Article

Migraine is well known as a vascular phenomenon, but research over time has shown that vasodilation is a secondary feature of headache rather than the cause of headache pain. Calcitonin gene-related peptide (CGRP) and other vasoactive inflammatory proteins transmit nociceptive signals through the trigeminal system, and although vasodilation occurs, it is not essential for migraine attacks to occur. White matter changes on MRI are a common finding in people with migraine, and the burden of migraine often correlates with the amount of white matter changes seen. This connection highlights the indirect connection between migraine and vascular risks factors, and this study attempts to better quantify this, specifically with respect to stroke and myocardial infarction (MI).

The study by Fuglsang and colleagues was a registry-based nationwide population-based cohort study that included over 200,000 individuals with migraine, using data collected from 1996 to 2018. Participants were differentiated as having or not having migraine on the basis of prescriptions of preventive or acute migraine medications. Male and female participants were further subdivided, and these groups were compared to healthy controls. The primary endpoints were hazard ratio and absolute risk differences for developing hemorrhagic or ischemic stroke or MI among all groups.

The researchers found an increased risk for ischemic stroke that was equal among male and female participants. Hemorrhagic stroke and MI were seen to be increased in migraine, but primarily among women with migraine. This study specifically investigated what the researchers termed "premature" stroke and MI, and there remains a likelihood that estrogen could be the differentiating factor between the difference in risk between male and female participants with migraine. I have recently highlighted a number of studies investigating vascular risk factors associated with migraine; this study will help clinicians appropriately educate their patients with migraine regarding vascular risk.

The first medications reported as helpful preventively for migraine were antihypertensives, specifically beta-blockers (BB). A number of other medications in other antihypertensive subclasses have also subsequently been shown to be helpful for migraine prevention. These include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and alpha-blockers (AB). Carcel and colleagues conducted a meta-analysis that investigated a wide variety of antihypertensive medications in multiple classes and compared the reduction in headache frequency as defined as headache days per month.

This analysis reviewed 50 studies involving over 4000 participants. The majority of the studies (35 out 50 [70%]) had a cross-over design. The medications evaluated included clonidine (an alpha agonist), candesartan (an ARB), telmisartan (an ARB), propranolol (a BB), timolol (a BB), pindolol (a BB), metoprolol (a BB), bisoprolol (a BB), atenolol (a BB), alprenolol (a BB), nimodipine (a CCB), nifedipine (a CCB), verapamil (a CCB), nicardipine (a CCB), enalapril (an ACE inhibitor), and lisinopril (an ACE inhibitor). For each class of antihypertensive, there was a lower number of monthly headache days with treatment compared with placebo; the greatest reduction was for the CCB with a mean difference of about 2 days per month. BB on average decreased headache days per month by 0.7 days. For BB, there was no clear trend to increased efficacy with increased dose. Only six trials reported the difference in blood pressure: On average, there was a 9.3 mm Hg drop in systolic and 3.0 mm Hg drop in diastolic pressure.

The authors showed that there is statistical significance for the use of antihypertensive medications for decreasing migraine days per month, and this was statistically significant separately for numerous specific drugs within the classes: clonidine, candesartan, atenolol, bisoprolol, propranolol, timolol, nicardipine, and verapamil. Antihypertensive medications remain some of the most popular first-line preventive options for migraine, and although the benefit of this class as a whole is mild (slightly more than 1 day per month), it can be an excellent option for many patients

The relationship between migraine and caffeine is necessarily controversial. Caffeine is included as a component of many over-the-counter migraine treatments, and the beneficial effect of caffeine as an acute treatment for migraine has been documented for decades. Reduction in caffeine, however, has also been established as a helpful lifestyle modification for prevention of migraine attacks. Zhang and colleagues used data from the National Health and Nutrition Examination Survey database, a program conducted by the Centers for Disease Control and Prevention to assess the health and nutritional status of adults and children in the United States.

This study sought to quantify the relationship between dietary caffeine and "severe headache." For this study, "severe headache" was defined as answering yes to the question: During the past 3 months, did you have severe headaches or migraines? Dietary caffeine intake was collected through two 24-hour dietary recall interviews, one in person and one 3-10 days later via telephone. The amount of caffeine consumed was estimated in mg/day from all caffeine-containing foods and beverages, including coffee, tea, soda, and chocolate, using the US Department of Agriculture's Food and Nutrient Database. Each participant's mean caffeine intake was defined as the difference between the first and second dietary recalls.

A large number of covariates were assessed as well, including age, race/ethnicity, body mass index, poverty-income ratio, educational level, marital status, hypertension, cancer, energy intake, protein intake, calcium intake, magnesium intake, iron intake, sodium intake, alcohol status, smoking status, and triglyceride level. A total of 8993 participants were included. Caffeine intake was divided into four groups: ≥ 0 to < 40 mg/day, ≥ 40 to < 200 mg/day, ≥ 200 to < 400 mg/day, and ≥ 400 mg/day. After adjusting for confounders, a significant association between dietary caffeine intake and severe headaches or migraines was detected.

Curiously, in this study, only male participants were included. The authors found a clear correlation between the amount of caffeine consumed over a 24-hour period and severe migraine attacks. Further evaluation should investigate the frequency of attacks rather than just individual experience over a 3-month period. Although caffeine is helpful acutely, higher dose consumption is a risk factor for worsening migraine.

Migraine is well known as a vascular phenomenon, but research over time has shown that vasodilation is a secondary feature of headache rather than the cause of headache pain. Calcitonin gene-related peptide (CGRP) and other vasoactive inflammatory proteins transmit nociceptive signals through the trigeminal system, and although vasodilation occurs, it is not essential for migraine attacks to occur. White matter changes on MRI are a common finding in people with migraine, and the burden of migraine often correlates with the amount of white matter changes seen. This connection highlights the indirect connection between migraine and vascular risks factors, and this study attempts to better quantify this, specifically with respect to stroke and myocardial infarction (MI).

The study by Fuglsang and colleagues was a registry-based nationwide population-based cohort study that included over 200,000 individuals with migraine, using data collected from 1996 to 2018. Participants were differentiated as having or not having migraine on the basis of prescriptions of preventive or acute migraine medications. Male and female participants were further subdivided, and these groups were compared to healthy controls. The primary endpoints were hazard ratio and absolute risk differences for developing hemorrhagic or ischemic stroke or MI among all groups.

The researchers found an increased risk for ischemic stroke that was equal among male and female participants. Hemorrhagic stroke and MI were seen to be increased in migraine, but primarily among women with migraine. This study specifically investigated what the researchers termed "premature" stroke and MI, and there remains a likelihood that estrogen could be the differentiating factor between the difference in risk between male and female participants with migraine. I have recently highlighted a number of studies investigating vascular risk factors associated with migraine; this study will help clinicians appropriately educate their patients with migraine regarding vascular risk.

The first medications reported as helpful preventively for migraine were antihypertensives, specifically beta-blockers (BB). A number of other medications in other antihypertensive subclasses have also subsequently been shown to be helpful for migraine prevention. These include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and alpha-blockers (AB). Carcel and colleagues conducted a meta-analysis that investigated a wide variety of antihypertensive medications in multiple classes and compared the reduction in headache frequency as defined as headache days per month.

This analysis reviewed 50 studies involving over 4000 participants. The majority of the studies (35 out 50 [70%]) had a cross-over design. The medications evaluated included clonidine (an alpha agonist), candesartan (an ARB), telmisartan (an ARB), propranolol (a BB), timolol (a BB), pindolol (a BB), metoprolol (a BB), bisoprolol (a BB), atenolol (a BB), alprenolol (a BB), nimodipine (a CCB), nifedipine (a CCB), verapamil (a CCB), nicardipine (a CCB), enalapril (an ACE inhibitor), and lisinopril (an ACE inhibitor). For each class of antihypertensive, there was a lower number of monthly headache days with treatment compared with placebo; the greatest reduction was for the CCB with a mean difference of about 2 days per month. BB on average decreased headache days per month by 0.7 days. For BB, there was no clear trend to increased efficacy with increased dose. Only six trials reported the difference in blood pressure: On average, there was a 9.3 mm Hg drop in systolic and 3.0 mm Hg drop in diastolic pressure.

The authors showed that there is statistical significance for the use of antihypertensive medications for decreasing migraine days per month, and this was statistically significant separately for numerous specific drugs within the classes: clonidine, candesartan, atenolol, bisoprolol, propranolol, timolol, nicardipine, and verapamil. Antihypertensive medications remain some of the most popular first-line preventive options for migraine, and although the benefit of this class as a whole is mild (slightly more than 1 day per month), it can be an excellent option for many patients

The relationship between migraine and caffeine is necessarily controversial. Caffeine is included as a component of many over-the-counter migraine treatments, and the beneficial effect of caffeine as an acute treatment for migraine has been documented for decades. Reduction in caffeine, however, has also been established as a helpful lifestyle modification for prevention of migraine attacks. Zhang and colleagues used data from the National Health and Nutrition Examination Survey database, a program conducted by the Centers for Disease Control and Prevention to assess the health and nutritional status of adults and children in the United States.

This study sought to quantify the relationship between dietary caffeine and "severe headache." For this study, "severe headache" was defined as answering yes to the question: During the past 3 months, did you have severe headaches or migraines? Dietary caffeine intake was collected through two 24-hour dietary recall interviews, one in person and one 3-10 days later via telephone. The amount of caffeine consumed was estimated in mg/day from all caffeine-containing foods and beverages, including coffee, tea, soda, and chocolate, using the US Department of Agriculture's Food and Nutrient Database. Each participant's mean caffeine intake was defined as the difference between the first and second dietary recalls.

A large number of covariates were assessed as well, including age, race/ethnicity, body mass index, poverty-income ratio, educational level, marital status, hypertension, cancer, energy intake, protein intake, calcium intake, magnesium intake, iron intake, sodium intake, alcohol status, smoking status, and triglyceride level. A total of 8993 participants were included. Caffeine intake was divided into four groups: ≥ 0 to < 40 mg/day, ≥ 40 to < 200 mg/day, ≥ 200 to < 400 mg/day, and ≥ 400 mg/day. After adjusting for confounders, a significant association between dietary caffeine intake and severe headaches or migraines was detected.

Curiously, in this study, only male participants were included. The authors found a clear correlation between the amount of caffeine consumed over a 24-hour period and severe migraine attacks. Further evaluation should investigate the frequency of attacks rather than just individual experience over a 3-month period. Although caffeine is helpful acutely, higher dose consumption is a risk factor for worsening migraine.

Migraine is well known as a vascular phenomenon, but research over time has shown that vasodilation is a secondary feature of headache rather than the cause of headache pain. Calcitonin gene-related peptide (CGRP) and other vasoactive inflammatory proteins transmit nociceptive signals through the trigeminal system, and although vasodilation occurs, it is not essential for migraine attacks to occur. White matter changes on MRI are a common finding in people with migraine, and the burden of migraine often correlates with the amount of white matter changes seen. This connection highlights the indirect connection between migraine and vascular risks factors, and this study attempts to better quantify this, specifically with respect to stroke and myocardial infarction (MI).

