance diversity in educational resources in order to provide equitable care to patients of all skin types.

Mycosis fungoides (MF) and Sézary syndrome (SS) are non-Hodgkin T-cell lymphomas that make up the majority of cutaneous T-cell lymphomas. These conditions commonly affect Black patients, with an incidence rate of 12.6 cases of cutaneous T-cell lymphomas per million individuals vs 9.8 per million individuals in non–skin of color (SoC) patients.¹ However, educational resources tend to focus on the clinical manifestations of MF/SS in lighter skin types, describing MF as erythematous patches, plaques, or tumors presenting in non–sun-exposed areas of the skin and SS as generalized erythroderma.² Skin of color, comprised of Fitzpatrick skin types (FSTs) IV to VI,³ is poorly represented across dermatology textbooks,^4,5 medical student resources,⁶ and peer-reviewed publications,⁷ raising awareness for the need to address this disparity.

Skin of color patients with MF/SS display variable morphologies, including features such as hyperpigmentation and hypopigmentation,⁸ the latter being exceedingly rare in non-SoC patients.⁹ Familiarity with these differences among providers is essential to allow for equitable diagnosis and treatment across all skin types, especially in light of data predicting that by 2044 more than 50% of the US population will be people of color.¹⁰ Patients with SoC are of many ethnic and racial backgrounds, including Black, Hispanic, American Indian, Pacific Islander, and Asian.¹¹

Along with morphologic differences, there also are several racial disparities in the prognosis and survival of patients with MF/SS. Black patients diagnosed with MF present with greater body surface area affected, and Black women with MF have reduced survival rates compared to their White counterparts.¹² Given these racial disparities in survival and representation in educational resources, we aimed to quantify the frequency of various morphologic characteristics of MF/SS in patients with SoC vs non-SoC patients to facilitate better recognition of early MF/SS in SoC patients by medical providers.

Methods

We performed a retrospective chart review following approval from the institutional review board at Northwestern University (Chicago, Illinois). We identified all patients with FSTs IV to VI and biopsy-proven MF/SS who had been clinically photographed in our clinic from January 1998 to December 2019. Only photographs that were high quality enough to review morphologic features were included in our review. Fitzpatrick skin type was determined based on electronic medical record documentation. If photographs were available from multiple visits for the same patient, only those showing posttreatment nonactive lesions were included. Additionally, 36 patients with FSTs I to III (non-SoC) and biopsy-proven MF/SS were included in our review as a comparison with the SoC cohort. The primary outcomes for this study included the presence of scale, erythema, hyperpigmentation, hypopigmentation, violaceous color, lichenification, silver hue, dyschromia, alopecia, poikiloderma, atrophy, and ulceration in active lesions. Dyschromia was defined by the presence of both hypopigmentation and hyperpigmentation. Poikiloderma was defined by hypopigmentation and hyperpigmentation, telangiectasia, and atrophy. Secondary outcomes included evaluation of those same characteristics in posttreatment nonactive lesions. All photographs were independently assessed by 3 authors (M.L.E., C.J.W., J.M.M.), and discrepancies were resolved by further review of the photograph in question and discussion.

Statistical Analysis—Summary statistics were applied to describe demographic and clinical characteristics. The χ² test was used for categorical variables. Results achieving P<.05 were considered statistically significant.

Results

We reviewed photographs of 111 patients across all skin types (8, FST I; 12, FST II; 16, FST III; 17, FST IV; 44, FST V; 14, FST VI). The cohort was 47% female, and the mean age was 49.7 years (range, 15–86 years). The majority of the cohort had early-stage MF (stage IA or IB). There were more cases of SS in the SoC cohort than the non-SoC cohort (Table). Only 5 photographs had discrepancies and required discussion among the reviewers to achieve consensus.

Regarding morphologic characteristics in active lesions (Figure 1), scale was present in almost all patients (99% in SoC, 94% in non-SoC). Erythema was present in nearly all non-SoC patients (94%) but only in 69% of SoC patients (P=.003). Poikiloderma also was found to be present at higher frequencies in non-SoC patients compared with SoC patients (19% and 4%, respectively [P=.008]). However, hyperpigmentation (80% vs 39%), lichenification (43% vs 17%), and silver hue (25% vs 3%) were more common in SoC patients than non-SoC patients (P<.05). There were no significant differences in the remaining features, including hypopigmentation (39% vs 25%), dyschromia (24% vs 19%), violaceous color (44% vs 25%), atrophy (11% vs 22%), alopecia (23% vs 31%), and ulceration (16% vs 8%) between SoC and non-SoC patients (P>.05). Photographs of MF in patients with SoC can be seen in Figure 2.

Posttreatment (nonactive) photographs were available for 26 patients (6 non-SoC, 20 SoC). We found that across all FST groups, hyperpigmentation was more common than hypopigmentation in areas of previously active disease. Statistical analysis was not completed given that few non-SoC photographs were available for comparison.

Comment

This qualitative review demonstrates the heterogeneity of MF/SS in SoC patients and that these conditions do not present in this population with the classic erythematous patches and plaques found in non-SoC patients. We found that hyperpigmentation, lichenification, and silver hue were present at higher rates in patients with FSTs IV to VI compared to those with FSTs I to III, which had higher rates of erythema and poikiloderma. Familiarity with these morphologic features along with increased exposure to clinical photographs of MF/SS in SoC patients will aid in the visual recognition required for this diagnosis, since erythema is harder to identify in darker skin types. Recognizing the unique findings of MF in patients with SoC as well as in patients with lighter skin types will enable earlier diagnosis and treatment of MF/SS across all skin types. If MF is diagnosed and treated early, life expectancy is similar to that of patients without MF.¹³ However, the 5-year survival rate for advanced-stage MF/SS is 52% across all skin types, and studies have found that Black patients with advanced-stage disease have worse outcomes despite accounting for demographic factors and tumor stage.^14,15 Given the worse outcomes in SoC patients with advanced-stage MF/SS, earlier diagnosis could help address this disparity.^8,13,14 Similar morphologic features could be used in diagnosing other inflammatory conditions; studies have shown that the lack of recognition of erythema in Black children has led to delayed diagnosis of atopic dermatitis and subsequent inadequate treatment.^16,17

The morphologic presentation of MF/SS in SoC patients also can influence an optimal treatment plan for this population. Hypopigmented MF responds better to phototherapy than hyperpigmented MF, as phototherapy has been shown to have decreased efficacy with increasing FST.¹⁸ Therefore, for patients with FSTs IV to VI, topical agents such as nitrogen mustard or bexarotene may be more suitable treatment options, as the efficacy of these treatments is independent of skin color.⁸ However, nitrogen mustard commonly leads to postinflammatory hyperpigmentation, and topical bexarotene may lead to erythema or irritation; therefore, providers must counsel patients on these possible side effects. For refractory disease, adjunct systemic treatments such as oral bexarotene, subcutaneous interferon, methotrexate, or radiation therapy may be considered.⁸

In addition to aiding in the prompt diagnosis and treatment of MF/SS in SoC patients, our findings may be used to better assess the extent of disease and distinguish between active MF/SS lesions vs xerosis cutis or residual dyschromia from previously treated lesions. It is important to note that these morphologic features must be taken into account with a complete history and work-up. The differential diagnosis of MF/SS includes conditions such as atopic dermatitis, psoriasis, tinea corporis, and drug reactions, which may have similar morphology in SoC.¹⁹

Limitations of our study include the single-center design and the use of photographs instead of in-person examination; however, our cutaneous lymphoma clinic serves a diverse patient population, and our 3 reviewers rated the photographs independently. Discussion amongst the reviewers to address discrepancies was only required for 5 photographs, indicating the high inter-reviewer reliability. Additionally, the original purpose of FST was to assess for the propensity of the skin to burn when undergoing phototherapy, not to serve as a marker for skin color. We recommend trainees and clinicians be mindful about the purpose of FST and to use inclusive language (eg, using the terms skin irritation, skin tenderness, or skin becoming darker from the sun instead of tanning) when determining FST in darker-skinned individuals.²⁰ Future directions include examining if certain treatments are associated with prolonged dyschromia.

Conclusion

In our single-institution retrospective study, we found differences in the morphologic presentation of MF/SS in SoC patients vs non-SoC patients. While erythema is a common feature in non-SoC patients, clinical features of hyperpigmentation, lichenification, and silver hue should be carefully evaluated in the diagnosis of MF/SS in SoC patients. Knowledge of the heterogenous presentation of MF/SS in patients with SoC allows for expedited diagnosis and treatment, leading to better clinical outcomes. Valuable resources, including Taylor and Kelly’s Dermatology for Skin of Color, the Skin of Color Society, and VisualDx educate providers on how dermatologic conditions present in darker skin types. However, there is still work to be done to enhance diversity in educational resources in order to provide equitable care to patients of all skin types.

Mycosis fungoides (MF) and Sézary syndrome (SS) are non-Hodgkin T-cell lymphomas that make up the majority of cutaneous T-cell lymphomas. These conditions commonly affect Black patients, with an incidence rate of 12.6 cases of cutaneous T-cell lymphomas per million individuals vs 9.8 per million individuals in non–skin of color (SoC) patients.¹ However, educational resources tend to focus on the clinical manifestations of MF/SS in lighter skin types, describing MF as erythematous patches, plaques, or tumors presenting in non–sun-exposed areas of the skin and SS as generalized erythroderma.² Skin of color, comprised of Fitzpatrick skin types (FSTs) IV to VI,³ is poorly represented across dermatology textbooks,^4,5 medical student resources,⁶ and peer-reviewed publications,⁷ raising awareness for the need to address this disparity.

Skin of color patients with MF/SS display variable morphologies, including features such as hyperpigmentation and hypopigmentation,⁸ the latter being exceedingly rare in non-SoC patients.⁹ Familiarity with these differences among providers is essential to allow for equitable diagnosis and treatment across all skin types, especially in light of data predicting that by 2044 more than 50% of the US population will be people of color.¹⁰ Patients with SoC are of many ethnic and racial backgrounds, including Black, Hispanic, American Indian, Pacific Islander, and Asian.¹¹

Along with morphologic differences, there also are several racial disparities in the prognosis and survival of patients with MF/SS. Black patients diagnosed with MF present with greater body surface area affected, and Black women with MF have reduced survival rates compared to their White counterparts.¹² Given these racial disparities in survival and representation in educational resources, we aimed to quantify the frequency of various morphologic characteristics of MF/SS in patients with SoC vs non-SoC patients to facilitate better recognition of early MF/SS in SoC patients by medical providers.

Methods

We performed a retrospective chart review following approval from the institutional review board at Northwestern University (Chicago, Illinois). We identified all patients with FSTs IV to VI and biopsy-proven MF/SS who had been clinically photographed in our clinic from January 1998 to December 2019. Only photographs that were high quality enough to review morphologic features were included in our review. Fitzpatrick skin type was determined based on electronic medical record documentation. If photographs were available from multiple visits for the same patient, only those showing posttreatment nonactive lesions were included. Additionally, 36 patients with FSTs I to III (non-SoC) and biopsy-proven MF/SS were included in our review as a comparison with the SoC cohort. The primary outcomes for this study included the presence of scale, erythema, hyperpigmentation, hypopigmentation, violaceous color, lichenification, silver hue, dyschromia, alopecia, poikiloderma, atrophy, and ulceration in active lesions. Dyschromia was defined by the presence of both hypopigmentation and hyperpigmentation. Poikiloderma was defined by hypopigmentation and hyperpigmentation, telangiectasia, and atrophy. Secondary outcomes included evaluation of those same characteristics in posttreatment nonactive lesions. All photographs were independently assessed by 3 authors (M.L.E., C.J.W., J.M.M.), and discrepancies were resolved by further review of the photograph in question and discussion.

Statistical Analysis—Summary statistics were applied to describe demographic and clinical characteristics. The χ² test was used for categorical variables. Results achieving P<.05 were considered statistically significant.

Results

We reviewed photographs of 111 patients across all skin types (8, FST I; 12, FST II; 16, FST III; 17, FST IV; 44, FST V; 14, FST VI). The cohort was 47% female, and the mean age was 49.7 years (range, 15–86 years). The majority of the cohort had early-stage MF (stage IA or IB). There were more cases of SS in the SoC cohort than the non-SoC cohort (Table). Only 5 photographs had discrepancies and required discussion among the reviewers to achieve consensus.

Regarding morphologic characteristics in active lesions (Figure 1), scale was present in almost all patients (99% in SoC, 94% in non-SoC). Erythema was present in nearly all non-SoC patients (94%) but only in 69% of SoC patients (P=.003). Poikiloderma also was found to be present at higher frequencies in non-SoC patients compared with SoC patients (19% and 4%, respectively [P=.008]). However, hyperpigmentation (80% vs 39%), lichenification (43% vs 17%), and silver hue (25% vs 3%) were more common in SoC patients than non-SoC patients (P<.05). There were no significant differences in the remaining features, including hypopigmentation (39% vs 25%), dyschromia (24% vs 19%), violaceous color (44% vs 25%), atrophy (11% vs 22%), alopecia (23% vs 31%), and ulceration (16% vs 8%) between SoC and non-SoC patients (P>.05). Photographs of MF in patients with SoC can be seen in Figure 2.

Posttreatment (nonactive) photographs were available for 26 patients (6 non-SoC, 20 SoC). We found that across all FST groups, hyperpigmentation was more common than hypopigmentation in areas of previously active disease. Statistical analysis was not completed given that few non-SoC photographs were available for comparison.

Comment

This qualitative review demonstrates the heterogeneity of MF/SS in SoC patients and that these conditions do not present in this population with the classic erythematous patches and plaques found in non-SoC patients. We found that hyperpigmentation, lichenification, and silver hue were present at higher rates in patients with FSTs IV to VI compared to those with FSTs I to III, which had higher rates of erythema and poikiloderma. Familiarity with these morphologic features along with increased exposure to clinical photographs of MF/SS in SoC patients will aid in the visual recognition required for this diagnosis, since erythema is harder to identify in darker skin types. Recognizing the unique findings of MF in patients with SoC as well as in patients with lighter skin types will enable earlier diagnosis and treatment of MF/SS across all skin types. If MF is diagnosed and treated early, life expectancy is similar to that of patients without MF.¹³ However, the 5-year survival rate for advanced-stage MF/SS is 52% across all skin types, and studies have found that Black patients with advanced-stage disease have worse outcomes despite accounting for demographic factors and tumor stage.^14,15 Given the worse outcomes in SoC patients with advanced-stage MF/SS, earlier diagnosis could help address this disparity.^8,13,14 Similar morphologic features could be used in diagnosing other inflammatory conditions; studies have shown that the lack of recognition of erythema in Black children has led to delayed diagnosis of atopic dermatitis and subsequent inadequate treatment.^16,17

The morphologic presentation of MF/SS in SoC patients also can influence an optimal treatment plan for this population. Hypopigmented MF responds better to phototherapy than hyperpigmented MF, as phototherapy has been shown to have decreased efficacy with increasing FST.¹⁸ Therefore, for patients with FSTs IV to VI, topical agents such as nitrogen mustard or bexarotene may be more suitable treatment options, as the efficacy of these treatments is independent of skin color.⁸ However, nitrogen mustard commonly leads to postinflammatory hyperpigmentation, and topical bexarotene may lead to erythema or irritation; therefore, providers must counsel patients on these possible side effects. For refractory disease, adjunct systemic treatments such as oral bexarotene, subcutaneous interferon, methotrexate, or radiation therapy may be considered.⁸

In addition to aiding in the prompt diagnosis and treatment of MF/SS in SoC patients, our findings may be used to better assess the extent of disease and distinguish between active MF/SS lesions vs xerosis cutis or residual dyschromia from previously treated lesions. It is important to note that these morphologic features must be taken into account with a complete history and work-up. The differential diagnosis of MF/SS includes conditions such as atopic dermatitis, psoriasis, tinea corporis, and drug reactions, which may have similar morphology in SoC.¹⁹

Limitations of our study include the single-center design and the use of photographs instead of in-person examination; however, our cutaneous lymphoma clinic serves a diverse patient population, and our 3 reviewers rated the photographs independently. Discussion amongst the reviewers to address discrepancies was only required for 5 photographs, indicating the high inter-reviewer reliability. Additionally, the original purpose of FST was to assess for the propensity of the skin to burn when undergoing phototherapy, not to serve as a marker for skin color. We recommend trainees and clinicians be mindful about the purpose of FST and to use inclusive language (eg, using the terms skin irritation, skin tenderness, or skin becoming darker from the sun instead of tanning) when determining FST in darker-skinned individuals.²⁰ Future directions include examining if certain treatments are associated with prolonged dyschromia.

Conclusion

In our single-institution retrospective study, we found differences in the morphologic presentation of MF/SS in SoC patients vs non-SoC patients. While erythema is a common feature in non-SoC patients, clinical features of hyperpigmentation, lichenification, and silver hue should be carefully evaluated in the diagnosis of MF/SS in SoC patients. Knowledge of the heterogenous presentation of MF/SS in patients with SoC allows for expedited diagnosis and treatment, leading to better clinical outcomes. Valuable resources, including Taylor and Kelly’s Dermatology for Skin of Color, the Skin of Color Society, and VisualDx educate providers on how dermatologic conditions present in darker skin types. However, there is still work to be done to enhance diversity in educational resources in order to provide equitable care to patients of all skin types.

Despite the challenges of an ongoing COVID-19 pandemic, researchers in 2021 delivered practice-changing studies in gynecologic oncology. In this cancer Update, we highlight 4 studies that shed light on the surgical and systemic therapies that may improve outcomes for patients with cancers of the ovary, endometrium, and cervix. We review DESKTOP III, a trial that investigated the role of cytoreductive surgery in patients with recurrent ovarian cancer, and SENTOR, a study that evaluated the performance of sentinel lymph node biopsy in patients with high-grade endometrial cancers. Additionally, we examine 2 studies of systemic therapy that reveal the growing role of targeted therapies and immuno-oncology in the treatment of gynecologic malignancies.

A new era for patients with BRCA mutation–associated ovarian cancer

Banerjee S, Moore KN, Colombo N, et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22:1721-1731.

Ovarian cancer remains the most lethal gynecologic malignancy due to the frequency of advanced-stage diagnosis and frequent relapse after primary therapy. But for ovarian cancer patients with inherited mutations of the BRCA1 or BRCA2 genes, poly(ADP-ribose) polymerase (PARP) inhibitors, a class of oral anticancer medicines that target DNA repair, have ushered in a new era in which the possibility of long-term remission, and even cure, is more likely than at any other time.

Olaparib trial details

The SOLO1 study was a double-blind, placebo-controlled, phase 3 trial that investigated the role of PARP inhibitor maintenance therapy with olaparib in patients with pathologic BRCA1 or BRCA2 mutations who responded to platinum-based chemotherapy administered for a newly diagnosed, advanced-stage ovarian cancer.¹ The study enrolled 391 patients, with 260 randomly assigned to receive olaparib for 24 months and 131 patients randomly assigned to receive placebo tablets. Most patients in the study had a mutation in the BRCA1 gene (72%), 27% had a BRCA2 mutation, and 1% had mutations in both genes.

The primary analysis of SOLO1 was published in 2018 and was based on a median follow-up of 3.4 years.¹ That study showed that olaparib maintenance therapy resulted in a large progression-free survival benefit and led to its approval by the US Food and Drug Administration (FDA) as a maintenance therapy for patients with BRCA-mutated advanced ovarian cancer who responded to first-line platinum-based chemotherapy.

In 2021, Banerjee and colleagues updated the progression-free survival results for the SOLO1 trial after 5 years of follow-up.² In this study, the patients randomly assigned to olaparib maintenance therapy had a persistent and statistically significant progression-free survival benefit, with the median progression-free survival reaching 56 months among the olaparib group compared with 13.8 months in the placebo group (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.25–0.43).² Olaparib maintenance therapy resulted in more clinically significant adverse events, including anemia and neutropenia. Serious adverse events occurred in 55 (21%) of the olaparib-treated patients and 17 (13%) of the placebo-treated patients, but no treatment-related adverse events were fatal.

Continue to: Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients...

Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients

Harter P, Sehouli J, Vergote I, et al; DESKTOP III Investigators. Randomized trial of cytoreductive surgery for relapsed ovarian cancer. N Engl J Med. 2021;385:2123- 2131.

In the DESKTOP III trial, Harter and colleagues contribute results to the ongoing discourse surrounding treatment options for patients with recurrent, platinum-sensitive ovarian cancer.³ Systemic therapies continue to be the mainstay of treatment in this setting; however, several groups have attempted to evaluate the role of secondary cytoreductive surgery in this setting.^4,5

Specific inclusion criteria employed

The DESKTOP III investigators randomly assigned 407 patients with platinum-sensitive recurrent ovarian cancer to secondary cytoreductive surgery followed by platinum-based chemotherapy (n = 206) or platinum-based chemotherapy alone (n = 201).³ An essential aspect of the study’s design was the use of specific inclusion criteria known to identify patients with a high likelihood of complete resection at the time of secondary cytoreduction.^6,7 Patients were eligible only if they had at least a 6-month remission following platinum-based chemotherapy, had a complete resection at their previous surgery, had no restriction on physical activity, and had ascites of no more than 500 mL.

Surgery group had superior overall and progression-free survival

After a median follow-up of approximately 70 months, patients randomly assigned to surgery had superior overall survival (53.7 months) compared with those assigned to chemotherapy alone (46.0 months; HR, 0.75; 95% CI, 0.59–0.96).³ Progression-free survival also was improved among patients who underwent surgery (median 18.4 vs 12.7 months; HR, 0.66; 95% CI, 0.54–0.82). Subgroup analyses did not identify any subset of patients who did not benefit from surgery. Whether a complete resection was achieved at secondary cytoreduction was highly prognostic: Patients who had a complete resection had a median overall survival of 61.9 months compared with 27.7 months in patients with residual disease. There were no deaths within 90 days of surgery.

Continue to: Immunotherapy enters first-line treatment regimen for advanced cervical cancer...