The study by Fuglsang and colleagues was a registry-based nationwide population-based cohort study that included over 200,000 individuals with migraine, using data collected from 1996 to 2018. Participants were differentiated as having or not having migraine on the basis of prescriptions of preventive or acute migraine medications. Male and female participants were further subdivided, and these groups were compared to healthy controls. The primary endpoints were hazard ratio and absolute risk differences for developing hemorrhagic or ischemic stroke or MI among all groups.

The researchers found an increased risk for ischemic stroke that was equal among male and female participants. Hemorrhagic stroke and MI were seen to be increased in migraine, but primarily among women with migraine. This study specifically investigated what the researchers termed "premature" stroke and MI, and there remains a likelihood that estrogen could be the differentiating factor between the difference in risk between male and female participants with migraine. I have recently highlighted a number of studies investigating vascular risk factors associated with migraine; this study will help clinicians appropriately educate their patients with migraine regarding vascular risk.

The first medications reported as helpful preventively for migraine were antihypertensives, specifically beta-blockers (BB). A number of other medications in other antihypertensive subclasses have also subsequently been shown to be helpful for migraine prevention. These include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and alpha-blockers (AB). Carcel and colleagues conducted a meta-analysis that investigated a wide variety of antihypertensive medications in multiple classes and compared the reduction in headache frequency as defined as headache days per month.

This analysis reviewed 50 studies involving over 4000 participants. The majority of the studies (35 out 50 [70%]) had a cross-over design. The medications evaluated included clonidine (an alpha agonist), candesartan (an ARB), telmisartan (an ARB), propranolol (a BB), timolol (a BB), pindolol (a BB), metoprolol (a BB), bisoprolol (a BB), atenolol (a BB), alprenolol (a BB), nimodipine (a CCB), nifedipine (a CCB), verapamil (a CCB), nicardipine (a CCB), enalapril (an ACE inhibitor), and lisinopril (an ACE inhibitor). For each class of antihypertensive, there was a lower number of monthly headache days with treatment compared with placebo; the greatest reduction was for the CCB with a mean difference of about 2 days per month. BB on average decreased headache days per month by 0.7 days. For BB, there was no clear trend to increased efficacy with increased dose. Only six trials reported the difference in blood pressure: On average, there was a 9.3 mm Hg drop in systolic and 3.0 mm Hg drop in diastolic pressure.

The authors showed that there is statistical significance for the use of antihypertensive medications for decreasing migraine days per month, and this was statistically significant separately for numerous specific drugs within the classes: clonidine, candesartan, atenolol, bisoprolol, propranolol, timolol, nicardipine, and verapamil. Antihypertensive medications remain some of the most popular first-line preventive options for migraine, and although the benefit of this class as a whole is mild (slightly more than 1 day per month), it can be an excellent option for many patients

The relationship between migraine and caffeine is necessarily controversial. Caffeine is included as a component of many over-the-counter migraine treatments, and the beneficial effect of caffeine as an acute treatment for migraine has been documented for decades. Reduction in caffeine, however, has also been established as a helpful lifestyle modification for prevention of migraine attacks. Zhang and colleagues used data from the National Health and Nutrition Examination Survey database, a program conducted by the Centers for Disease Control and Prevention to assess the health and nutritional status of adults and children in the United States.

This study sought to quantify the relationship between dietary caffeine and "severe headache." For this study, "severe headache" was defined as answering yes to the question: During the past 3 months, did you have severe headaches or migraines? Dietary caffeine intake was collected through two 24-hour dietary recall interviews, one in person and one 3-10 days later via telephone. The amount of caffeine consumed was estimated in mg/day from all caffeine-containing foods and beverages, including coffee, tea, soda, and chocolate, using the US Department of Agriculture's Food and Nutrient Database. Each participant's mean caffeine intake was defined as the difference between the first and second dietary recalls.

A large number of covariates were assessed as well, including age, race/ethnicity, body mass index, poverty-income ratio, educational level, marital status, hypertension, cancer, energy intake, protein intake, calcium intake, magnesium intake, iron intake, sodium intake, alcohol status, smoking status, and triglyceride level. A total of 8993 participants were included. Caffeine intake was divided into four groups: ≥ 0 to < 40 mg/day, ≥ 40 to < 200 mg/day, ≥ 200 to < 400 mg/day, and ≥ 400 mg/day. After adjusting for confounders, a significant association between dietary caffeine intake and severe headaches or migraines was detected.

Curiously, in this study, only male participants were included. The authors found a clear correlation between the amount of caffeine consumed over a 24-hour period and severe migraine attacks. Further evaluation should investigate the frequency of attacks rather than just individual experience over a 3-month period. Although caffeine is helpful acutely, higher dose consumption is a risk factor for worsening migraine.

Ryu KJ, Kim MS, Lee JY, et al. Risk of endometrial polyps, hyperplasia, carcinoma, and uterine cancer after tamoxifen treatment in premenopausal women with breast cancer. JAMA Netw Open. 2022;5:e2243951.

EXPERT COMMENTARY

Tamoxifen is a selective estrogen receptor modulator (SERM) approved by the US Food and Drug Administration (FDA) for both adjuvant treatment of invasive or metastatic breast cancer with hormone receptor (HR)–positive tumors (duration, 5 to 10 years) and for reduction of future breast cancers in certain high-risk individuals (duration, 5 years). It is also occasionally used for non-FDA approved indications, such as cyclic mastodynia.

Because breast cancer is among the most frequently diagnosed cancers in the United States (297,790 new cases expected in 2023) and approximately 80% are HR-positive tumors that will require hormonal adjuvant therapy,¹ physicians and other gynecologic clinicians should have a working understanding of tamoxifen, including the risks and benefits associated with its use. Among the recognized serious adverse effects of tamoxifen is the increased risk of endometrial cancer in menopausal patients. This adverse effect creates a potential conundrum for clinicians who may be managing patients with tamoxifen to treat or prevent breast cancer, while also increasing the risk of another cancer. Prior prospective studies of tamoxifen have demonstrated a statistically and clinically significant increased risk of endometrial cancer in menopausal patients but not in premenopausal patients.

A recent study challenged those previous findings, suggesting that the risk of endometrial cancer is similar in both premenopausal and postmenopausal patients taking tamoxifen for treatment of breast cancer.²

Details of the study

The study by Ryu and colleagues used data from the Korean National Health Insurance Service, which covers 97% of the Korean population.² The authors selected patients being treated for invasive breast cancer from January 1, 2003, through December 31, 2018, who were between the ages of 20 and 50 years when the breast cancer diagnosis was first made. Patients with a diagnostic code entered into their electronic health record that was consistent with menopausal status were excluded, along with any patients with a current or prior history of aromatase inhibitor use (for which one must be naturally, medically, or surgically menopausal to use). Based on these exclusions, the study cohort was then assumed to be premenopausal.

The study group included patients diagnosed with invasive breast cancer who were treated with adjuvant hormonal therapy with tamoxifen (n = 34,637), and the control group included patients with invasive breast cancer who were not treated with adjuvant hormonal therapy (n = 43,683). The primary study end point was the finding of endometrial or uterine pathology, including endometrial polyps, endometrial hyperplasia, endometrial cancer, and other uterine malignant neoplasms not originating in the endometrium (for example, uterine sarcomas).

Because this was a retrospective cohort study that included all eligible patients, the 2 groups were not matched. The treatment group was statistically older, had a higher body mass index (BMI) and a larger waist circumference, were more likely to be hypertensive, and included more patients with diabetes than the control group—all known risk factors for endometrial cancer. However, after adjusting for these 4 factors, an increased risk of endometrial cancer remained in the tamoxifen group compared with the control group (hazard ratio [HR], 3.77; 95% confidence interval [CI], 3.04–4.66). In addition, tamoxifen use was independently associated with an increased risk of endometrial polyps (HR, 3.90; 95% CI, 3.65–4.16), endometrial hyperplasia (HR, 5.56; 95% CI, 5.06–6.12), and other uterine cancers (HR, 2.27; 95% CI, 1.54–3.33). In a subgroup analysis, the risk for endometrial cancer was not higher in patients treated for more than 5 years of tamoxifen compared with those treated for 5 years or less.

Study strengths and limitations

A major strength of this study was the large number of study participants (n = 34,637 tamoxifen; n = 43,683 control), the long duration of follow-up (up to 15 years), and use of a single source of data with coverage of nearly the entire population of Korea. While the 2 study populations (tamoxifen vs no tamoxifen) were initially unbalanced in terms of endometrial cancer risk (age, BMI, concurrent diagnoses of hypertension and diabetes), the authors corrected for this with a multivariate analysis.

Furthermore, while the likely homogeneity of the study population may not make the results generalizable, the authors noted that Korean patients have a higher tendency toward early-onset breast cancer. This observation could make this cohort better suited for a study on premenopausal effects of tamoxifen.

Limitations. These data are provocative as they conflict with level 1 evidence based on multiple well-designed, double-blind, placebo-controlled randomized trials in which tamoxifen use for 5 years did not demonstrate a statistically increased risk of endometrial cancer in patients younger than age 50.^3-5 Because of the importance of the question and the implications for many premenopausal women being treated with tamoxifen, we carefully evaluated the study methodology to better understand this discrepancy.

Continue to: Methodological concerns...

In the study by Ryu and colleagues, we found the definition of premenopausal to be problematic. Ultimately, if patients did not have a diagnosis of menopause in the problem summary list, they were assumed to be premenopausal if they were between the ages of 20 and 50 and not taking an aromatase inhibitor. However, important considerations in this population include the cancer stage and treatment regimens that can and do directly impact menopausal status.

Data demonstrate that early-onset breast cancer tends to be associated with more biologically aggressive characteristics that frequently require adjuvant or neoadjuvant chemotherapy.^6,7 This chemotherapy regimen is comprised most commonly of Adriamycin (doxorubicin), paclitaxel, and cyclophosphamide. Cyclophosphamide is an alkylating agent that is a known gonadotoxin, and it often renders patients either temporarily or permanently menopausal due to chemotherapy-induced ovarian failure. Prior studies have demonstrated that for patients in their 40s, approximately 90% of those treated with cyclophosphamide-containing chemo-therapy for breast cancer will experience chemotherapy-induced amenorrhea (CIA).⁸ Although some patients in their 40s with CIA will resume ovarian function, the majority will not.^8,9

Due to the lack of reliability in diagnosing CIA, blood levels of estradiol and follicle stimulating hormone are often necessary for confirmation and, even so, may be only temporary. One prospective analysis of 4 randomized neoadjuvant/adjuvant breast cancer trials used this approach and demonstrated that 85.1% of the study cohort experienced chemotherapy-induced ovarian failure at the end of their treatment, with some fluctuating back to premenopausal hormonal levels at 6 and 12 months.¹⁰

Furthermore, in the study by Ryu and colleagues, there is no description or confirmation of menstrual patterns in the study group to support the diagnosis of ongoing premenopausal status. Data on CIA and loss of ovarian function, therefore, are critical to the accurate categorization of patients as premenopausal or menopausal in this study. The study also relied on consistent and accurate recording of appropriate medical codes to capture a patient’s menopausal status, which is unclear for this particular population and health system.