Immunotherapy enters first-line treatment regimen for advanced cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Persistent, recurrent, and metastatic cervical cancer carries a very poor prognosis: Most patients progress less than a year after starting treatment, and fewer than half survive for 2 years. First-line treatment in this setting has been platinum-based chemotherapy, often given with bevacizumab, a humanized monoclonal antibody that inhibits tumor growth by blocking angiogenesis.⁸ Pembrolizumab, an immune checkpoint inhibitor, targets cancer cells by blocking their ability to evade the immune system, and it is FDA approved and widely administered to patients with advanced cervical cancer who progress after first-line treatment.⁹

Addition of pembrolizumab extended survival

In the KEYNOTE-826 trial, Colombo and colleagues investigated the efficacy of incorporating an immune checkpoint inhibitor into the first-line treatment regimen for patients with persistent, recurrent, and metastatic cervical cancer.¹⁰ Researchers in this double-blinded, phase 3, randomized controlled trial assigned 617 patients to receive pembrolizumab or placebo concurrently with the investigator’s choice platinum-based chemotherapy. Bevacizumab was administered at the discretion of the treating oncologist.

The proportion of patients who survived at least 2 years following randomization was significantly higher among those assigned to pembrolizumab compared with placebo (53% vs 42%; HR, 0.67, 95% CI, 0.54–0.84).¹⁰ Similarly, median progression-free survival was superior among patients who received pembrolizumab compared with those who received placebo (10.4 months vs 8.2 months; HR, 0.65; 95% CI, 0.53–0.79). The role of bevacizumab in conjunction with pembrolizumab and platinum-based chemotherapy was not elucidated in this study because bevacizumab administration was not randomly assigned.

Anemia and neutropenia were the most common adverse events and were more frequent in the pembrolizumab group, but there were no new safety concerns related to concurrent use of pembrolizumab with cytotoxic chemotherapy and bevacizumab. Importantly, subgroup analysis results suggested that pembrolizumab was effective only in patients whose tumors expressed PD-L1 (programmed death ligand 1), a biomarker of pembrolizumab sensitivity in cervical cancer.

Continue to: Endometrial cancer surgical staging...

Endometrial cancer surgical staging: Is sentinel lymph node biopsy a viable option for high-risk histologies?

Cusimano MC, Vicus D, Pulman K, et al. Assessment of sentinel lymph node biopsy vs lymphadenectomy for intermediate- and high-grade endometrial cancer staging. JAMA Surg. 2021;156:157-164.

The use of intraoperative sentinel lymph node mapping and biopsy to identify lymph node metastases among patients undergoing surgical staging for endometrial cancer has become increasingly common. Lymph node status is an important prognostic factor, and it guides adjuvant treatment decisions in endometrial cancer. However, traditional pelvic and para-aortic lymphadenectomy is associated with increased risk of lower-extremity lymphedema, postoperative complications, and intraoperative injury.

Sentinel lymph node biopsy seeks to identify lymph node metastases while minimizing surgical morbidity by identifying and excising only lymph nodes that directly receive lymphatic drainage from the uterus. The combination of a fluorescent dye (indocyanine green) and near infrared cameras have led to the broad adoption of sentinel lymph node biopsy in endometrial cancer staging surgery. This practice is supported by prospective studies that demonstrate the high diagnostic accuracy of this approach.^11,12 However, because most patients included in prior studies had low-grade endometrial cancer, the utility of sentinel lymph node biopsy in cases of high-grade histology has been less clear.

Sentinel lymph node biopsy vs lymphadenectomy for staging

In the SENTOR trial, Cusimano and colleagues examined the diagnostic accuracy of sentinel lymph node mapping and biopsy, using indocyanine green, in patients with intermediate- or high-grade early-stage endometrial cancer.¹³

All eligible patients (N = 156) underwent traditional or robot-assisted laparoscopic hysterectomy with sentinel lymph node biopsy. Subsequently, patients with grade 2 endometrioid carcinoma underwent bilateral pelvic lymphadenectomy, and those with high-grade histology (grade 3 endometrioid, serous, carcinosarcoma, clear cell, undifferentiated or dedifferentiated, and mixed high grade) underwent bilateral pelvic and para-aortic lymphadenectomy. The investigators evaluated the diagnostic characteristics of sentinel lymph node biopsy, treating complete lymphadenectomy as the gold standard.

Of the 156 patients enrolled, the median age was 65.5 and median body mass index was 27.5; 126 patients (81%) had high-grade histology. The sentinel lymph node biopsy had a sensitivity of 96% (95% CI, 81%–100%), identifying 26 of the 27 patients with nodal metastases. The false-negative rate was 4% (95% CI, 0%–9%) and the negative predictive value was 99% (95% CI, 96%–100%). Intraoperative adverse events occurred in 5 patients (3%), but none occurred during the sentinel lymph node biopsy. ●

Despite the challenges of an ongoing COVID-19 pandemic, researchers in 2021 delivered practice-changing studies in gynecologic oncology. In this cancer Update, we highlight 4 studies that shed light on the surgical and systemic therapies that may improve outcomes for patients with cancers of the ovary, endometrium, and cervix. We review DESKTOP III, a trial that investigated the role of cytoreductive surgery in patients with recurrent ovarian cancer, and SENTOR, a study that evaluated the performance of sentinel lymph node biopsy in patients with high-grade endometrial cancers. Additionally, we examine 2 studies of systemic therapy that reveal the growing role of targeted therapies and immuno-oncology in the treatment of gynecologic malignancies.

A new era for patients with BRCA mutation–associated ovarian cancer

Banerjee S, Moore KN, Colombo N, et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22:1721-1731.

Ovarian cancer remains the most lethal gynecologic malignancy due to the frequency of advanced-stage diagnosis and frequent relapse after primary therapy. But for ovarian cancer patients with inherited mutations of the BRCA1 or BRCA2 genes, poly(ADP-ribose) polymerase (PARP) inhibitors, a class of oral anticancer medicines that target DNA repair, have ushered in a new era in which the possibility of long-term remission, and even cure, is more likely than at any other time.

Olaparib trial details

The SOLO1 study was a double-blind, placebo-controlled, phase 3 trial that investigated the role of PARP inhibitor maintenance therapy with olaparib in patients with pathologic BRCA1 or BRCA2 mutations who responded to platinum-based chemotherapy administered for a newly diagnosed, advanced-stage ovarian cancer.¹ The study enrolled 391 patients, with 260 randomly assigned to receive olaparib for 24 months and 131 patients randomly assigned to receive placebo tablets. Most patients in the study had a mutation in the BRCA1 gene (72%), 27% had a BRCA2 mutation, and 1% had mutations in both genes.

The primary analysis of SOLO1 was published in 2018 and was based on a median follow-up of 3.4 years.¹ That study showed that olaparib maintenance therapy resulted in a large progression-free survival benefit and led to its approval by the US Food and Drug Administration (FDA) as a maintenance therapy for patients with BRCA-mutated advanced ovarian cancer who responded to first-line platinum-based chemotherapy.

In 2021, Banerjee and colleagues updated the progression-free survival results for the SOLO1 trial after 5 years of follow-up.² In this study, the patients randomly assigned to olaparib maintenance therapy had a persistent and statistically significant progression-free survival benefit, with the median progression-free survival reaching 56 months among the olaparib group compared with 13.8 months in the placebo group (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.25–0.43).² Olaparib maintenance therapy resulted in more clinically significant adverse events, including anemia and neutropenia. Serious adverse events occurred in 55 (21%) of the olaparib-treated patients and 17 (13%) of the placebo-treated patients, but no treatment-related adverse events were fatal.

Continue to: Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients...

Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients

Harter P, Sehouli J, Vergote I, et al; DESKTOP III Investigators. Randomized trial of cytoreductive surgery for relapsed ovarian cancer. N Engl J Med. 2021;385:2123- 2131.

In the DESKTOP III trial, Harter and colleagues contribute results to the ongoing discourse surrounding treatment options for patients with recurrent, platinum-sensitive ovarian cancer.³ Systemic therapies continue to be the mainstay of treatment in this setting; however, several groups have attempted to evaluate the role of secondary cytoreductive surgery in this setting.^4,5

Specific inclusion criteria employed

The DESKTOP III investigators randomly assigned 407 patients with platinum-sensitive recurrent ovarian cancer to secondary cytoreductive surgery followed by platinum-based chemotherapy (n = 206) or platinum-based chemotherapy alone (n = 201).³ An essential aspect of the study’s design was the use of specific inclusion criteria known to identify patients with a high likelihood of complete resection at the time of secondary cytoreduction.^6,7 Patients were eligible only if they had at least a 6-month remission following platinum-based chemotherapy, had a complete resection at their previous surgery, had no restriction on physical activity, and had ascites of no more than 500 mL.

Surgery group had superior overall and progression-free survival

After a median follow-up of approximately 70 months, patients randomly assigned to surgery had superior overall survival (53.7 months) compared with those assigned to chemotherapy alone (46.0 months; HR, 0.75; 95% CI, 0.59–0.96).³ Progression-free survival also was improved among patients who underwent surgery (median 18.4 vs 12.7 months; HR, 0.66; 95% CI, 0.54–0.82). Subgroup analyses did not identify any subset of patients who did not benefit from surgery. Whether a complete resection was achieved at secondary cytoreduction was highly prognostic: Patients who had a complete resection had a median overall survival of 61.9 months compared with 27.7 months in patients with residual disease. There were no deaths within 90 days of surgery.

Continue to: Immunotherapy enters first-line treatment regimen for advanced cervical cancer...

Immunotherapy enters first-line treatment regimen for advanced cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Persistent, recurrent, and metastatic cervical cancer carries a very poor prognosis: Most patients progress less than a year after starting treatment, and fewer than half survive for 2 years. First-line treatment in this setting has been platinum-based chemotherapy, often given with bevacizumab, a humanized monoclonal antibody that inhibits tumor growth by blocking angiogenesis.⁸ Pembrolizumab, an immune checkpoint inhibitor, targets cancer cells by blocking their ability to evade the immune system, and it is FDA approved and widely administered to patients with advanced cervical cancer who progress after first-line treatment.⁹

Addition of pembrolizumab extended survival

In the KEYNOTE-826 trial, Colombo and colleagues investigated the efficacy of incorporating an immune checkpoint inhibitor into the first-line treatment regimen for patients with persistent, recurrent, and metastatic cervical cancer.¹⁰ Researchers in this double-blinded, phase 3, randomized controlled trial assigned 617 patients to receive pembrolizumab or placebo concurrently with the investigator’s choice platinum-based chemotherapy. Bevacizumab was administered at the discretion of the treating oncologist.

The proportion of patients who survived at least 2 years following randomization was significantly higher among those assigned to pembrolizumab compared with placebo (53% vs 42%; HR, 0.67, 95% CI, 0.54–0.84).¹⁰ Similarly, median progression-free survival was superior among patients who received pembrolizumab compared with those who received placebo (10.4 months vs 8.2 months; HR, 0.65; 95% CI, 0.53–0.79). The role of bevacizumab in conjunction with pembrolizumab and platinum-based chemotherapy was not elucidated in this study because bevacizumab administration was not randomly assigned.

Anemia and neutropenia were the most common adverse events and were more frequent in the pembrolizumab group, but there were no new safety concerns related to concurrent use of pembrolizumab with cytotoxic chemotherapy and bevacizumab. Importantly, subgroup analysis results suggested that pembrolizumab was effective only in patients whose tumors expressed PD-L1 (programmed death ligand 1), a biomarker of pembrolizumab sensitivity in cervical cancer.

Continue to: Endometrial cancer surgical staging...

Endometrial cancer surgical staging: Is sentinel lymph node biopsy a viable option for high-risk histologies?

Cusimano MC, Vicus D, Pulman K, et al. Assessment of sentinel lymph node biopsy vs lymphadenectomy for intermediate- and high-grade endometrial cancer staging. JAMA Surg. 2021;156:157-164.

The use of intraoperative sentinel lymph node mapping and biopsy to identify lymph node metastases among patients undergoing surgical staging for endometrial cancer has become increasingly common. Lymph node status is an important prognostic factor, and it guides adjuvant treatment decisions in endometrial cancer. However, traditional pelvic and para-aortic lymphadenectomy is associated with increased risk of lower-extremity lymphedema, postoperative complications, and intraoperative injury.

Sentinel lymph node biopsy seeks to identify lymph node metastases while minimizing surgical morbidity by identifying and excising only lymph nodes that directly receive lymphatic drainage from the uterus. The combination of a fluorescent dye (indocyanine green) and near infrared cameras have led to the broad adoption of sentinel lymph node biopsy in endometrial cancer staging surgery. This practice is supported by prospective studies that demonstrate the high diagnostic accuracy of this approach.^11,12 However, because most patients included in prior studies had low-grade endometrial cancer, the utility of sentinel lymph node biopsy in cases of high-grade histology has been less clear.

Sentinel lymph node biopsy vs lymphadenectomy for staging

In the SENTOR trial, Cusimano and colleagues examined the diagnostic accuracy of sentinel lymph node mapping and biopsy, using indocyanine green, in patients with intermediate- or high-grade early-stage endometrial cancer.¹³

All eligible patients (N = 156) underwent traditional or robot-assisted laparoscopic hysterectomy with sentinel lymph node biopsy. Subsequently, patients with grade 2 endometrioid carcinoma underwent bilateral pelvic lymphadenectomy, and those with high-grade histology (grade 3 endometrioid, serous, carcinosarcoma, clear cell, undifferentiated or dedifferentiated, and mixed high grade) underwent bilateral pelvic and para-aortic lymphadenectomy. The investigators evaluated the diagnostic characteristics of sentinel lymph node biopsy, treating complete lymphadenectomy as the gold standard.

Of the 156 patients enrolled, the median age was 65.5 and median body mass index was 27.5; 126 patients (81%) had high-grade histology. The sentinel lymph node biopsy had a sensitivity of 96% (95% CI, 81%–100%), identifying 26 of the 27 patients with nodal metastases. The false-negative rate was 4% (95% CI, 0%–9%) and the negative predictive value was 99% (95% CI, 96%–100%). Intraoperative adverse events occurred in 5 patients (3%), but none occurred during the sentinel lymph node biopsy. ●

Despite the challenges of an ongoing COVID-19 pandemic, researchers in 2021 delivered practice-changing studies in gynecologic oncology. In this cancer Update, we highlight 4 studies that shed light on the surgical and systemic therapies that may improve outcomes for patients with cancers of the ovary, endometrium, and cervix. We review DESKTOP III, a trial that investigated the role of cytoreductive surgery in patients with recurrent ovarian cancer, and SENTOR, a study that evaluated the performance of sentinel lymph node biopsy in patients with high-grade endometrial cancers. Additionally, we examine 2 studies of systemic therapy that reveal the growing role of targeted therapies and immuno-oncology in the treatment of gynecologic malignancies.

A new era for patients with BRCA mutation–associated ovarian cancer

Banerjee S, Moore KN, Colombo N, et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22:1721-1731.

Ovarian cancer remains the most lethal gynecologic malignancy due to the frequency of advanced-stage diagnosis and frequent relapse after primary therapy. But for ovarian cancer patients with inherited mutations of the BRCA1 or BRCA2 genes, poly(ADP-ribose) polymerase (PARP) inhibitors, a class of oral anticancer medicines that target DNA repair, have ushered in a new era in which the possibility of long-term remission, and even cure, is more likely than at any other time.

Olaparib trial details

The SOLO1 study was a double-blind, placebo-controlled, phase 3 trial that investigated the role of PARP inhibitor maintenance therapy with olaparib in patients with pathologic BRCA1 or BRCA2 mutations who responded to platinum-based chemotherapy administered for a newly diagnosed, advanced-stage ovarian cancer.¹ The study enrolled 391 patients, with 260 randomly assigned to receive olaparib for 24 months and 131 patients randomly assigned to receive placebo tablets. Most patients in the study had a mutation in the BRCA1 gene (72%), 27% had a BRCA2 mutation, and 1% had mutations in both genes.

The primary analysis of SOLO1 was published in 2018 and was based on a median follow-up of 3.4 years.¹ That study showed that olaparib maintenance therapy resulted in a large progression-free survival benefit and led to its approval by the US Food and Drug Administration (FDA) as a maintenance therapy for patients with BRCA-mutated advanced ovarian cancer who responded to first-line platinum-based chemotherapy.

In 2021, Banerjee and colleagues updated the progression-free survival results for the SOLO1 trial after 5 years of follow-up.² In this study, the patients randomly assigned to olaparib maintenance therapy had a persistent and statistically significant progression-free survival benefit, with the median progression-free survival reaching 56 months among the olaparib group compared with 13.8 months in the placebo group (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.25–0.43).² Olaparib maintenance therapy resulted in more clinically significant adverse events, including anemia and neutropenia. Serious adverse events occurred in 55 (21%) of the olaparib-treated patients and 17 (13%) of the placebo-treated patients, but no treatment-related adverse events were fatal.

Continue to: Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients...

Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients

Harter P, Sehouli J, Vergote I, et al; DESKTOP III Investigators. Randomized trial of cytoreductive surgery for relapsed ovarian cancer. N Engl J Med. 2021;385:2123- 2131.

In the DESKTOP III trial, Harter and colleagues contribute results to the ongoing discourse surrounding treatment options for patients with recurrent, platinum-sensitive ovarian cancer.³ Systemic therapies continue to be the mainstay of treatment in this setting; however, several groups have attempted to evaluate the role of secondary cytoreductive surgery in this setting.^4,5

Specific inclusion criteria employed

The DESKTOP III investigators randomly assigned 407 patients with platinum-sensitive recurrent ovarian cancer to secondary cytoreductive surgery followed by platinum-based chemotherapy (n = 206) or platinum-based chemotherapy alone (n = 201).³ An essential aspect of the study’s design was the use of specific inclusion criteria known to identify patients with a high likelihood of complete resection at the time of secondary cytoreduction.^6,7 Patients were eligible only if they had at least a 6-month remission following platinum-based chemotherapy, had a complete resection at their previous surgery, had no restriction on physical activity, and had ascites of no more than 500 mL.

Surgery group had superior overall and progression-free survival

After a median follow-up of approximately 70 months, patients randomly assigned to surgery had superior overall survival (53.7 months) compared with those assigned to chemotherapy alone (46.0 months; HR, 0.75; 95% CI, 0.59–0.96).³ Progression-free survival also was improved among patients who underwent surgery (median 18.4 vs 12.7 months; HR, 0.66; 95% CI, 0.54–0.82). Subgroup analyses did not identify any subset of patients who did not benefit from surgery. Whether a complete resection was achieved at secondary cytoreduction was highly prognostic: Patients who had a complete resection had a median overall survival of 61.9 months compared with 27.7 months in patients with residual disease. There were no deaths within 90 days of surgery.

Continue to: Immunotherapy enters first-line treatment regimen for advanced cervical cancer...

Immunotherapy enters first-line treatment regimen for advanced cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Persistent, recurrent, and metastatic cervical cancer carries a very poor prognosis: Most patients progress less than a year after starting treatment, and fewer than half survive for 2 years. First-line treatment in this setting has been platinum-based chemotherapy, often given with bevacizumab, a humanized monoclonal antibody that inhibits tumor growth by blocking angiogenesis.⁸ Pembrolizumab, an immune checkpoint inhibitor, targets cancer cells by blocking their ability to evade the immune system, and it is FDA approved and widely administered to patients with advanced cervical cancer who progress after first-line treatment.⁹

Addition of pembrolizumab extended survival

In the KEYNOTE-826 trial, Colombo and colleagues investigated the efficacy of incorporating an immune checkpoint inhibitor into the first-line treatment regimen for patients with persistent, recurrent, and metastatic cervical cancer.¹⁰ Researchers in this double-blinded, phase 3, randomized controlled trial assigned 617 patients to receive pembrolizumab or placebo concurrently with the investigator’s choice platinum-based chemotherapy. Bevacizumab was administered at the discretion of the treating oncologist.

The proportion of patients who survived at least 2 years following randomization was significantly higher among those assigned to pembrolizumab compared with placebo (53% vs 42%; HR, 0.67, 95% CI, 0.54–0.84).¹⁰ Similarly, median progression-free survival was superior among patients who received pembrolizumab compared with those who received placebo (10.4 months vs 8.2 months; HR, 0.65; 95% CI, 0.53–0.79). The role of bevacizumab in conjunction with pembrolizumab and platinum-based chemotherapy was not elucidated in this study because bevacizumab administration was not randomly assigned.

Anemia and neutropenia were the most common adverse events and were more frequent in the pembrolizumab group, but there were no new safety concerns related to concurrent use of pembrolizumab with cytotoxic chemotherapy and bevacizumab. Importantly, subgroup analysis results suggested that pembrolizumab was effective only in patients whose tumors expressed PD-L1 (programmed death ligand 1), a biomarker of pembrolizumab sensitivity in cervical cancer.

Continue to: Endometrial cancer surgical staging...

Endometrial cancer surgical staging: Is sentinel lymph node biopsy a viable option for high-risk histologies?

Cusimano MC, Vicus D, Pulman K, et al. Assessment of sentinel lymph node biopsy vs lymphadenectomy for intermediate- and high-grade endometrial cancer staging. JAMA Surg. 2021;156:157-164.

The use of intraoperative sentinel lymph node mapping and biopsy to identify lymph node metastases among patients undergoing surgical staging for endometrial cancer has become increasingly common. Lymph node status is an important prognostic factor, and it guides adjuvant treatment decisions in endometrial cancer. However, traditional pelvic and para-aortic lymphadenectomy is associated with increased risk of lower-extremity lymphedema, postoperative complications, and intraoperative injury.

Sentinel lymph node biopsy seeks to identify lymph node metastases while minimizing surgical morbidity by identifying and excising only lymph nodes that directly receive lymphatic drainage from the uterus. The combination of a fluorescent dye (indocyanine green) and near infrared cameras have led to the broad adoption of sentinel lymph node biopsy in endometrial cancer staging surgery. This practice is supported by prospective studies that demonstrate the high diagnostic accuracy of this approach.^11,12 However, because most patients included in prior studies had low-grade endometrial cancer, the utility of sentinel lymph node biopsy in cases of high-grade histology has been less clear.