In evaluating prior research, multiple studies demonstrated no increased risk of endometrial cancer in premenopausal women taking tamoxifen for breast cancer prevention (TABLE).^3,5 These breast cancer prevention trials have several major advantages in assessing tamoxifen-associated endometrial cancer risk for premenopausal patients compared with the current study:

• Both studies were prospective double-blind, placebo-controlled randomized clinical breast cancer prevention trials with carefully designed and measured outcomes.
• Since these were breast cancer prevention trials, administration of gonadotoxic chemotherapy was not a concern. As a result, miscategorizing patients with chemotherapy-induced menopause as premenopausal would not be expected, and premature menopause would not be expected at a higher rate than the general population.
• Careful histories were required prior to study entry and throughout the study, including data on menopausal status and menstrual and uterine bleeding histories.¹¹

In these prevention trials, the effect of tamoxifen on uterine pathology demonstratedrepeatable evidence that there was a statistically significant increased risk of endometrial cancer in postmenopausal women, but there was no similar increased risk of endometrial cancer in premenopausal women (TABLE).^3,5 Interestingly, the magnitude of the endometrial cancer risk found in the premenopausal patients in the study by Ryu and colleagues (RR, 3.77) is comparable to that of the menopausal group in the prevention trials, raising concern that many or most of the patients in the treatment group assumed to be premenopausal may have indeed been “menopausal” for some or all the time they were taking tamoxifen due to the possible aforementioned reasons. ●

Ryu KJ, Kim MS, Lee JY, et al. Risk of endometrial polyps, hyperplasia, carcinoma, and uterine cancer after tamoxifen treatment in premenopausal women with breast cancer. JAMA Netw Open. 2022;5:e2243951.

EXPERT COMMENTARY

Tamoxifen is a selective estrogen receptor modulator (SERM) approved by the US Food and Drug Administration (FDA) for both adjuvant treatment of invasive or metastatic breast cancer with hormone receptor (HR)–positive tumors (duration, 5 to 10 years) and for reduction of future breast cancers in certain high-risk individuals (duration, 5 years). It is also occasionally used for non-FDA approved indications, such as cyclic mastodynia.

Because breast cancer is among the most frequently diagnosed cancers in the United States (297,790 new cases expected in 2023) and approximately 80% are HR-positive tumors that will require hormonal adjuvant therapy,¹ physicians and other gynecologic clinicians should have a working understanding of tamoxifen, including the risks and benefits associated with its use. Among the recognized serious adverse effects of tamoxifen is the increased risk of endometrial cancer in menopausal patients. This adverse effect creates a potential conundrum for clinicians who may be managing patients with tamoxifen to treat or prevent breast cancer, while also increasing the risk of another cancer. Prior prospective studies of tamoxifen have demonstrated a statistically and clinically significant increased risk of endometrial cancer in menopausal patients but not in premenopausal patients.

A recent study challenged those previous findings, suggesting that the risk of endometrial cancer is similar in both premenopausal and postmenopausal patients taking tamoxifen for treatment of breast cancer.²

Details of the study

The study by Ryu and colleagues used data from the Korean National Health Insurance Service, which covers 97% of the Korean population.² The authors selected patients being treated for invasive breast cancer from January 1, 2003, through December 31, 2018, who were between the ages of 20 and 50 years when the breast cancer diagnosis was first made. Patients with a diagnostic code entered into their electronic health record that was consistent with menopausal status were excluded, along with any patients with a current or prior history of aromatase inhibitor use (for which one must be naturally, medically, or surgically menopausal to use). Based on these exclusions, the study cohort was then assumed to be premenopausal.

The study group included patients diagnosed with invasive breast cancer who were treated with adjuvant hormonal therapy with tamoxifen (n = 34,637), and the control group included patients with invasive breast cancer who were not treated with adjuvant hormonal therapy (n = 43,683). The primary study end point was the finding of endometrial or uterine pathology, including endometrial polyps, endometrial hyperplasia, endometrial cancer, and other uterine malignant neoplasms not originating in the endometrium (for example, uterine sarcomas).

Because this was a retrospective cohort study that included all eligible patients, the 2 groups were not matched. The treatment group was statistically older, had a higher body mass index (BMI) and a larger waist circumference, were more likely to be hypertensive, and included more patients with diabetes than the control group—all known risk factors for endometrial cancer. However, after adjusting for these 4 factors, an increased risk of endometrial cancer remained in the tamoxifen group compared with the control group (hazard ratio [HR], 3.77; 95% confidence interval [CI], 3.04–4.66). In addition, tamoxifen use was independently associated with an increased risk of endometrial polyps (HR, 3.90; 95% CI, 3.65–4.16), endometrial hyperplasia (HR, 5.56; 95% CI, 5.06–6.12), and other uterine cancers (HR, 2.27; 95% CI, 1.54–3.33). In a subgroup analysis, the risk for endometrial cancer was not higher in patients treated for more than 5 years of tamoxifen compared with those treated for 5 years or less.

Study strengths and limitations

A major strength of this study was the large number of study participants (n = 34,637 tamoxifen; n = 43,683 control), the long duration of follow-up (up to 15 years), and use of a single source of data with coverage of nearly the entire population of Korea. While the 2 study populations (tamoxifen vs no tamoxifen) were initially unbalanced in terms of endometrial cancer risk (age, BMI, concurrent diagnoses of hypertension and diabetes), the authors corrected for this with a multivariate analysis.

Furthermore, while the likely homogeneity of the study population may not make the results generalizable, the authors noted that Korean patients have a higher tendency toward early-onset breast cancer. This observation could make this cohort better suited for a study on premenopausal effects of tamoxifen.

Limitations. These data are provocative as they conflict with level 1 evidence based on multiple well-designed, double-blind, placebo-controlled randomized trials in which tamoxifen use for 5 years did not demonstrate a statistically increased risk of endometrial cancer in patients younger than age 50.^3-5 Because of the importance of the question and the implications for many premenopausal women being treated with tamoxifen, we carefully evaluated the study methodology to better understand this discrepancy.

Continue to: Methodological concerns...

In the study by Ryu and colleagues, we found the definition of premenopausal to be problematic. Ultimately, if patients did not have a diagnosis of menopause in the problem summary list, they were assumed to be premenopausal if they were between the ages of 20 and 50 and not taking an aromatase inhibitor. However, important considerations in this population include the cancer stage and treatment regimens that can and do directly impact menopausal status.

Data demonstrate that early-onset breast cancer tends to be associated with more biologically aggressive characteristics that frequently require adjuvant or neoadjuvant chemotherapy.^6,7 This chemotherapy regimen is comprised most commonly of Adriamycin (doxorubicin), paclitaxel, and cyclophosphamide. Cyclophosphamide is an alkylating agent that is a known gonadotoxin, and it often renders patients either temporarily or permanently menopausal due to chemotherapy-induced ovarian failure. Prior studies have demonstrated that for patients in their 40s, approximately 90% of those treated with cyclophosphamide-containing chemo-therapy for breast cancer will experience chemotherapy-induced amenorrhea (CIA).⁸ Although some patients in their 40s with CIA will resume ovarian function, the majority will not.^8,9

Due to the lack of reliability in diagnosing CIA, blood levels of estradiol and follicle stimulating hormone are often necessary for confirmation and, even so, may be only temporary. One prospective analysis of 4 randomized neoadjuvant/adjuvant breast cancer trials used this approach and demonstrated that 85.1% of the study cohort experienced chemotherapy-induced ovarian failure at the end of their treatment, with some fluctuating back to premenopausal hormonal levels at 6 and 12 months.¹⁰

Furthermore, in the study by Ryu and colleagues, there is no description or confirmation of menstrual patterns in the study group to support the diagnosis of ongoing premenopausal status. Data on CIA and loss of ovarian function, therefore, are critical to the accurate categorization of patients as premenopausal or menopausal in this study. The study also relied on consistent and accurate recording of appropriate medical codes to capture a patient’s menopausal status, which is unclear for this particular population and health system.

In evaluating prior research, multiple studies demonstrated no increased risk of endometrial cancer in premenopausal women taking tamoxifen for breast cancer prevention (TABLE).^3,5 These breast cancer prevention trials have several major advantages in assessing tamoxifen-associated endometrial cancer risk for premenopausal patients compared with the current study:

• Both studies were prospective double-blind, placebo-controlled randomized clinical breast cancer prevention trials with carefully designed and measured outcomes.
• Since these were breast cancer prevention trials, administration of gonadotoxic chemotherapy was not a concern. As a result, miscategorizing patients with chemotherapy-induced menopause as premenopausal would not be expected, and premature menopause would not be expected at a higher rate than the general population.
• Careful histories were required prior to study entry and throughout the study, including data on menopausal status and menstrual and uterine bleeding histories.¹¹

In these prevention trials, the effect of tamoxifen on uterine pathology demonstratedrepeatable evidence that there was a statistically significant increased risk of endometrial cancer in postmenopausal women, but there was no similar increased risk of endometrial cancer in premenopausal women (TABLE).^3,5 Interestingly, the magnitude of the endometrial cancer risk found in the premenopausal patients in the study by Ryu and colleagues (RR, 3.77) is comparable to that of the menopausal group in the prevention trials, raising concern that many or most of the patients in the treatment group assumed to be premenopausal may have indeed been “menopausal” for some or all the time they were taking tamoxifen due to the possible aforementioned reasons. ●

Ryu KJ, Kim MS, Lee JY, et al. Risk of endometrial polyps, hyperplasia, carcinoma, and uterine cancer after tamoxifen treatment in premenopausal women with breast cancer. JAMA Netw Open. 2022;5:e2243951.

EXPERT COMMENTARY

Tamoxifen is a selective estrogen receptor modulator (SERM) approved by the US Food and Drug Administration (FDA) for both adjuvant treatment of invasive or metastatic breast cancer with hormone receptor (HR)–positive tumors (duration, 5 to 10 years) and for reduction of future breast cancers in certain high-risk individuals (duration, 5 years). It is also occasionally used for non-FDA approved indications, such as cyclic mastodynia.

Because breast cancer is among the most frequently diagnosed cancers in the United States (297,790 new cases expected in 2023) and approximately 80% are HR-positive tumors that will require hormonal adjuvant therapy,¹ physicians and other gynecologic clinicians should have a working understanding of tamoxifen, including the risks and benefits associated with its use. Among the recognized serious adverse effects of tamoxifen is the increased risk of endometrial cancer in menopausal patients. This adverse effect creates a potential conundrum for clinicians who may be managing patients with tamoxifen to treat or prevent breast cancer, while also increasing the risk of another cancer. Prior prospective studies of tamoxifen have demonstrated a statistically and clinically significant increased risk of endometrial cancer in menopausal patients but not in premenopausal patients.

A recent study challenged those previous findings, suggesting that the risk of endometrial cancer is similar in both premenopausal and postmenopausal patients taking tamoxifen for treatment of breast cancer.²

Details of the study

The study by Ryu and colleagues used data from the Korean National Health Insurance Service, which covers 97% of the Korean population.² The authors selected patients being treated for invasive breast cancer from January 1, 2003, through December 31, 2018, who were between the ages of 20 and 50 years when the breast cancer diagnosis was first made. Patients with a diagnostic code entered into their electronic health record that was consistent with menopausal status were excluded, along with any patients with a current or prior history of aromatase inhibitor use (for which one must be naturally, medically, or surgically menopausal to use). Based on these exclusions, the study cohort was then assumed to be premenopausal.