Sentinel lymph node biopsy vs lymphadenectomy for staging

In the SENTOR trial, Cusimano and colleagues examined the diagnostic accuracy of sentinel lymph node mapping and biopsy, using indocyanine green, in patients with intermediate- or high-grade early-stage endometrial cancer.¹³

All eligible patients (N = 156) underwent traditional or robot-assisted laparoscopic hysterectomy with sentinel lymph node biopsy. Subsequently, patients with grade 2 endometrioid carcinoma underwent bilateral pelvic lymphadenectomy, and those with high-grade histology (grade 3 endometrioid, serous, carcinosarcoma, clear cell, undifferentiated or dedifferentiated, and mixed high grade) underwent bilateral pelvic and para-aortic lymphadenectomy. The investigators evaluated the diagnostic characteristics of sentinel lymph node biopsy, treating complete lymphadenectomy as the gold standard.

Of the 156 patients enrolled, the median age was 65.5 and median body mass index was 27.5; 126 patients (81%) had high-grade histology. The sentinel lymph node biopsy had a sensitivity of 96% (95% CI, 81%–100%), identifying 26 of the 27 patients with nodal metastases. The false-negative rate was 4% (95% CI, 0%–9%) and the negative predictive value was 99% (95% CI, 96%–100%). Intraoperative adverse events occurred in 5 patients (3%), but none occurred during the sentinel lymph node biopsy. ●

CASE 1 Pregnant patient endures extensive wait and travel times to have antenatal testing

Pregnant at age 35 without comorbidities, Ms. H was instructed to schedule weekly biophysical profiles (BPP) after 36 weeks’ gestation for advanced maternal age. She receives care at a community office 25 miles from the hospital where she will deliver. Ms. H must complete her antenatal testing at the hospital where the sonographer performs BPPs. She sees her physician at the nearby clinic and then takes public transit to the hospital. She waits 2 hours to be seen then makes her way back home. Her prenatal care visit, which usually takes 30 minutes, turns into a 5-hour ordeal. Ms. H delivered a healthy baby at 39 weeks. Unfortunately, she was fired from her job for missing too many workdays.

Antenatal testing has become routine, and it is costly

For the prescriber, antenatal testing is simple: Order a weekly ultrasound exam to reduce the risk of stillbirth, decrease litigation, generate income, and maximize patient satisfaction (with the assumption that everyone likes to peek at their baby). Recommending antenatal testing has—with the best intentions—become a habit and therefore is difficult to break. However, the American College of Obstetricians and Gynecologists (ACOG) recognizes that “there is a paucity of evidenced-based recommendations on the timing and frequency of antenatal fetal surveillance because of the challenges of conducting prospective trials in pregnancies complicated by stillbirths and the varying conditions that place pregnancies at high risk for stillbirth. As a result, evidence for the efficacy of antenatal fetal surveillance, when available, is largely circumstantial.”¹

Antenatal testing without an evidence-based indication can be costly for the health care system, insurance companies, and patients. Many clinics, especially those in rural communities, do not have the equipment or personnel to complete antenatal testing on site. Asking a pregnant patient to travel repeatedly to another location for antenatal testing can increase her time off from work, complicate childcare, pose a financial burden, and lead to nonadherence. As clinicians, it is imperative that we work with our patients to create an individualized care plan to minimize these burdens and increase adherence.

Antenatal fetal surveillance can be considered for conditions in which stillbirth is reported more frequently than 0.8 per 1,000.

Advanced maternal age and stillbirth risk

One of the most common reasons for antenatal testing is advanced maternal age, that is, age older than 35. According to the Centers for Disease Control and Prevention and the National Vital Statistics System, from 2000 to 2012, 46 states and the District of Columbia (DC) reported an increase in first birth rates for women aged 35 to 39. Thirty-one states and DC saw a rise among women aged 40 to 44 in the same period (FIGURE).²

Advanced maternal age is an independent risk factor for stillbirth, with women aged 35 to 39 at 1.9-fold increased risk and women older than age 40 with a 2.4-fold higher risk compared with women younger than age 30.³ In a review of 44 studies including nearly 45,000,000 births, case-control studies, versus cohort studies, demonstrated a higher odds for stillbirth among women aged 35 and older (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.57-3.66 vs OR, 1.73; 95% CI, 1.6-1.87).⁴ Now, many women older than age 35 may have a concomitant risk factor, such as diabetes or hypertension, that requires antenatal testing. However, for those without other risk factors, nearly 863 antenatal tests and 71 inductions would need to be completed to reduce the number of stillbirths by 1. Antenatal testing for women older than age 35 without other risk factors should be individualized through shared decision making.⁵ See the ACOG committee opinion for a table that outlines factors associated with an increased risk of stillbirth and suggested strategies for antenatal surveillance after viability.¹

Continue to: CASE 2 Patient with high BPP score and altered...

CASE 2 Patient with high BPP score and altered fetal movements delivered for nonreassuring fetal heart rate

Ms. Q was undergoing weekly BPPs for diet-controlled gestational diabetes and a prepregnancy body mass index (BMI) of 52. At 37 weeks’ gestation, she had a BPP score of 8/8. However, it took almost 30 minutes to see 2 discrete body or limb movements. Ms. Q mentioned to the nurse taking her vitals after the BPP that the baby’s movements had changed over the previous few days, especially after contractions. Ms. Q then completed a nonstress test (NST); she had 2 contractions and 2 fetal heart rate decelerations, each lasting approximately 60 seconds. Ms. Q was sent to labor and delivery for prolonged monitoring, and she was delivered that day for a nonreassuring fetal heart rate tracing. Meconium-stained amniotic fluid and a tight triple nuchal cord were noted at delivery.

BPP considerations

While considered an in-depth look at the fetal status, BPPs may not predict overall fetal well-being during acute changes, such as umbilical cord compression or placental abruption. BPPs take longer to complete, require a trained sonographer, and include components like fetal breathing that may be influenced by such factors as nicotine,^6-8 labor,⁹ rupture of membranes,¹⁰ magnesium sulfate,¹¹ and infection.¹²

If medically indicated, which antenatal surveillance technique is right for your patient?

Frequently used antepartum fetal surveillance techniques include maternal perception of fetal movement or “kick counting,” NST, BPP, modified BPP, contraction stress test (CST), and umbilical artery Doppler velocimetry.

Worldwide, the most common form of antenatal surveillance is fetal kick counting. It is noninvasive, can be completed frequently, may decrease maternal anxiety, may improve maternal-fetal bonding, and is free.¹³ According to the results of a 2020 meta-analysis of 468,601 fetuses, however, there was no difference in perinatal death among patients who assessed fetal movements (0.54%) and those who did not (0.59%).¹⁴ There was a statistically significant increase in induction of labor, cesarean delivery, and preterm delivery among patients who counted fetal movements. Women who perceive a decrease in fetal movement should seek medical attention from a health care provider.

An evaluation for decreased fetal movement typically includes taking a history that focuses on risk factors that may increase stillbirth, including hypertension, growth restriction, fetal anomalies, diabetes, and substance use, and auscultation with a fetal Doppler. In the absence of risk factors and the presence of a normal fetal heartbeat, pregnant women should be reassured of fetal well-being. In a pregnancy at greater than 28 weeks, a 20-minute NST can be completed as well; this has become part of the standard workup of decreased fetal movement in developed countries. A reactive NST indicates normal fetal autonomic function in real time and a low incidence of stillbirth (1.9/1,000) within 1 week.¹⁵

Additionally, by measuring the amniotic fluid volume using the largest maximal vertical pocket (MVP), clinicians can gain insight into overall uteroplacental function. The combination of the NST and the MVP—otherwise known as a modified BPP—provides both short-term acid-base status and long-term uteroplacental function. The incidence of stillbirth in the 1 week after a modified BPP has been reported to be 0.8/1,000, which is equivalent to stillbirth incidence using a full BPP (0.8/1,000).¹⁶ The negative predictive value for both the modified BPP and the BPP is 99.9%—equivalent.

The case for modified BPP use

The modified BPP requires less time, is less costly (cost savings of approximately 50%), does not require a specialized sonographer, and can be performed in local community clinics.

Perhaps the initial antepartum surveillance test of choice should be the modified BPP, with the BPP used in cases in which the results of a modified BPP are abnormal. ●

CASE 1 Pregnant patient endures extensive wait and travel times to have antenatal testing

Pregnant at age 35 without comorbidities, Ms. H was instructed to schedule weekly biophysical profiles (BPP) after 36 weeks’ gestation for advanced maternal age. She receives care at a community office 25 miles from the hospital where she will deliver. Ms. H must complete her antenatal testing at the hospital where the sonographer performs BPPs. She sees her physician at the nearby clinic and then takes public transit to the hospital. She waits 2 hours to be seen then makes her way back home. Her prenatal care visit, which usually takes 30 minutes, turns into a 5-hour ordeal. Ms. H delivered a healthy baby at 39 weeks. Unfortunately, she was fired from her job for missing too many workdays.

Antenatal testing has become routine, and it is costly

For the prescriber, antenatal testing is simple: Order a weekly ultrasound exam to reduce the risk of stillbirth, decrease litigation, generate income, and maximize patient satisfaction (with the assumption that everyone likes to peek at their baby). Recommending antenatal testing has—with the best intentions—become a habit and therefore is difficult to break. However, the American College of Obstetricians and Gynecologists (ACOG) recognizes that “there is a paucity of evidenced-based recommendations on the timing and frequency of antenatal fetal surveillance because of the challenges of conducting prospective trials in pregnancies complicated by stillbirths and the varying conditions that place pregnancies at high risk for stillbirth. As a result, evidence for the efficacy of antenatal fetal surveillance, when available, is largely circumstantial.”¹

Antenatal testing without an evidence-based indication can be costly for the health care system, insurance companies, and patients. Many clinics, especially those in rural communities, do not have the equipment or personnel to complete antenatal testing on site. Asking a pregnant patient to travel repeatedly to another location for antenatal testing can increase her time off from work, complicate childcare, pose a financial burden, and lead to nonadherence. As clinicians, it is imperative that we work with our patients to create an individualized care plan to minimize these burdens and increase adherence.

Antenatal fetal surveillance can be considered for conditions in which stillbirth is reported more frequently than 0.8 per 1,000.

Advanced maternal age and stillbirth risk

One of the most common reasons for antenatal testing is advanced maternal age, that is, age older than 35. According to the Centers for Disease Control and Prevention and the National Vital Statistics System, from 2000 to 2012, 46 states and the District of Columbia (DC) reported an increase in first birth rates for women aged 35 to 39. Thirty-one states and DC saw a rise among women aged 40 to 44 in the same period (FIGURE).²

Advanced maternal age is an independent risk factor for stillbirth, with women aged 35 to 39 at 1.9-fold increased risk and women older than age 40 with a 2.4-fold higher risk compared with women younger than age 30.³ In a review of 44 studies including nearly 45,000,000 births, case-control studies, versus cohort studies, demonstrated a higher odds for stillbirth among women aged 35 and older (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.57-3.66 vs OR, 1.73; 95% CI, 1.6-1.87).⁴ Now, many women older than age 35 may have a concomitant risk factor, such as diabetes or hypertension, that requires antenatal testing. However, for those without other risk factors, nearly 863 antenatal tests and 71 inductions would need to be completed to reduce the number of stillbirths by 1. Antenatal testing for women older than age 35 without other risk factors should be individualized through shared decision making.⁵ See the ACOG committee opinion for a table that outlines factors associated with an increased risk of stillbirth and suggested strategies for antenatal surveillance after viability.¹

Continue to: CASE 2 Patient with high BPP score and altered...

CASE 2 Patient with high BPP score and altered fetal movements delivered for nonreassuring fetal heart rate

Ms. Q was undergoing weekly BPPs for diet-controlled gestational diabetes and a prepregnancy body mass index (BMI) of 52. At 37 weeks’ gestation, she had a BPP score of 8/8. However, it took almost 30 minutes to see 2 discrete body or limb movements. Ms. Q mentioned to the nurse taking her vitals after the BPP that the baby’s movements had changed over the previous few days, especially after contractions. Ms. Q then completed a nonstress test (NST); she had 2 contractions and 2 fetal heart rate decelerations, each lasting approximately 60 seconds. Ms. Q was sent to labor and delivery for prolonged monitoring, and she was delivered that day for a nonreassuring fetal heart rate tracing. Meconium-stained amniotic fluid and a tight triple nuchal cord were noted at delivery.

BPP considerations

While considered an in-depth look at the fetal status, BPPs may not predict overall fetal well-being during acute changes, such as umbilical cord compression or placental abruption. BPPs take longer to complete, require a trained sonographer, and include components like fetal breathing that may be influenced by such factors as nicotine,^6-8 labor,⁹ rupture of membranes,¹⁰ magnesium sulfate,¹¹ and infection.¹²

If medically indicated, which antenatal surveillance technique is right for your patient?

Frequently used antepartum fetal surveillance techniques include maternal perception of fetal movement or “kick counting,” NST, BPP, modified BPP, contraction stress test (CST), and umbilical artery Doppler velocimetry.

Worldwide, the most common form of antenatal surveillance is fetal kick counting. It is noninvasive, can be completed frequently, may decrease maternal anxiety, may improve maternal-fetal bonding, and is free.¹³ According to the results of a 2020 meta-analysis of 468,601 fetuses, however, there was no difference in perinatal death among patients who assessed fetal movements (0.54%) and those who did not (0.59%).¹⁴ There was a statistically significant increase in induction of labor, cesarean delivery, and preterm delivery among patients who counted fetal movements. Women who perceive a decrease in fetal movement should seek medical attention from a health care provider.

An evaluation for decreased fetal movement typically includes taking a history that focuses on risk factors that may increase stillbirth, including hypertension, growth restriction, fetal anomalies, diabetes, and substance use, and auscultation with a fetal Doppler. In the absence of risk factors and the presence of a normal fetal heartbeat, pregnant women should be reassured of fetal well-being. In a pregnancy at greater than 28 weeks, a 20-minute NST can be completed as well; this has become part of the standard workup of decreased fetal movement in developed countries. A reactive NST indicates normal fetal autonomic function in real time and a low incidence of stillbirth (1.9/1,000) within 1 week.¹⁵

Additionally, by measuring the amniotic fluid volume using the largest maximal vertical pocket (MVP), clinicians can gain insight into overall uteroplacental function. The combination of the NST and the MVP—otherwise known as a modified BPP—provides both short-term acid-base status and long-term uteroplacental function. The incidence of stillbirth in the 1 week after a modified BPP has been reported to be 0.8/1,000, which is equivalent to stillbirth incidence using a full BPP (0.8/1,000).¹⁶ The negative predictive value for both the modified BPP and the BPP is 99.9%—equivalent.

The case for modified BPP use

The modified BPP requires less time, is less costly (cost savings of approximately 50%), does not require a specialized sonographer, and can be performed in local community clinics.

Perhaps the initial antepartum surveillance test of choice should be the modified BPP, with the BPP used in cases in which the results of a modified BPP are abnormal. ●

CASE 1 Pregnant patient endures extensive wait and travel times to have antenatal testing

Pregnant at age 35 without comorbidities, Ms. H was instructed to schedule weekly biophysical profiles (BPP) after 36 weeks’ gestation for advanced maternal age. She receives care at a community office 25 miles from the hospital where she will deliver. Ms. H must complete her antenatal testing at the hospital where the sonographer performs BPPs. She sees her physician at the nearby clinic and then takes public transit to the hospital. She waits 2 hours to be seen then makes her way back home. Her prenatal care visit, which usually takes 30 minutes, turns into a 5-hour ordeal. Ms. H delivered a healthy baby at 39 weeks. Unfortunately, she was fired from her job for missing too many workdays.

Antenatal testing has become routine, and it is costly

For the prescriber, antenatal testing is simple: Order a weekly ultrasound exam to reduce the risk of stillbirth, decrease litigation, generate income, and maximize patient satisfaction (with the assumption that everyone likes to peek at their baby). Recommending antenatal testing has—with the best intentions—become a habit and therefore is difficult to break. However, the American College of Obstetricians and Gynecologists (ACOG) recognizes that “there is a paucity of evidenced-based recommendations on the timing and frequency of antenatal fetal surveillance because of the challenges of conducting prospective trials in pregnancies complicated by stillbirths and the varying conditions that place pregnancies at high risk for stillbirth. As a result, evidence for the efficacy of antenatal fetal surveillance, when available, is largely circumstantial.”¹

Antenatal testing without an evidence-based indication can be costly for the health care system, insurance companies, and patients. Many clinics, especially those in rural communities, do not have the equipment or personnel to complete antenatal testing on site. Asking a pregnant patient to travel repeatedly to another location for antenatal testing can increase her time off from work, complicate childcare, pose a financial burden, and lead to nonadherence. As clinicians, it is imperative that we work with our patients to create an individualized care plan to minimize these burdens and increase adherence.

Antenatal fetal surveillance can be considered for conditions in which stillbirth is reported more frequently than 0.8 per 1,000.

Advanced maternal age and stillbirth risk

One of the most common reasons for antenatal testing is advanced maternal age, that is, age older than 35. According to the Centers for Disease Control and Prevention and the National Vital Statistics System, from 2000 to 2012, 46 states and the District of Columbia (DC) reported an increase in first birth rates for women aged 35 to 39. Thirty-one states and DC saw a rise among women aged 40 to 44 in the same period (FIGURE).²

Advanced maternal age is an independent risk factor for stillbirth, with women aged 35 to 39 at 1.9-fold increased risk and women older than age 40 with a 2.4-fold higher risk compared with women younger than age 30.³ In a review of 44 studies including nearly 45,000,000 births, case-control studies, versus cohort studies, demonstrated a higher odds for stillbirth among women aged 35 and older (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.57-3.66 vs OR, 1.73; 95% CI, 1.6-1.87).⁴ Now, many women older than age 35 may have a concomitant risk factor, such as diabetes or hypertension, that requires antenatal testing. However, for those without other risk factors, nearly 863 antenatal tests and 71 inductions would need to be completed to reduce the number of stillbirths by 1. Antenatal testing for women older than age 35 without other risk factors should be individualized through shared decision making.⁵ See the ACOG committee opinion for a table that outlines factors associated with an increased risk of stillbirth and suggested strategies for antenatal surveillance after viability.¹

Continue to: CASE 2 Patient with high BPP score and altered...

CASE 2 Patient with high BPP score and altered fetal movements delivered for nonreassuring fetal heart rate

Ms. Q was undergoing weekly BPPs for diet-controlled gestational diabetes and a prepregnancy body mass index (BMI) of 52. At 37 weeks’ gestation, she had a BPP score of 8/8. However, it took almost 30 minutes to see 2 discrete body or limb movements. Ms. Q mentioned to the nurse taking her vitals after the BPP that the baby’s movements had changed over the previous few days, especially after contractions. Ms. Q then completed a nonstress test (NST); she had 2 contractions and 2 fetal heart rate decelerations, each lasting approximately 60 seconds. Ms. Q was sent to labor and delivery for prolonged monitoring, and she was delivered that day for a nonreassuring fetal heart rate tracing. Meconium-stained amniotic fluid and a tight triple nuchal cord were noted at delivery.

BPP considerations

While considered an in-depth look at the fetal status, BPPs may not predict overall fetal well-being during acute changes, such as umbilical cord compression or placental abruption. BPPs take longer to complete, require a trained sonographer, and include components like fetal breathing that may be influenced by such factors as nicotine,^6-8 labor,⁹ rupture of membranes,¹⁰ magnesium sulfate,¹¹ and infection.¹²

If medically indicated, which antenatal surveillance technique is right for your patient?

Frequently used antepartum fetal surveillance techniques include maternal perception of fetal movement or “kick counting,” NST, BPP, modified BPP, contraction stress test (CST), and umbilical artery Doppler velocimetry.

Worldwide, the most common form of antenatal surveillance is fetal kick counting. It is noninvasive, can be completed frequently, may decrease maternal anxiety, may improve maternal-fetal bonding, and is free.¹³ According to the results of a 2020 meta-analysis of 468,601 fetuses, however, there was no difference in perinatal death among patients who assessed fetal movements (0.54%) and those who did not (0.59%).¹⁴ There was a statistically significant increase in induction of labor, cesarean delivery, and preterm delivery among patients who counted fetal movements. Women who perceive a decrease in fetal movement should seek medical attention from a health care provider.

An evaluation for decreased fetal movement typically includes taking a history that focuses on risk factors that may increase stillbirth, including hypertension, growth restriction, fetal anomalies, diabetes, and substance use, and auscultation with a fetal Doppler. In the absence of risk factors and the presence of a normal fetal heartbeat, pregnant women should be reassured of fetal well-being. In a pregnancy at greater than 28 weeks, a 20-minute NST can be completed as well; this has become part of the standard workup of decreased fetal movement in developed countries. A reactive NST indicates normal fetal autonomic function in real time and a low incidence of stillbirth (1.9/1,000) within 1 week.¹⁵

Additionally, by measuring the amniotic fluid volume using the largest maximal vertical pocket (MVP), clinicians can gain insight into overall uteroplacental function. The combination of the NST and the MVP—otherwise known as a modified BPP—provides both short-term acid-base status and long-term uteroplacental function. The incidence of stillbirth in the 1 week after a modified BPP has been reported to be 0.8/1,000, which is equivalent to stillbirth incidence using a full BPP (0.8/1,000).¹⁶ The negative predictive value for both the modified BPP and the BPP is 99.9%—equivalent.

The case for modified BPP use

The modified BPP requires less time, is less costly (cost savings of approximately 50%), does not require a specialized sonographer, and can be performed in local community clinics.

Perhaps the initial antepartum surveillance test of choice should be the modified BPP, with the BPP used in cases in which the results of a modified BPP are abnormal. ●

Copyright: Digital illustrations by John J. DeNapoli/Cristian Storto Fotografia/IStock/Getty Images Plus/Prostock-Studio/IStock/Getty Images Plus/ClaudioVentrella/IStock Getty Images Plus

COVID-19 vaccination is recommended for all reproductive-aged women, regardless of pregnancy status.¹ Yet, national vaccination rates in pregnancy remain woefully low—lower than vaccine coverage rates for other recommended vaccines during pregnancy.^2,3 COVID-19 infection has clearly documented risks for maternal and fetal health, and data continue to accumulate on the maternal and neonatal benefits of COVID-19 vaccination in pregnancy, as well as the safety of vaccination during pregnancy.