The study group included patients diagnosed with invasive breast cancer who were treated with adjuvant hormonal therapy with tamoxifen (n = 34,637), and the control group included patients with invasive breast cancer who were not treated with adjuvant hormonal therapy (n = 43,683). The primary study end point was the finding of endometrial or uterine pathology, including endometrial polyps, endometrial hyperplasia, endometrial cancer, and other uterine malignant neoplasms not originating in the endometrium (for example, uterine sarcomas).

Because this was a retrospective cohort study that included all eligible patients, the 2 groups were not matched. The treatment group was statistically older, had a higher body mass index (BMI) and a larger waist circumference, were more likely to be hypertensive, and included more patients with diabetes than the control group—all known risk factors for endometrial cancer. However, after adjusting for these 4 factors, an increased risk of endometrial cancer remained in the tamoxifen group compared with the control group (hazard ratio [HR], 3.77; 95% confidence interval [CI], 3.04–4.66). In addition, tamoxifen use was independently associated with an increased risk of endometrial polyps (HR, 3.90; 95% CI, 3.65–4.16), endometrial hyperplasia (HR, 5.56; 95% CI, 5.06–6.12), and other uterine cancers (HR, 2.27; 95% CI, 1.54–3.33). In a subgroup analysis, the risk for endometrial cancer was not higher in patients treated for more than 5 years of tamoxifen compared with those treated for 5 years or less.

Study strengths and limitations

A major strength of this study was the large number of study participants (n = 34,637 tamoxifen; n = 43,683 control), the long duration of follow-up (up to 15 years), and use of a single source of data with coverage of nearly the entire population of Korea. While the 2 study populations (tamoxifen vs no tamoxifen) were initially unbalanced in terms of endometrial cancer risk (age, BMI, concurrent diagnoses of hypertension and diabetes), the authors corrected for this with a multivariate analysis.

Furthermore, while the likely homogeneity of the study population may not make the results generalizable, the authors noted that Korean patients have a higher tendency toward early-onset breast cancer. This observation could make this cohort better suited for a study on premenopausal effects of tamoxifen.

Limitations. These data are provocative as they conflict with level 1 evidence based on multiple well-designed, double-blind, placebo-controlled randomized trials in which tamoxifen use for 5 years did not demonstrate a statistically increased risk of endometrial cancer in patients younger than age 50.^3-5 Because of the importance of the question and the implications for many premenopausal women being treated with tamoxifen, we carefully evaluated the study methodology to better understand this discrepancy.

Continue to: Methodological concerns...

In the study by Ryu and colleagues, we found the definition of premenopausal to be problematic. Ultimately, if patients did not have a diagnosis of menopause in the problem summary list, they were assumed to be premenopausal if they were between the ages of 20 and 50 and not taking an aromatase inhibitor. However, important considerations in this population include the cancer stage and treatment regimens that can and do directly impact menopausal status.

Data demonstrate that early-onset breast cancer tends to be associated with more biologically aggressive characteristics that frequently require adjuvant or neoadjuvant chemotherapy.^6,7 This chemotherapy regimen is comprised most commonly of Adriamycin (doxorubicin), paclitaxel, and cyclophosphamide. Cyclophosphamide is an alkylating agent that is a known gonadotoxin, and it often renders patients either temporarily or permanently menopausal due to chemotherapy-induced ovarian failure. Prior studies have demonstrated that for patients in their 40s, approximately 90% of those treated with cyclophosphamide-containing chemo-therapy for breast cancer will experience chemotherapy-induced amenorrhea (CIA).⁸ Although some patients in their 40s with CIA will resume ovarian function, the majority will not.^8,9

Due to the lack of reliability in diagnosing CIA, blood levels of estradiol and follicle stimulating hormone are often necessary for confirmation and, even so, may be only temporary. One prospective analysis of 4 randomized neoadjuvant/adjuvant breast cancer trials used this approach and demonstrated that 85.1% of the study cohort experienced chemotherapy-induced ovarian failure at the end of their treatment, with some fluctuating back to premenopausal hormonal levels at 6 and 12 months.¹⁰

Furthermore, in the study by Ryu and colleagues, there is no description or confirmation of menstrual patterns in the study group to support the diagnosis of ongoing premenopausal status. Data on CIA and loss of ovarian function, therefore, are critical to the accurate categorization of patients as premenopausal or menopausal in this study. The study also relied on consistent and accurate recording of appropriate medical codes to capture a patient’s menopausal status, which is unclear for this particular population and health system.

In evaluating prior research, multiple studies demonstrated no increased risk of endometrial cancer in premenopausal women taking tamoxifen for breast cancer prevention (TABLE).^3,5 These breast cancer prevention trials have several major advantages in assessing tamoxifen-associated endometrial cancer risk for premenopausal patients compared with the current study:

• Both studies were prospective double-blind, placebo-controlled randomized clinical breast cancer prevention trials with carefully designed and measured outcomes.
• Since these were breast cancer prevention trials, administration of gonadotoxic chemotherapy was not a concern. As a result, miscategorizing patients with chemotherapy-induced menopause as premenopausal would not be expected, and premature menopause would not be expected at a higher rate than the general population.
• Careful histories were required prior to study entry and throughout the study, including data on menopausal status and menstrual and uterine bleeding histories.¹¹

In these prevention trials, the effect of tamoxifen on uterine pathology demonstratedrepeatable evidence that there was a statistically significant increased risk of endometrial cancer in postmenopausal women, but there was no similar increased risk of endometrial cancer in premenopausal women (TABLE).^3,5 Interestingly, the magnitude of the endometrial cancer risk found in the premenopausal patients in the study by Ryu and colleagues (RR, 3.77) is comparable to that of the menopausal group in the prevention trials, raising concern that many or most of the patients in the treatment group assumed to be premenopausal may have indeed been “menopausal” for some or all the time they were taking tamoxifen due to the possible aforementioned reasons. ●

THE COMPARISON

A A 51-year-old Hispanic man with a squamous cell carcinoma (SCC) of the keratoacanthoma type on the arm.

B A 75-year-old Black man with an SCC of the keratoacanthoma type on the abdomen.

C An African woman with an SCC on the lower lip decades after a large facial burn, which is known as a Marjolin ulcer.

Cutaneous squamous cell carcinoma (SCC) develops from a malignant tumor of the keratinocytes, eccrine glands, or pilosebaceous units that invades the dermis. Risk factors include lighter skin tone, higher cumulative sun exposure, human papillomavirus (HPV) infection, hidradenitis suppurativa (HS), lichen sclerosus, family history of skin cancer,1 and immunosuppression.² It typically affects sun-exposed areas of the body such as the face, scalp, neck, and extensor surfaces of the arms (Figure, A).^3,4 However, in those with darker skin tones, the most common anatomic sites are those that are not exposed to the sun (Figure, B). Squamous cell carcinoma is diagnosed via skin biopsy. Treatment options include surgical excision, destructive methods such as electrodesiccation and curettage, and Mohs micrographic surgery. Cutaneous SCC has a cure rate of more than 95% and a mortality rate of 1.5% to 2% in the United States.³

Photographs courtesy of Richard P. Usatine, MD.

Epidemiology

Squamous cell carcinoma is the most common skin cancer occurring in Black individuals, manifesting primarily in the fifth decade of life.^5-7 It is the second most common skin cancer in White, Hispanic, and Asian individuals and is more common in males.⁸ In a study of organ transplant recipients (N=413), Pritchett et al⁹ reported that HPV infection was a major risk factor in Hispanic patients because 66.7% of those with SCC had a history of HPV. However, HPV is a risk factor for SCC in all ethnic groups.¹⁰

Key clinical features in people with darker skin tones

Anatomic location

• The lower legs and anogenital areas are the most common sites for SCC in patients with skin of color.^4,11
• In Black women, SCC occurs more often on sun-exposed areas such as the arms and legs compared to Black men.^7,12-14
• The genitalia, perianal area, ocular mucosa, and oral mucosa are the least likely areas to be routinely examined, even in skin cancer clinics that see high-risk patients, despite the SCC risk in the anogenital area.^15,16
• Squamous cell carcinoma of the lips and scalp is more likely to occur in Black women vs Black men.^4,7,17 Clinical appearance
• In those with darker skin tones, SCCs may appear hyperpigmented4 or hyperkeratotic with a lack of erythema and an inconsistent appearance.^6,7,18
• A nonhealing ulceration of the skin should prompt a biopsy to rule out SCC.^3,19

Worth noting

In patients with darker skin tones, the risk for SCC increases in areas with chronic inflammation and scarring of the skin.^{4,6,7,11,18,20-22} In Black patients, 20% to 40% of cases of SCC occur in the setting of chronic inflammation and scarring.^6,7,18 Chronic inflammatory conditions include ulcers, lupus vulgaris, discoid lupus erythematosus, and HPV. In patients with discoid lupus erythematosus, there is an additive effect of sun exposure on the scars, which may play a role in the pathogenesis and metastasis risk for skin cancer in Black patients.⁴ Other scarring conditions include thermal or chemical burn scars, areas of physical trauma, and prior sites of radiation treatment.^14,23 Squamous cell carcinoma arising in a burn scar is called a Marjolin ulcer or malignant degeneration of a scar (Figure, C). It is reported more often in lower-income, underresourced countries, which may suggest the need for early detection in populations with skin of color.²⁴

Squamous cell carcinoma is more aggressive in sites that are not exposed to sun compared to sun-exposed areas.^17,25

The risk for SCC is increased in immunocompromised patients,² especially those with HPV.¹⁰

The prevalence of SCC in those with HS is approximately 4.6%. The chronic inflammation and irritation from HS in association with other risk factors such as tobacco use may contribute to the malignant transformation to SCC.²⁶

Health disparity highlight

• The risk for metastasis from SCC is 20% to 40% in Black patients vs 1% to 4% in White patients.^4,6,27
• Penile SCC was associated with a lower overall survival rate in patients of African descent.^20,21
• The increased morbidity and mortality from SCC in patients with skin of color may be attributed to delays in diagnosis and treatment as well as an incomplete understanding of tumor genetics.^4,6,18

Acknowledgment—The authors thank Elyse Gadra (Philadelphia, Pennsylvania) for assistance in the preparation of this manuscript.

THE COMPARISON

A A 51-year-old Hispanic man with a squamous cell carcinoma (SCC) of the keratoacanthoma type on the arm.

B A 75-year-old Black man with an SCC of the keratoacanthoma type on the abdomen.

C An African woman with an SCC on the lower lip decades after a large facial burn, which is known as a Marjolin ulcer.

Cutaneous squamous cell carcinoma (SCC) develops from a malignant tumor of the keratinocytes, eccrine glands, or pilosebaceous units that invades the dermis. Risk factors include lighter skin tone, higher cumulative sun exposure, human papillomavirus (HPV) infection, hidradenitis suppurativa (HS), lichen sclerosus, family history of skin cancer,1 and immunosuppression.² It typically affects sun-exposed areas of the body such as the face, scalp, neck, and extensor surfaces of the arms (Figure, A).^3,4 However, in those with darker skin tones, the most common anatomic sites are those that are not exposed to the sun (Figure, B). Squamous cell carcinoma is diagnosed via skin biopsy. Treatment options include surgical excision, destructive methods such as electrodesiccation and curettage, and Mohs micrographic surgery. Cutaneous SCC has a cure rate of more than 95% and a mortality rate of 1.5% to 2% in the United States.³

Photographs courtesy of Richard P. Usatine, MD.