Maternal and neonatal benefits of COVID-19 vaccination

Does vaccination in pregnancy result in decreased rates of severe COVID-19 infection? Results from a study from a Louisiana health system comparing maternal outcomes between fully vaccinated (defined as 2 weeks after the final vaccine dose) and unvaccinated or partially vaccinated pregnant women during the delta variant—predominant COVID-19 surge clearly answer this question. Vaccination in pregnancy resulted in a 90% risk reduction in severe or critical COVID-19 infection and a 70% risk reduction in COVID-19 infection of any severity among fully vaccinated women. The study also provides some useful absolute numbers for patient counseling: Although none of the 1,332 vaccinated pregnant women in the study required supplemental oxygen or intensive care unit (ICU) admission, there was 1 maternal death, 5 ICU admissions, and 6 stillbirths among the 8,760 unvaccinated pregnant women.⁴

A larger population-based data set from Scotland and Israel demonstrated similar findings.⁵ Most importantly, the Scotland data, with most patients having had an mRNA-based vaccine, showed that, while 77% of all COVID-19 infections occurred in unvaccinated pregnant women, 91% of all hospital admissions occurred in unvaccinated women, and 98% of all critical care admissions occurred in unvaccinated women. Furthermore, although 13% of all COVID-19 hospitalizations in pregnancy occurred among vaccinated women, only 2% of critical care admissions occurred among vaccinated women. The Israeli experience (which identified nearly 30,000 eligible pregnancies from 1 of 4 state-mandated health funds in the country), demonstrated that the efficacy of the Pfizer/BioNTech vaccine to prevent a SARS-CoV-2 infection of any severity once fully vaccinated is more than 80%.⁶

Breakthrough infections, which were more prevalent during the omicron surge, have caused some patients to question the utility of COVID-19 vaccination. Recent data from South Africa, where the omicron variant was first identified, noted that efficacy of the Pfizer/ BioNTech vaccine to prevent hospitalization with COVID-19 infection during an omicron-predominant period was 70%—versus 93% efficacy in a delta-predominant period.⁷ These data, however, were in the absence of a booster dose, and in vitro studies suggest increased vaccine efficacy with a booster dose.⁸

Continue to: Counseling women on vaccination benefits and risks...

Counseling women on vaccination benefits and risks. No matter the specific numeric rate of efficacy against a COVID-19 infection, it is important to counsel women that the goal of vaccination is to prevent severe or critical COVID-19 infections, and these data all demonstrate that COVID-19 vaccination meets this goal. However, women may have additional questions regarding both fetal/neonatal benefits and safety with immunization in pregnancy.

Let us address the question of benefit first. In a large cohort of more than 1,300 women vaccinated during pregnancy and delivering at >34 weeks’ gestation, a few observations are worth noting.⁹ The first is that women who were fully vaccinated by the time of delivery had detectable antibodies at birth, even with first trimester vaccination, and these antibodies did cross the placenta to the neonate. Although higher maternal and neonatal antibody levels are achieved with early third trimester vaccination, it is key that women interpret this finding in light of 2 important points:

1. women cannot know what gestational age they will deliver, thus waiting until the early third trimester for vaccination to optimize neonatal antibody levels could result in delivery prior to planned vaccination, with benefit for neither the woman nor the baby
2. partial vaccination in the early third trimester resulted in lower maternal and neonatal antibody levels than full vaccination in the first trimester.

In addition, while the data were limited, a booster dose in the third trimester results in the highest antibody levels at delivery. Given the recommendation to initiate a booster dose 5 months after the completion of the primary vaccine series,¹⁰ many women will be eligible for a booster prior to delivery and thus can achieve the goals of high maternal and neonatal antibody levels simultaneously. One caveat to these data is that, while higher antibody levels seem comforting and may be better, we do not yet know the level of neonatal antibody necessary to decrease risks of COVID-19 infection in early newborn life.⁹ Recent data from the Centers for Disease Control and Prevention provide real-world evidence that maternal vaccination decreases the risk of hospitalization from COVID-19 for infants aged <6 months, with vaccine efficacy estimated to be 61% during a period of both Delta and Omicron predominance.¹¹

The evidence is clear—the time for COVID-19 vaccination is now. There is no “optimal” time of vaccination in pregnancy for neonatal benefit that would be worth risking any amount of time a woman is susceptible to COVID-19, especially given the promising data regarding maternal and neonatal antibody levels achieved after a booster dose.

Safety of COVID-19 vaccination: Current data

Risks for pregnancy loss, birth defects, and preterm delivery often are concerns of pregnant women considering a COVID-19 vaccination. Data from more than 2,400 women who submitted their information to the v-SAFE registry demonstrated a 14% risk for pregnancy loss between 6 and 20 weeks’ gestation—well within the expected rate of pregnancy loss in this gestational age range.¹²

Data from more than 46,000 pregnancies included in the Vaccine Safety Datalink, which includes data from health care organizations in 6 states, demonstrated a preterm birth rate of 6.6% and a small-for-gestational-age rate of 8.2% among fully vaccinated women, rates that were no different among unvaccinated women. There were no differences in the outcomes by trimester of vaccination, and these rates are comparable to the expected rates of these outcomes.¹³

Women also worry about the risks of vaccine side effects, such as fever or rare adverse events. Although all adverse events (ie, Guillain-Barre syndrome, pericarditis/myocarditis, thrombosis with thrombocytopenia syndrome [TTS]) are very rare, the American College of Obstetricians and Gynecologists does recommend that women get an mRNA COVID-19 vaccine, as the Johnson & Johnson/Janssen vaccine is associated with TTS, which occurred more commonly (although still rare) in women of reproductive age.¹⁴

Two large studies of typical side effects experienced after COVID-19 vaccination in pregnancy are incredibly reassuring. In the first, authors of a large study of more than 12,000 pregnant women enrolled in the v-SAFE registry reported that the most common side effect after each mRNA dose was injection site pain (88% after dose 1, 92% after dose 2).¹⁵ Self-reported fever occurred in 4% of women after dose 1 and 35% after dose 2. Although this frequency may seem high, a fever of 38.0°C (100.4°F) or higher only occurred among 8% of all participants.

In another study of almost 8,000 women self-reporting side effects (some of whom also may have contributed data to the v-SAFE study), fever occurred in approximately 5% after dose 1 and in about 20% after dose 2.¹⁶ In this study, the highest mean temperature was 38.1°C (100.6°F) after dose 1 and 38.2°C (100.7°F) after dose 2. Although it is a reasonable expectation for fever to follow COVID-19 vaccination, particularly after the second dose, the typical fever is a low-grade temperature that will not harm a developing fetus and will be responsive to acetaminophen administration. Moreover, if the fever were the harbinger of harm, then it might stand to reason that an increased signal of preterm delivery may be observed, but data from nearly 10,000 pregnant women vaccinated during the second or third trimesters showed no association with preterm birth (adjusted hazard ratio, 0.91; 95% confidence interval, 0.82–1.01).¹³

The bottom line

The data are clear. COVID-19 vaccination decreases the risks of severe infection in pregnancy, confers antibodies to neonates with at least some level of protection, and has no demonstrated harmful side effects in pregnancy. ●

Copyright: Digital illustrations by John J. DeNapoli/Cristian Storto Fotografia/IStock/Getty Images Plus/Prostock-Studio/IStock/Getty Images Plus/ClaudioVentrella/IStock Getty Images Plus

COVID-19 vaccination is recommended for all reproductive-aged women, regardless of pregnancy status.¹ Yet, national vaccination rates in pregnancy remain woefully low—lower than vaccine coverage rates for other recommended vaccines during pregnancy.^2,3 COVID-19 infection has clearly documented risks for maternal and fetal health, and data continue to accumulate on the maternal and neonatal benefits of COVID-19 vaccination in pregnancy, as well as the safety of vaccination during pregnancy.

Maternal and neonatal benefits of COVID-19 vaccination

Does vaccination in pregnancy result in decreased rates of severe COVID-19 infection? Results from a study from a Louisiana health system comparing maternal outcomes between fully vaccinated (defined as 2 weeks after the final vaccine dose) and unvaccinated or partially vaccinated pregnant women during the delta variant—predominant COVID-19 surge clearly answer this question. Vaccination in pregnancy resulted in a 90% risk reduction in severe or critical COVID-19 infection and a 70% risk reduction in COVID-19 infection of any severity among fully vaccinated women. The study also provides some useful absolute numbers for patient counseling: Although none of the 1,332 vaccinated pregnant women in the study required supplemental oxygen or intensive care unit (ICU) admission, there was 1 maternal death, 5 ICU admissions, and 6 stillbirths among the 8,760 unvaccinated pregnant women.⁴

A larger population-based data set from Scotland and Israel demonstrated similar findings.⁵ Most importantly, the Scotland data, with most patients having had an mRNA-based vaccine, showed that, while 77% of all COVID-19 infections occurred in unvaccinated pregnant women, 91% of all hospital admissions occurred in unvaccinated women, and 98% of all critical care admissions occurred in unvaccinated women. Furthermore, although 13% of all COVID-19 hospitalizations in pregnancy occurred among vaccinated women, only 2% of critical care admissions occurred among vaccinated women. The Israeli experience (which identified nearly 30,000 eligible pregnancies from 1 of 4 state-mandated health funds in the country), demonstrated that the efficacy of the Pfizer/BioNTech vaccine to prevent a SARS-CoV-2 infection of any severity once fully vaccinated is more than 80%.⁶

Breakthrough infections, which were more prevalent during the omicron surge, have caused some patients to question the utility of COVID-19 vaccination. Recent data from South Africa, where the omicron variant was first identified, noted that efficacy of the Pfizer/ BioNTech vaccine to prevent hospitalization with COVID-19 infection during an omicron-predominant period was 70%—versus 93% efficacy in a delta-predominant period.⁷ These data, however, were in the absence of a booster dose, and in vitro studies suggest increased vaccine efficacy with a booster dose.⁸

Continue to: Counseling women on vaccination benefits and risks...

Counseling women on vaccination benefits and risks. No matter the specific numeric rate of efficacy against a COVID-19 infection, it is important to counsel women that the goal of vaccination is to prevent severe or critical COVID-19 infections, and these data all demonstrate that COVID-19 vaccination meets this goal. However, women may have additional questions regarding both fetal/neonatal benefits and safety with immunization in pregnancy.

Let us address the question of benefit first. In a large cohort of more than 1,300 women vaccinated during pregnancy and delivering at >34 weeks’ gestation, a few observations are worth noting.⁹ The first is that women who were fully vaccinated by the time of delivery had detectable antibodies at birth, even with first trimester vaccination, and these antibodies did cross the placenta to the neonate. Although higher maternal and neonatal antibody levels are achieved with early third trimester vaccination, it is key that women interpret this finding in light of 2 important points:

1. women cannot know what gestational age they will deliver, thus waiting until the early third trimester for vaccination to optimize neonatal antibody levels could result in delivery prior to planned vaccination, with benefit for neither the woman nor the baby
2. partial vaccination in the early third trimester resulted in lower maternal and neonatal antibody levels than full vaccination in the first trimester.

In addition, while the data were limited, a booster dose in the third trimester results in the highest antibody levels at delivery. Given the recommendation to initiate a booster dose 5 months after the completion of the primary vaccine series,¹⁰ many women will be eligible for a booster prior to delivery and thus can achieve the goals of high maternal and neonatal antibody levels simultaneously. One caveat to these data is that, while higher antibody levels seem comforting and may be better, we do not yet know the level of neonatal antibody necessary to decrease risks of COVID-19 infection in early newborn life.⁹ Recent data from the Centers for Disease Control and Prevention provide real-world evidence that maternal vaccination decreases the risk of hospitalization from COVID-19 for infants aged <6 months, with vaccine efficacy estimated to be 61% during a period of both Delta and Omicron predominance.¹¹

The evidence is clear—the time for COVID-19 vaccination is now. There is no “optimal” time of vaccination in pregnancy for neonatal benefit that would be worth risking any amount of time a woman is susceptible to COVID-19, especially given the promising data regarding maternal and neonatal antibody levels achieved after a booster dose.

Safety of COVID-19 vaccination: Current data

Risks for pregnancy loss, birth defects, and preterm delivery often are concerns of pregnant women considering a COVID-19 vaccination. Data from more than 2,400 women who submitted their information to the v-SAFE registry demonstrated a 14% risk for pregnancy loss between 6 and 20 weeks’ gestation—well within the expected rate of pregnancy loss in this gestational age range.¹²

Data from more than 46,000 pregnancies included in the Vaccine Safety Datalink, which includes data from health care organizations in 6 states, demonstrated a preterm birth rate of 6.6% and a small-for-gestational-age rate of 8.2% among fully vaccinated women, rates that were no different among unvaccinated women. There were no differences in the outcomes by trimester of vaccination, and these rates are comparable to the expected rates of these outcomes.¹³

Women also worry about the risks of vaccine side effects, such as fever or rare adverse events. Although all adverse events (ie, Guillain-Barre syndrome, pericarditis/myocarditis, thrombosis with thrombocytopenia syndrome [TTS]) are very rare, the American College of Obstetricians and Gynecologists does recommend that women get an mRNA COVID-19 vaccine, as the Johnson & Johnson/Janssen vaccine is associated with TTS, which occurred more commonly (although still rare) in women of reproductive age.¹⁴

Two large studies of typical side effects experienced after COVID-19 vaccination in pregnancy are incredibly reassuring. In the first, authors of a large study of more than 12,000 pregnant women enrolled in the v-SAFE registry reported that the most common side effect after each mRNA dose was injection site pain (88% after dose 1, 92% after dose 2).¹⁵ Self-reported fever occurred in 4% of women after dose 1 and 35% after dose 2. Although this frequency may seem high, a fever of 38.0°C (100.4°F) or higher only occurred among 8% of all participants.

In another study of almost 8,000 women self-reporting side effects (some of whom also may have contributed data to the v-SAFE study), fever occurred in approximately 5% after dose 1 and in about 20% after dose 2.¹⁶ In this study, the highest mean temperature was 38.1°C (100.6°F) after dose 1 and 38.2°C (100.7°F) after dose 2. Although it is a reasonable expectation for fever to follow COVID-19 vaccination, particularly after the second dose, the typical fever is a low-grade temperature that will not harm a developing fetus and will be responsive to acetaminophen administration. Moreover, if the fever were the harbinger of harm, then it might stand to reason that an increased signal of preterm delivery may be observed, but data from nearly 10,000 pregnant women vaccinated during the second or third trimesters showed no association with preterm birth (adjusted hazard ratio, 0.91; 95% confidence interval, 0.82–1.01).¹³

The bottom line

The data are clear. COVID-19 vaccination decreases the risks of severe infection in pregnancy, confers antibodies to neonates with at least some level of protection, and has no demonstrated harmful side effects in pregnancy. ●

Copyright: Digital illustrations by John J. DeNapoli/Cristian Storto Fotografia/IStock/Getty Images Plus/Prostock-Studio/IStock/Getty Images Plus/ClaudioVentrella/IStock Getty Images Plus

COVID-19 vaccination is recommended for all reproductive-aged women, regardless of pregnancy status.¹ Yet, national vaccination rates in pregnancy remain woefully low—lower than vaccine coverage rates for other recommended vaccines during pregnancy.^2,3 COVID-19 infection has clearly documented risks for maternal and fetal health, and data continue to accumulate on the maternal and neonatal benefits of COVID-19 vaccination in pregnancy, as well as the safety of vaccination during pregnancy.

Maternal and neonatal benefits of COVID-19 vaccination

Does vaccination in pregnancy result in decreased rates of severe COVID-19 infection? Results from a study from a Louisiana health system comparing maternal outcomes between fully vaccinated (defined as 2 weeks after the final vaccine dose) and unvaccinated or partially vaccinated pregnant women during the delta variant—predominant COVID-19 surge clearly answer this question. Vaccination in pregnancy resulted in a 90% risk reduction in severe or critical COVID-19 infection and a 70% risk reduction in COVID-19 infection of any severity among fully vaccinated women. The study also provides some useful absolute numbers for patient counseling: Although none of the 1,332 vaccinated pregnant women in the study required supplemental oxygen or intensive care unit (ICU) admission, there was 1 maternal death, 5 ICU admissions, and 6 stillbirths among the 8,760 unvaccinated pregnant women.⁴

A larger population-based data set from Scotland and Israel demonstrated similar findings.⁵ Most importantly, the Scotland data, with most patients having had an mRNA-based vaccine, showed that, while 77% of all COVID-19 infections occurred in unvaccinated pregnant women, 91% of all hospital admissions occurred in unvaccinated women, and 98% of all critical care admissions occurred in unvaccinated women. Furthermore, although 13% of all COVID-19 hospitalizations in pregnancy occurred among vaccinated women, only 2% of critical care admissions occurred among vaccinated women. The Israeli experience (which identified nearly 30,000 eligible pregnancies from 1 of 4 state-mandated health funds in the country), demonstrated that the efficacy of the Pfizer/BioNTech vaccine to prevent a SARS-CoV-2 infection of any severity once fully vaccinated is more than 80%.⁶

Breakthrough infections, which were more prevalent during the omicron surge, have caused some patients to question the utility of COVID-19 vaccination. Recent data from South Africa, where the omicron variant was first identified, noted that efficacy of the Pfizer/ BioNTech vaccine to prevent hospitalization with COVID-19 infection during an omicron-predominant period was 70%—versus 93% efficacy in a delta-predominant period.⁷ These data, however, were in the absence of a booster dose, and in vitro studies suggest increased vaccine efficacy with a booster dose.⁸

Continue to: Counseling women on vaccination benefits and risks...

Counseling women on vaccination benefits and risks. No matter the specific numeric rate of efficacy against a COVID-19 infection, it is important to counsel women that the goal of vaccination is to prevent severe or critical COVID-19 infections, and these data all demonstrate that COVID-19 vaccination meets this goal. However, women may have additional questions regarding both fetal/neonatal benefits and safety with immunization in pregnancy.

Let us address the question of benefit first. In a large cohort of more than 1,300 women vaccinated during pregnancy and delivering at >34 weeks’ gestation, a few observations are worth noting.⁹ The first is that women who were fully vaccinated by the time of delivery had detectable antibodies at birth, even with first trimester vaccination, and these antibodies did cross the placenta to the neonate. Although higher maternal and neonatal antibody levels are achieved with early third trimester vaccination, it is key that women interpret this finding in light of 2 important points:

1. women cannot know what gestational age they will deliver, thus waiting until the early third trimester for vaccination to optimize neonatal antibody levels could result in delivery prior to planned vaccination, with benefit for neither the woman nor the baby
2. partial vaccination in the early third trimester resulted in lower maternal and neonatal antibody levels than full vaccination in the first trimester.

In addition, while the data were limited, a booster dose in the third trimester results in the highest antibody levels at delivery. Given the recommendation to initiate a booster dose 5 months after the completion of the primary vaccine series,¹⁰ many women will be eligible for a booster prior to delivery and thus can achieve the goals of high maternal and neonatal antibody levels simultaneously. One caveat to these data is that, while higher antibody levels seem comforting and may be better, we do not yet know the level of neonatal antibody necessary to decrease risks of COVID-19 infection in early newborn life.⁹ Recent data from the Centers for Disease Control and Prevention provide real-world evidence that maternal vaccination decreases the risk of hospitalization from COVID-19 for infants aged <6 months, with vaccine efficacy estimated to be 61% during a period of both Delta and Omicron predominance.¹¹

The evidence is clear—the time for COVID-19 vaccination is now. There is no “optimal” time of vaccination in pregnancy for neonatal benefit that would be worth risking any amount of time a woman is susceptible to COVID-19, especially given the promising data regarding maternal and neonatal antibody levels achieved after a booster dose.

Safety of COVID-19 vaccination: Current data

Risks for pregnancy loss, birth defects, and preterm delivery often are concerns of pregnant women considering a COVID-19 vaccination. Data from more than 2,400 women who submitted their information to the v-SAFE registry demonstrated a 14% risk for pregnancy loss between 6 and 20 weeks’ gestation—well within the expected rate of pregnancy loss in this gestational age range.¹²

Data from more than 46,000 pregnancies included in the Vaccine Safety Datalink, which includes data from health care organizations in 6 states, demonstrated a preterm birth rate of 6.6% and a small-for-gestational-age rate of 8.2% among fully vaccinated women, rates that were no different among unvaccinated women. There were no differences in the outcomes by trimester of vaccination, and these rates are comparable to the expected rates of these outcomes.¹³

Women also worry about the risks of vaccine side effects, such as fever or rare adverse events. Although all adverse events (ie, Guillain-Barre syndrome, pericarditis/myocarditis, thrombosis with thrombocytopenia syndrome [TTS]) are very rare, the American College of Obstetricians and Gynecologists does recommend that women get an mRNA COVID-19 vaccine, as the Johnson & Johnson/Janssen vaccine is associated with TTS, which occurred more commonly (although still rare) in women of reproductive age.¹⁴

Two large studies of typical side effects experienced after COVID-19 vaccination in pregnancy are incredibly reassuring. In the first, authors of a large study of more than 12,000 pregnant women enrolled in the v-SAFE registry reported that the most common side effect after each mRNA dose was injection site pain (88% after dose 1, 92% after dose 2).¹⁵ Self-reported fever occurred in 4% of women after dose 1 and 35% after dose 2. Although this frequency may seem high, a fever of 38.0°C (100.4°F) or higher only occurred among 8% of all participants.

In another study of almost 8,000 women self-reporting side effects (some of whom also may have contributed data to the v-SAFE study), fever occurred in approximately 5% after dose 1 and in about 20% after dose 2.¹⁶ In this study, the highest mean temperature was 38.1°C (100.6°F) after dose 1 and 38.2°C (100.7°F) after dose 2. Although it is a reasonable expectation for fever to follow COVID-19 vaccination, particularly after the second dose, the typical fever is a low-grade temperature that will not harm a developing fetus and will be responsive to acetaminophen administration. Moreover, if the fever were the harbinger of harm, then it might stand to reason that an increased signal of preterm delivery may be observed, but data from nearly 10,000 pregnant women vaccinated during the second or third trimesters showed no association with preterm birth (adjusted hazard ratio, 0.91; 95% confidence interval, 0.82–1.01).¹³

The bottom line

The data are clear. COVID-19 vaccination decreases the risks of severe infection in pregnancy, confers antibodies to neonates with at least some level of protection, and has no demonstrated harmful side effects in pregnancy. ●