Epidemiology

Squamous cell carcinoma is the most common skin cancer occurring in Black individuals, manifesting primarily in the fifth decade of life.^5-7 It is the second most common skin cancer in White, Hispanic, and Asian individuals and is more common in males.⁸ In a study of organ transplant recipients (N=413), Pritchett et al⁹ reported that HPV infection was a major risk factor in Hispanic patients because 66.7% of those with SCC had a history of HPV. However, HPV is a risk factor for SCC in all ethnic groups.¹⁰

Key clinical features in people with darker skin tones

Anatomic location

• The lower legs and anogenital areas are the most common sites for SCC in patients with skin of color.^4,11
• In Black women, SCC occurs more often on sun-exposed areas such as the arms and legs compared to Black men.^7,12-14
• The genitalia, perianal area, ocular mucosa, and oral mucosa are the least likely areas to be routinely examined, even in skin cancer clinics that see high-risk patients, despite the SCC risk in the anogenital area.^15,16
• Squamous cell carcinoma of the lips and scalp is more likely to occur in Black women vs Black men.^4,7,17 Clinical appearance
• In those with darker skin tones, SCCs may appear hyperpigmented4 or hyperkeratotic with a lack of erythema and an inconsistent appearance.^6,7,18
• A nonhealing ulceration of the skin should prompt a biopsy to rule out SCC.^3,19

Worth noting

In patients with darker skin tones, the risk for SCC increases in areas with chronic inflammation and scarring of the skin.^{4,6,7,11,18,20-22} In Black patients, 20% to 40% of cases of SCC occur in the setting of chronic inflammation and scarring.^6,7,18 Chronic inflammatory conditions include ulcers, lupus vulgaris, discoid lupus erythematosus, and HPV. In patients with discoid lupus erythematosus, there is an additive effect of sun exposure on the scars, which may play a role in the pathogenesis and metastasis risk for skin cancer in Black patients.⁴ Other scarring conditions include thermal or chemical burn scars, areas of physical trauma, and prior sites of radiation treatment.^14,23 Squamous cell carcinoma arising in a burn scar is called a Marjolin ulcer or malignant degeneration of a scar (Figure, C). It is reported more often in lower-income, underresourced countries, which may suggest the need for early detection in populations with skin of color.²⁴

Squamous cell carcinoma is more aggressive in sites that are not exposed to sun compared to sun-exposed areas.^17,25

The risk for SCC is increased in immunocompromised patients,² especially those with HPV.¹⁰

The prevalence of SCC in those with HS is approximately 4.6%. The chronic inflammation and irritation from HS in association with other risk factors such as tobacco use may contribute to the malignant transformation to SCC.²⁶

Health disparity highlight

• The risk for metastasis from SCC is 20% to 40% in Black patients vs 1% to 4% in White patients.^4,6,27
• Penile SCC was associated with a lower overall survival rate in patients of African descent.^20,21
• The increased morbidity and mortality from SCC in patients with skin of color may be attributed to delays in diagnosis and treatment as well as an incomplete understanding of tumor genetics.^4,6,18

Acknowledgment—The authors thank Elyse Gadra (Philadelphia, Pennsylvania) for assistance in the preparation of this manuscript.

THE COMPARISON

A A 51-year-old Hispanic man with a squamous cell carcinoma (SCC) of the keratoacanthoma type on the arm.

B A 75-year-old Black man with an SCC of the keratoacanthoma type on the abdomen.

C An African woman with an SCC on the lower lip decades after a large facial burn, which is known as a Marjolin ulcer.

Cutaneous squamous cell carcinoma (SCC) develops from a malignant tumor of the keratinocytes, eccrine glands, or pilosebaceous units that invades the dermis. Risk factors include lighter skin tone, higher cumulative sun exposure, human papillomavirus (HPV) infection, hidradenitis suppurativa (HS), lichen sclerosus, family history of skin cancer,1 and immunosuppression.² It typically affects sun-exposed areas of the body such as the face, scalp, neck, and extensor surfaces of the arms (Figure, A).^3,4 However, in those with darker skin tones, the most common anatomic sites are those that are not exposed to the sun (Figure, B). Squamous cell carcinoma is diagnosed via skin biopsy. Treatment options include surgical excision, destructive methods such as electrodesiccation and curettage, and Mohs micrographic surgery. Cutaneous SCC has a cure rate of more than 95% and a mortality rate of 1.5% to 2% in the United States.³

Photographs courtesy of Richard P. Usatine, MD.

Epidemiology

Squamous cell carcinoma is the most common skin cancer occurring in Black individuals, manifesting primarily in the fifth decade of life.^5-7 It is the second most common skin cancer in White, Hispanic, and Asian individuals and is more common in males.⁸ In a study of organ transplant recipients (N=413), Pritchett et al⁹ reported that HPV infection was a major risk factor in Hispanic patients because 66.7% of those with SCC had a history of HPV. However, HPV is a risk factor for SCC in all ethnic groups.¹⁰

Key clinical features in people with darker skin tones

Anatomic location

• The lower legs and anogenital areas are the most common sites for SCC in patients with skin of color.^4,11
• In Black women, SCC occurs more often on sun-exposed areas such as the arms and legs compared to Black men.^7,12-14
• The genitalia, perianal area, ocular mucosa, and oral mucosa are the least likely areas to be routinely examined, even in skin cancer clinics that see high-risk patients, despite the SCC risk in the anogenital area.^15,16
• Squamous cell carcinoma of the lips and scalp is more likely to occur in Black women vs Black men.^4,7,17 Clinical appearance
• In those with darker skin tones, SCCs may appear hyperpigmented4 or hyperkeratotic with a lack of erythema and an inconsistent appearance.^6,7,18
• A nonhealing ulceration of the skin should prompt a biopsy to rule out SCC.^3,19

Worth noting

In patients with darker skin tones, the risk for SCC increases in areas with chronic inflammation and scarring of the skin.^{4,6,7,11,18,20-22} In Black patients, 20% to 40% of cases of SCC occur in the setting of chronic inflammation and scarring.^6,7,18 Chronic inflammatory conditions include ulcers, lupus vulgaris, discoid lupus erythematosus, and HPV. In patients with discoid lupus erythematosus, there is an additive effect of sun exposure on the scars, which may play a role in the pathogenesis and metastasis risk for skin cancer in Black patients.⁴ Other scarring conditions include thermal or chemical burn scars, areas of physical trauma, and prior sites of radiation treatment.^14,23 Squamous cell carcinoma arising in a burn scar is called a Marjolin ulcer or malignant degeneration of a scar (Figure, C). It is reported more often in lower-income, underresourced countries, which may suggest the need for early detection in populations with skin of color.²⁴

Squamous cell carcinoma is more aggressive in sites that are not exposed to sun compared to sun-exposed areas.^17,25

The risk for SCC is increased in immunocompromised patients,² especially those with HPV.¹⁰

The prevalence of SCC in those with HS is approximately 4.6%. The chronic inflammation and irritation from HS in association with other risk factors such as tobacco use may contribute to the malignant transformation to SCC.²⁶

Health disparity highlight

• The risk for metastasis from SCC is 20% to 40% in Black patients vs 1% to 4% in White patients.^4,6,27
• Penile SCC was associated with a lower overall survival rate in patients of African descent.^20,21
• The increased morbidity and mortality from SCC in patients with skin of color may be attributed to delays in diagnosis and treatment as well as an incomplete understanding of tumor genetics.^4,6,18

Acknowledgment—The authors thank Elyse Gadra (Philadelphia, Pennsylvania) for assistance in the preparation of this manuscript.

Lanolin was announced as the Allergen of the Year by the American Contact Dermatitis Society in March 2023.¹ However, allergic contact dermatitis (ACD) to lanolin remains a matter of fierce debate among dermatologists. Herein, we discuss this important contact allergen, emphasizing the controversy behind its allergenicity and nuances to consider when patch testing.

What is Lanolin?

Lanolin is a greasy, yellow, fatlike substance derived from the sebaceous glands of sheep. It is extracted from wool using an intricate process of scouring with dilute alkali, centrifuging, and refining with hot alkali and bleach.² It is comprised of a complex mixture of esters, alcohols, sterols, fatty acids, lactose, and hydrocarbons.³

The hydrophobic property of lanolin helps sheep shed water from their coats.³ In humans, this hydrophobicity benefits the skin by retaining moisture already present in the epidermis. Lanolin can hold as much as twice its weight in water and may reduce transepidermal water loss by 20% to 30%.^4-6 In addition, lanolin maintains tissue breathability, which supports proper gas exchange, promoting wound healing and protecting against infection.^3,7

Many personal care products (PCPs), cosmetics, and topical medicaments contain lanolin, particularly products marketed to help restore dry cracked skin. The range of permitted concentrations of lanolin in over-the-counter products in the United States is 12.5% to 50%.³ Lanolin also may be found in industrial goods. The Table provides a comprehensive list of common items that may contain lanolin.^1,3,8,9

A Wolf in Sheep’s Clothing?

Despite its benefits, lanolin is a potential source of ACD. The first reported positive patch test (PPT) to lanolin worldwide was in the late 1920s.¹⁰ Subsequent cases of ACD to lanolin were described over the next 30 years, reaching a peak of recognition in the latter half of the 20th century with rates of PPT ranging from 0% to 7.4%, though the patient population and lanolin patch-test formulation used differed across studies.⁹ The North American Contact Dermatitis Group observed that 3.3% (1431/43,691) of patients tested from 2001 to 2018 had a PPT to either lanolin alcohol 30% in petrolatum (pet) or Amerchol L101 (10% lanolin alcohol dissolved in mineral oil) 50% pet.¹¹ Compared to patients referred for patch testing, the prevalence of contact allergy to lanolin is lower in the general population; 0.4% of the general population in Europe (N=3119) tested positive to wool alcohols 1.0 mg/cm² on the thin-layer rapid use Epicutaneous (TRUE) test.¹²

Allergic contact dermatitis to lanolin is unrelated to an allergy to wool itself, which probably does not exist, though wool is well known to cause irritant contact dermatitis, particularly in atopic individuals.¹³

Who Is at Risk for Lanolin Allergy?

In a recent comprehensive review of lanolin allergy, Jenkins and Belsito¹ summarized 4 high-risk subgroups of patients for the development of lanolin contact allergy: stasis dermatitis, chronic leg ulcers, atopic dermatitis (AD), and perianal/genital dermatitis. These chronic inflammatory skin conditions may increase the risk for ACD to lanolin via increased exposure in topical therapies and/or increased allergen penetration through an impaired epidermal barrier.^14-16 Demographically, older adults and children are at-risk groups, likely secondary to the higher prevalence of stasis dermatitis/leg ulcers in the former group and AD in the latter.¹

The allergenicity of lanolin is far from straightforward. In 1996, Wolf¹⁷ first described the “lanolin paradox,” modeled after the earlier “paraben paradox” described by Fisher.¹⁸ There are 4 clinical phenomena of the lanolin paradox¹⁷:

• Lanolin generally does not cause contact allergy when found in PCPs but may cause ACD when found in topical medicaments.
• Some patients can use lanolin-containing PCPs on healthy skin without issue but will develop ACD when a lanolin-containing topical medicament is applied to inflamed skin. This is because inflamed skin is more easily sensitized.
• False-negative patch test reactions to pure lanolin may occur. Since Wolf’s¹⁷ initial description of the paradox, free alcohols of lanolin have been found to be its principal allergen, though it also is possible that oxidation of lanolin could generate additional allergenic substances.¹
• Patch testing with wool alcohol 30% can generate both false-negative and false-positive results.

At one extreme, Kligman¹⁹ also was concerned about false-positive reactions to lanolin, describing lanolin allergy as a myth attributed to overzealous patch testing and a failure to appreciate the limitations of this diagnostic modality. Indeed, just having a PPT to lanolin (ie, contact allergy) does not automatically translate to a relevant ACD,¹ and determining the clinical relevance of a PPT is of utmost importance. In 2001, Wakelin et al²⁰ reported that the majority (71% [92/130]) of positive reactions to Amerchol L101 50% or 100% pet showed current clinical relevance. Data from the North American Contact Dermatitis Group in 2009 and in 2022 were similar, with 83.4% (529/634) of positive reactions to lanolin alcohol 30% pet and 86.5% (1238/1431) of positive reactions to Amerchol L101 50% pet classified as current clinical relevance.^11,21 These findings demonstrate that although lanolin may be a weak sensitizer, a PPT usually represents a highly relevant cause of dermatitis.

Considerations for Patch Testing

Considering Wolf’s¹⁷ claim that even pure lanolin is not an appropriate formulation to use for patch testing due to the risk for inaccurate results, you might now be wondering which preparation should be used. Mortensen²² popularized another compound, Amerchol L101, in 1979. In this small study of 60 patients with a PPT to lanolin and/or its derivatives, the highest proportion (37% [22/60]) were positive to Amerchol L101 but negative to wool alcohol 30%, suggesting the need to test to more than one preparation simultaneously.²² In a larger study by Miest et al,²³ 3.9% (11/268) of patients had a PPT to Amerchol L101 50% pet, whereas only 1.1% (3/268) had a PPT to lanolin alcohol 30% pet. This highlighted the importance of including Amerchol L101 when patch testing because it was thought to capture more positive results; however, some studies suggest that Amerchol L101 is not superior at predicting lanolin contact allergy vs lanolin alcohol 30% pet. The risk for an irritant reaction when patch testing with Amerchol L101 should be considered due to its mineral oil component.²⁴

Although there is no universal consensus to date, some investigators suggest patch testing both lanolin alcohol 30% pet and Amerchol L101 50% pet simultaneously.¹ The TRUE test utilizes 1000 µg/cm² of wool alcohols, while the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core 90 Series contain Amerchol L101 50% pet. Patch testing to the most allergenic component of lanolin—the free fatty alcohols (particularly alkane-α,β-diols and alkane-α,ω-diols)—has been suggested,¹ though these formulations are not yet commercially available.

When available, the patient’s own lanolin-containing PCPs should be tested.¹ Performing a repeat open application test (ROAT) to a lanolin-containing product also may be highly useful to distinguish weak-positive from irritant patch test reactions and to determine if sensitized patients can tolerate lanolin-containing products on intact skin. To complete a ROAT, a patient should apply the suspected leave-on product to a patch of unaffected skin (classically the volar forearm) twice daily for at least 10 days.²⁵ If the application site is clear after 10 days, the patient is unlikely to have ACD to the product in question. Compared to patch testing, ROAT more accurately mimics a true use situation, which is particularly important for lanolin given its tendency to preferentially impact damaged or inflamed skin while sparing healthy skin.

Alternatives to Lanolin

Patients with confirmed ACD to lanolin may use plain petrolatum, a safe and inexpensive substitute with equivalent moisturizing efficacy. It can reduce transepidermal water loss by more than 98%,⁴ with essentially no risk for ACD. Humectants such as glycerin, sorbitol, and α-hydroxy acids also have moisturizing properties akin to those of lanolin. In addition, some oils may provide benefit to patients with chronic skin conditions. Sunflower seed oil and extra virgin coconut oil have anti-inflammatory, antibacterial, and barrier repair properties.^26,27 Allergic contact dermatitis to these oils rarely, if ever, occurs.²⁸

Final Interpretation

Lanolin is a well-known yet controversial contact allergen that is widely used in PCPs, cosmetics, topical medicaments, and industrial goods. Lanolin ACD preferentially impacts patients with stasis dermatitis, chronic leg ulcers, AD, and perianal/genital dermatitis. Patch testing with more than one lanolin formulation, including lanolin alcohol 30% pet and/or Amerchol L101 50% pet, as well as testing the patient’s own products may be necessary to confirm the diagnosis. In cases of ACD to lanolin, an alternative agent, such as plain petrolatum, may be used.

Lanolin was announced as the Allergen of the Year by the American Contact Dermatitis Society in March 2023.¹ However, allergic contact dermatitis (ACD) to lanolin remains a matter of fierce debate among dermatologists. Herein, we discuss this important contact allergen, emphasizing the controversy behind its allergenicity and nuances to consider when patch testing.

What is Lanolin?

Lanolin is a greasy, yellow, fatlike substance derived from the sebaceous glands of sheep. It is extracted from wool using an intricate process of scouring with dilute alkali, centrifuging, and refining with hot alkali and bleach.² It is comprised of a complex mixture of esters, alcohols, sterols, fatty acids, lactose, and hydrocarbons.³

The hydrophobic property of lanolin helps sheep shed water from their coats.³ In humans, this hydrophobicity benefits the skin by retaining moisture already present in the epidermis. Lanolin can hold as much as twice its weight in water and may reduce transepidermal water loss by 20% to 30%.^4-6 In addition, lanolin maintains tissue breathability, which supports proper gas exchange, promoting wound healing and protecting against infection.^3,7

Many personal care products (PCPs), cosmetics, and topical medicaments contain lanolin, particularly products marketed to help restore dry cracked skin. The range of permitted concentrations of lanolin in over-the-counter products in the United States is 12.5% to 50%.³ Lanolin also may be found in industrial goods. The Table provides a comprehensive list of common items that may contain lanolin.^1,3,8,9

A Wolf in Sheep’s Clothing?

Despite its benefits, lanolin is a potential source of ACD. The first reported positive patch test (PPT) to lanolin worldwide was in the late 1920s.¹⁰ Subsequent cases of ACD to lanolin were described over the next 30 years, reaching a peak of recognition in the latter half of the 20th century with rates of PPT ranging from 0% to 7.4%, though the patient population and lanolin patch-test formulation used differed across studies.⁹ The North American Contact Dermatitis Group observed that 3.3% (1431/43,691) of patients tested from 2001 to 2018 had a PPT to either lanolin alcohol 30% in petrolatum (pet) or Amerchol L101 (10% lanolin alcohol dissolved in mineral oil) 50% pet.¹¹ Compared to patients referred for patch testing, the prevalence of contact allergy to lanolin is lower in the general population; 0.4% of the general population in Europe (N=3119) tested positive to wool alcohols 1.0 mg/cm² on the thin-layer rapid use Epicutaneous (TRUE) test.¹²

Allergic contact dermatitis to lanolin is unrelated to an allergy to wool itself, which probably does not exist, though wool is well known to cause irritant contact dermatitis, particularly in atopic individuals.¹³

Who Is at Risk for Lanolin Allergy?

In a recent comprehensive review of lanolin allergy, Jenkins and Belsito¹ summarized 4 high-risk subgroups of patients for the development of lanolin contact allergy: stasis dermatitis, chronic leg ulcers, atopic dermatitis (AD), and perianal/genital dermatitis. These chronic inflammatory skin conditions may increase the risk for ACD to lanolin via increased exposure in topical therapies and/or increased allergen penetration through an impaired epidermal barrier.^14-16 Demographically, older adults and children are at-risk groups, likely secondary to the higher prevalence of stasis dermatitis/leg ulcers in the former group and AD in the latter.¹

The allergenicity of lanolin is far from straightforward. In 1996, Wolf¹⁷ first described the “lanolin paradox,” modeled after the earlier “paraben paradox” described by Fisher.¹⁸ There are 4 clinical phenomena of the lanolin paradox¹⁷:

• Lanolin generally does not cause contact allergy when found in PCPs but may cause ACD when found in topical medicaments.
• Some patients can use lanolin-containing PCPs on healthy skin without issue but will develop ACD when a lanolin-containing topical medicament is applied to inflamed skin. This is because inflamed skin is more easily sensitized.
• False-negative patch test reactions to pure lanolin may occur. Since Wolf’s¹⁷ initial description of the paradox, free alcohols of lanolin have been found to be its principal allergen, though it also is possible that oxidation of lanolin could generate additional allergenic substances.¹
• Patch testing with wool alcohol 30% can generate both false-negative and false-positive results.

At one extreme, Kligman¹⁹ also was concerned about false-positive reactions to lanolin, describing lanolin allergy as a myth attributed to overzealous patch testing and a failure to appreciate the limitations of this diagnostic modality. Indeed, just having a PPT to lanolin (ie, contact allergy) does not automatically translate to a relevant ACD,¹ and determining the clinical relevance of a PPT is of utmost importance. In 2001, Wakelin et al²⁰ reported that the majority (71% [92/130]) of positive reactions to Amerchol L101 50% or 100% pet showed current clinical relevance. Data from the North American Contact Dermatitis Group in 2009 and in 2022 were similar, with 83.4% (529/634) of positive reactions to lanolin alcohol 30% pet and 86.5% (1238/1431) of positive reactions to Amerchol L101 50% pet classified as current clinical relevance.^11,21 These findings demonstrate that although lanolin may be a weak sensitizer, a PPT usually represents a highly relevant cause of dermatitis.

Considerations for Patch Testing

Considering Wolf’s¹⁷ claim that even pure lanolin is not an appropriate formulation to use for patch testing due to the risk for inaccurate results, you might now be wondering which preparation should be used. Mortensen²² popularized another compound, Amerchol L101, in 1979. In this small study of 60 patients with a PPT to lanolin and/or its derivatives, the highest proportion (37% [22/60]) were positive to Amerchol L101 but negative to wool alcohol 30%, suggesting the need to test to more than one preparation simultaneously.²² In a larger study by Miest et al,²³ 3.9% (11/268) of patients had a PPT to Amerchol L101 50% pet, whereas only 1.1% (3/268) had a PPT to lanolin alcohol 30% pet. This highlighted the importance of including Amerchol L101 when patch testing because it was thought to capture more positive results; however, some studies suggest that Amerchol L101 is not superior at predicting lanolin contact allergy vs lanolin alcohol 30% pet. The risk for an irritant reaction when patch testing with Amerchol L101 should be considered due to its mineral oil component.²⁴

Although there is no universal consensus to date, some investigators suggest patch testing both lanolin alcohol 30% pet and Amerchol L101 50% pet simultaneously.¹ The TRUE test utilizes 1000 µg/cm² of wool alcohols, while the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core 90 Series contain Amerchol L101 50% pet. Patch testing to the most allergenic component of lanolin—the free fatty alcohols (particularly alkane-α,β-diols and alkane-α,ω-diols)—has been suggested,¹ though these formulations are not yet commercially available.

When available, the patient’s own lanolin-containing PCPs should be tested.¹ Performing a repeat open application test (ROAT) to a lanolin-containing product also may be highly useful to distinguish weak-positive from irritant patch test reactions and to determine if sensitized patients can tolerate lanolin-containing products on intact skin. To complete a ROAT, a patient should apply the suspected leave-on product to a patch of unaffected skin (classically the volar forearm) twice daily for at least 10 days.²⁵ If the application site is clear after 10 days, the patient is unlikely to have ACD to the product in question. Compared to patch testing, ROAT more accurately mimics a true use situation, which is particularly important for lanolin given its tendency to preferentially impact damaged or inflamed skin while sparing healthy skin.

Alternatives to Lanolin

Patients with confirmed ACD to lanolin may use plain petrolatum, a safe and inexpensive substitute with equivalent moisturizing efficacy. It can reduce transepidermal water loss by more than 98%,⁴ with essentially no risk for ACD. Humectants such as glycerin, sorbitol, and α-hydroxy acids also have moisturizing properties akin to those of lanolin. In addition, some oils may provide benefit to patients with chronic skin conditions. Sunflower seed oil and extra virgin coconut oil have anti-inflammatory, antibacterial, and barrier repair properties.^26,27 Allergic contact dermatitis to these oils rarely, if ever, occurs.²⁸

Final Interpretation

Lanolin is a well-known yet controversial contact allergen that is widely used in PCPs, cosmetics, topical medicaments, and industrial goods. Lanolin ACD preferentially impacts patients with stasis dermatitis, chronic leg ulcers, AD, and perianal/genital dermatitis. Patch testing with more than one lanolin formulation, including lanolin alcohol 30% pet and/or Amerchol L101 50% pet, as well as testing the patient’s own products may be necessary to confirm the diagnosis. In cases of ACD to lanolin, an alternative agent, such as plain petrolatum, may be used.

Lanolin was announced as the Allergen of the Year by the American Contact Dermatitis Society in March 2023.¹ However, allergic contact dermatitis (ACD) to lanolin remains a matter of fierce debate among dermatologists. Herein, we discuss this important contact allergen, emphasizing the controversy behind its allergenicity and nuances to consider when patch testing.

What is Lanolin?

Lanolin is a greasy, yellow, fatlike substance derived from the sebaceous glands of sheep. It is extracted from wool using an intricate process of scouring with dilute alkali, centrifuging, and refining with hot alkali and bleach.² It is comprised of a complex mixture of esters, alcohols, sterols, fatty acids, lactose, and hydrocarbons.³

The hydrophobic property of lanolin helps sheep shed water from their coats.³ In humans, this hydrophobicity benefits the skin by retaining moisture already present in the epidermis. Lanolin can hold as much as twice its weight in water and may reduce transepidermal water loss by 20% to 30%.^4-6 In addition, lanolin maintains tissue breathability, which supports proper gas exchange, promoting wound healing and protecting against infection.^3,7

Many personal care products (PCPs), cosmetics, and topical medicaments contain lanolin, particularly products marketed to help restore dry cracked skin. The range of permitted concentrations of lanolin in over-the-counter products in the United States is 12.5% to 50%.³ Lanolin also may be found in industrial goods. The Table provides a comprehensive list of common items that may contain lanolin.^1,3,8,9

A Wolf in Sheep’s Clothing?

Despite its benefits, lanolin is a potential source of ACD. The first reported positive patch test (PPT) to lanolin worldwide was in the late 1920s.¹⁰ Subsequent cases of ACD to lanolin were described over the next 30 years, reaching a peak of recognition in the latter half of the 20th century with rates of PPT ranging from 0% to 7.4%, though the patient population and lanolin patch-test formulation used differed across studies.⁹ The North American Contact Dermatitis Group observed that 3.3% (1431/43,691) of patients tested from 2001 to 2018 had a PPT to either lanolin alcohol 30% in petrolatum (pet) or Amerchol L101 (10% lanolin alcohol dissolved in mineral oil) 50% pet.¹¹ Compared to patients referred for patch testing, the prevalence of contact allergy to lanolin is lower in the general population; 0.4% of the general population in Europe (N=3119) tested positive to wool alcohols 1.0 mg/cm² on the thin-layer rapid use Epicutaneous (TRUE) test.¹²

Allergic contact dermatitis to lanolin is unrelated to an allergy to wool itself, which probably does not exist, though wool is well known to cause irritant contact dermatitis, particularly in atopic individuals.¹³

Who Is at Risk for Lanolin Allergy?

In a recent comprehensive review of lanolin allergy, Jenkins and Belsito¹ summarized 4 high-risk subgroups of patients for the development of lanolin contact allergy: stasis dermatitis, chronic leg ulcers, atopic dermatitis (AD), and perianal/genital dermatitis. These chronic inflammatory skin conditions may increase the risk for ACD to lanolin via increased exposure in topical therapies and/or increased allergen penetration through an impaired epidermal barrier.^14-16 Demographically, older adults and children are at-risk groups, likely secondary to the higher prevalence of stasis dermatitis/leg ulcers in the former group and AD in the latter.¹

The allergenicity of lanolin is far from straightforward. In 1996, Wolf¹⁷ first described the “lanolin paradox,” modeled after the earlier “paraben paradox” described by Fisher.¹⁸ There are 4 clinical phenomena of the lanolin paradox¹⁷:

• Lanolin generally does not cause contact allergy when found in PCPs but may cause ACD when found in topical medicaments.
• Some patients can use lanolin-containing PCPs on healthy skin without issue but will develop ACD when a lanolin-containing topical medicament is applied to inflamed skin. This is because inflamed skin is more easily sensitized.
• False-negative patch test reactions to pure lanolin may occur. Since Wolf’s¹⁷ initial description of the paradox, free alcohols of lanolin have been found to be its principal allergen, though it also is possible that oxidation of lanolin could generate additional allergenic substances.¹
• Patch testing with wool alcohol 30% can generate both false-negative and false-positive results.

At one extreme, Kligman¹⁹ also was concerned about false-positive reactions to lanolin, describing lanolin allergy as a myth attributed to overzealous patch testing and a failure to appreciate the limitations of this diagnostic modality. Indeed, just having a PPT to lanolin (ie, contact allergy) does not automatically translate to a relevant ACD,¹ and determining the clinical relevance of a PPT is of utmost importance. In 2001, Wakelin et al²⁰ reported that the majority (71% [92/130]) of positive reactions to Amerchol L101 50% or 100% pet showed current clinical relevance. Data from the North American Contact Dermatitis Group in 2009 and in 2022 were similar, with 83.4% (529/634) of positive reactions to lanolin alcohol 30% pet and 86.5% (1238/1431) of positive reactions to Amerchol L101 50% pet classified as current clinical relevance.^11,21 These findings demonstrate that although lanolin may be a weak sensitizer, a PPT usually represents a highly relevant cause of dermatitis.

Considerations for Patch Testing

Considering Wolf’s¹⁷ claim that even pure lanolin is not an appropriate formulation to use for patch testing due to the risk for inaccurate results, you might now be wondering which preparation should be used. Mortensen²² popularized another compound, Amerchol L101, in 1979. In this small study of 60 patients with a PPT to lanolin and/or its derivatives, the highest proportion (37% [22/60]) were positive to Amerchol L101 but negative to wool alcohol 30%, suggesting the need to test to more than one preparation simultaneously.²² In a larger study by Miest et al,²³ 3.9% (11/268) of patients had a PPT to Amerchol L101 50% pet, whereas only 1.1% (3/268) had a PPT to lanolin alcohol 30% pet. This highlighted the importance of including Amerchol L101 when patch testing because it was thought to capture more positive results; however, some studies suggest that Amerchol L101 is not superior at predicting lanolin contact allergy vs lanolin alcohol 30% pet. The risk for an irritant reaction when patch testing with Amerchol L101 should be considered due to its mineral oil component.²⁴

Although there is no universal consensus to date, some investigators suggest patch testing both lanolin alcohol 30% pet and Amerchol L101 50% pet simultaneously.¹ The TRUE test utilizes 1000 µg/cm² of wool alcohols, while the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core 90 Series contain Amerchol L101 50% pet. Patch testing to the most allergenic component of lanolin—the free fatty alcohols (particularly alkane-α,β-diols and alkane-α,ω-diols)—has been suggested,¹ though these formulations are not yet commercially available.

When available, the patient’s own lanolin-containing PCPs should be tested.¹ Performing a repeat open application test (ROAT) to a lanolin-containing product also may be highly useful to distinguish weak-positive from irritant patch test reactions and to determine if sensitized patients can tolerate lanolin-containing products on intact skin. To complete a ROAT, a patient should apply the suspected leave-on product to a patch of unaffected skin (classically the volar forearm) twice daily for at least 10 days.²⁵ If the application site is clear after 10 days, the patient is unlikely to have ACD to the product in question. Compared to patch testing, ROAT more accurately mimics a true use situation, which is particularly important for lanolin given its tendency to preferentially impact damaged or inflamed skin while sparing healthy skin.

Alternatives to Lanolin

Patients with confirmed ACD to lanolin may use plain petrolatum, a safe and inexpensive substitute with equivalent moisturizing efficacy. It can reduce transepidermal water loss by more than 98%,⁴ with essentially no risk for ACD. Humectants such as glycerin, sorbitol, and α-hydroxy acids also have moisturizing properties akin to those of lanolin. In addition, some oils may provide benefit to patients with chronic skin conditions. Sunflower seed oil and extra virgin coconut oil have anti-inflammatory, antibacterial, and barrier repair properties.^26,27 Allergic contact dermatitis to these oils rarely, if ever, occurs.²⁸

Final Interpretation

Lanolin is a well-known yet controversial contact allergen that is widely used in PCPs, cosmetics, topical medicaments, and industrial goods. Lanolin ACD preferentially impacts patients with stasis dermatitis, chronic leg ulcers, AD, and perianal/genital dermatitis. Patch testing with more than one lanolin formulation, including lanolin alcohol 30% pet and/or Amerchol L101 50% pet, as well as testing the patient’s own products may be necessary to confirm the diagnosis. In cases of ACD to lanolin, an alternative agent, such as plain petrolatum, may be used.

The Diagnosis: Localized Cutaneous Argyria

The differential diagnosis of an enlarging pigmented lesion is broad, including various neoplasms, pigmented deep fungal infections, and cutaneous deposits secondary to systemic or topical medications or other exogenous substances. In our patient, identification of black particulate material on biopsy prompted further questioning. After the sinus tract persisted for 6 months, our patient’s infectious disease physician started applying silver nitrate at 3-week intervals to minimize drainage, exudate, and granulation tissue formation. After 3 months, marked pigmentation of the skin around the sinus tract was noted.

Argyria is a rare skin disorder that results from deposition of silver via localized exposure or systemic ingestion. Discoloration can either be reversible or irreversible, usually dependent on the length of silver exposure.¹ Affected individuals exhibit blue-gray pigmentation of the skin that may be localized or diffuse. Photoactivated reduction of silver salts leads to conversion to elemental silver in the skin.² Although argyria is most common on sun-exposed areas, the mucosae and nails may be involved in systemic cases. The etiology of argyria includes occupational exposure by ingestion of dust or traumatic cutaneous exposure in jewelry manufacturing, mining, or photographic or radiograph manufacturing. Other sources of localized argyria include prolonged contact with topical silver nitrate or silver sulfadiazine for wound care, silver-coated jewelry or piercings, acupuncture, tooth restoration procedures using dental amalgam, silver-containing surgical implants, or other silver-containing medications or wound dressings. Discontinuing contact with the source of silver minimizes further pigmentation, and excision of deposits may be helpful in some instances.³

Histopathologic findings in argyria may be subtle and diverse. Small particulate material may be apparent on careful examination at high magnification only, and the depth of deposition can depend on the etiology of absorption or implantation as well as the length of exposure. Short-term exposure may be associated with deposition of dark, brown-black, coarse granules confined to the stratum corneum.¹ Frequently, cases of argyria reveal small, extracellular, brown-black, pigmented granules in a bandlike distribution primarily around vasculature, eccrine glands, perineural tissue, hair follicles, or arrector pili muscles or free in the dermis around collagen bundles. The granules can be highlighted by dark-field microscopy that will display scattered, refractile, white particles, described as a “stars in heaven” pattern.³ Rare ochre-colored collagen bundles have been reported in some cases, described as a pseudo-ochronosis pattern of argyria.⁴

Given the clinical history in our patient, a melanocytic lesion was considered but was excluded based on the histopathologic findings. Regressed melanoma clinically may resemble cutaneous silver deposition, as tumoral melanosis can be associated with an intense blue-black presentation. Histopathology will reveal an absence of melanocytes with residual coarse melanin in melanophages (Figure 1) rather than the particulate material associated with silver deposition. Although argyria can be associated with increased melanin in the basal epidermal keratinocytes and melanophages in the papillary dermis, silver granules can be distinguished by their uniform appearance and location throughout the skin (dermis, around vasculature/adnexal structures vs melanin in melanophages and basal epidermal keratinocytes).^3,5,6

Blue nevi typically present as well-circumscribed, blue to gray or even dark brown lesions most often located on the arms, legs, head, and neck. Histopathology reveals spindle-shaped dendritic melanocytes dissecting through collagen bundles in the dermis with melanophages (Figure 2). Pigmentation may vary from extensive to little or even none. Blue nevi are demarcated and may be associated with dermal sclerosis.⁷

Drug-induced hyperpigmentation has a variable presentation both clinically and histologically depending on the type of drug implicated. Tetracyclines, particularly minocycline, are known culprits of drug-induced pigmentation, which can present as blue-gray to brown discoloration in at least 3 classically described patterns: (1) blue-black pigmentation around scars or prior inflammatory sites, (2) blue-black pigmentation on the shins or upper extremities, or (3) brown pigmentation in photosensitive areas. Histopathology reveals brown-black granules intracellularly in macrophages or fibroblasts or localized around vessels or eccrine glands (Figure 3). Special stains such as Perls Prussian blue or Fontana-Masson may highlight the pigmented granules. Widespread pigmentation in other organs, such as the thyroid, and history of long-standing tetracycline use are helpful clues to distinguish drug-induced pigmentation from other entities.⁸

Tattoo ink reaction frequently presents as an irregular pigmented lesion that can have associated features of inflammation including rash, erythema, and swelling. Histopathology reveals small clumped pigment in the dermis localized either extracellularly preferentially around vascular structures and collagen fibers or intracellularly in macrophages or fibroblasts (Figure 4). Considering the pigment is foreign material, a mixed inflammatory infiltrate can be present or more rarely the presence of pigment may induce pseudoepitheliomatous hyperplasia. The inflammatory reaction pattern on histology can vary, but granulomatous and lichenoid patterns frequently have been described. Other helpful clues to suggest tattoo pigment include refractile granules under polarized light and multiple pigmented colors.³

Dermal melanocytosis also may be considered, which consists of blue-gray irregular macules to patches on the skin that are frequently present at birth but may develop later in life. Histopathology reveals pigmented dendritic to spindle-shaped dermal melanocytes and melanophages dissecting between collagen fibers localized to the deep dermis. In addition, some hematologic or vascular disorders, including resolving hemorrhage or cyanosis, may be considered in the clinical differential. Deposition disorders such as chrysiasis and ochronosis could exhibit clinical or histopathologic similarities.^3,8

Occasionally, prolonged use of topical silver nitrate may result in a pigmented lesion that mimics a melanocytic neoplasm or other pigmented lesions. However, these conditions can be readily differentiated by their characteristic histopathologic findings along with detailed clinical history.

The Diagnosis: Localized Cutaneous Argyria

The differential diagnosis of an enlarging pigmented lesion is broad, including various neoplasms, pigmented deep fungal infections, and cutaneous deposits secondary to systemic or topical medications or other exogenous substances. In our patient, identification of black particulate material on biopsy prompted further questioning. After the sinus tract persisted for 6 months, our patient’s infectious disease physician started applying silver nitrate at 3-week intervals to minimize drainage, exudate, and granulation tissue formation. After 3 months, marked pigmentation of the skin around the sinus tract was noted.

Argyria is a rare skin disorder that results from deposition of silver via localized exposure or systemic ingestion. Discoloration can either be reversible or irreversible, usually dependent on the length of silver exposure.¹ Affected individuals exhibit blue-gray pigmentation of the skin that may be localized or diffuse. Photoactivated reduction of silver salts leads to conversion to elemental silver in the skin.² Although argyria is most common on sun-exposed areas, the mucosae and nails may be involved in systemic cases. The etiology of argyria includes occupational exposure by ingestion of dust or traumatic cutaneous exposure in jewelry manufacturing, mining, or photographic or radiograph manufacturing. Other sources of localized argyria include prolonged contact with topical silver nitrate or silver sulfadiazine for wound care, silver-coated jewelry or piercings, acupuncture, tooth restoration procedures using dental amalgam, silver-containing surgical implants, or other silver-containing medications or wound dressings. Discontinuing contact with the source of silver minimizes further pigmentation, and excision of deposits may be helpful in some instances.³

Histopathologic findings in argyria may be subtle and diverse. Small particulate material may be apparent on careful examination at high magnification only, and the depth of deposition can depend on the etiology of absorption or implantation as well as the length of exposure. Short-term exposure may be associated with deposition of dark, brown-black, coarse granules confined to the stratum corneum.¹ Frequently, cases of argyria reveal small, extracellular, brown-black, pigmented granules in a bandlike distribution primarily around vasculature, eccrine glands, perineural tissue, hair follicles, or arrector pili muscles or free in the dermis around collagen bundles. The granules can be highlighted by dark-field microscopy that will display scattered, refractile, white particles, described as a “stars in heaven” pattern.³ Rare ochre-colored collagen bundles have been reported in some cases, described as a pseudo-ochronosis pattern of argyria.⁴

Given the clinical history in our patient, a melanocytic lesion was considered but was excluded based on the histopathologic findings. Regressed melanoma clinically may resemble cutaneous silver deposition, as tumoral melanosis can be associated with an intense blue-black presentation. Histopathology will reveal an absence of melanocytes with residual coarse melanin in melanophages (Figure 1) rather than the particulate material associated with silver deposition. Although argyria can be associated with increased melanin in the basal epidermal keratinocytes and melanophages in the papillary dermis, silver granules can be distinguished by their uniform appearance and location throughout the skin (dermis, around vasculature/adnexal structures vs melanin in melanophages and basal epidermal keratinocytes).^3,5,6

Blue nevi typically present as well-circumscribed, blue to gray or even dark brown lesions most often located on the arms, legs, head, and neck. Histopathology reveals spindle-shaped dendritic melanocytes dissecting through collagen bundles in the dermis with melanophages (Figure 2). Pigmentation may vary from extensive to little or even none. Blue nevi are demarcated and may be associated with dermal sclerosis.⁷

Drug-induced hyperpigmentation has a variable presentation both clinically and histologically depending on the type of drug implicated. Tetracyclines, particularly minocycline, are known culprits of drug-induced pigmentation, which can present as blue-gray to brown discoloration in at least 3 classically described patterns: (1) blue-black pigmentation around scars or prior inflammatory sites, (2) blue-black pigmentation on the shins or upper extremities, or (3) brown pigmentation in photosensitive areas. Histopathology reveals brown-black granules intracellularly in macrophages or fibroblasts or localized around vessels or eccrine glands (Figure 3). Special stains such as Perls Prussian blue or Fontana-Masson may highlight the pigmented granules. Widespread pigmentation in other organs, such as the thyroid, and history of long-standing tetracycline use are helpful clues to distinguish drug-induced pigmentation from other entities.⁸

Tattoo ink reaction frequently presents as an irregular pigmented lesion that can have associated features of inflammation including rash, erythema, and swelling. Histopathology reveals small clumped pigment in the dermis localized either extracellularly preferentially around vascular structures and collagen fibers or intracellularly in macrophages or fibroblasts (Figure 4). Considering the pigment is foreign material, a mixed inflammatory infiltrate can be present or more rarely the presence of pigment may induce pseudoepitheliomatous hyperplasia. The inflammatory reaction pattern on histology can vary, but granulomatous and lichenoid patterns frequently have been described. Other helpful clues to suggest tattoo pigment include refractile granules under polarized light and multiple pigmented colors.³

Dermal melanocytosis also may be considered, which consists of blue-gray irregular macules to patches on the skin that are frequently present at birth but may develop later in life. Histopathology reveals pigmented dendritic to spindle-shaped dermal melanocytes and melanophages dissecting between collagen fibers localized to the deep dermis. In addition, some hematologic or vascular disorders, including resolving hemorrhage or cyanosis, may be considered in the clinical differential. Deposition disorders such as chrysiasis and ochronosis could exhibit clinical or histopathologic similarities.^3,8

Occasionally, prolonged use of topical silver nitrate may result in a pigmented lesion that mimics a melanocytic neoplasm or other pigmented lesions. However, these conditions can be readily differentiated by their characteristic histopathologic findings along with detailed clinical history.

The Diagnosis: Localized Cutaneous Argyria

The differential diagnosis of an enlarging pigmented lesion is broad, including various neoplasms, pigmented deep fungal infections, and cutaneous deposits secondary to systemic or topical medications or other exogenous substances. In our patient, identification of black particulate material on biopsy prompted further questioning. After the sinus tract persisted for 6 months, our patient’s infectious disease physician started applying silver nitrate at 3-week intervals to minimize drainage, exudate, and granulation tissue formation. After 3 months, marked pigmentation of the skin around the sinus tract was noted.

Argyria is a rare skin disorder that results from deposition of silver via localized exposure or systemic ingestion. Discoloration can either be reversible or irreversible, usually dependent on the length of silver exposure.¹ Affected individuals exhibit blue-gray pigmentation of the skin that may be localized or diffuse. Photoactivated reduction of silver salts leads to conversion to elemental silver in the skin.² Although argyria is most common on sun-exposed areas, the mucosae and nails may be involved in systemic cases. The etiology of argyria includes occupational exposure by ingestion of dust or traumatic cutaneous exposure in jewelry manufacturing, mining, or photographic or radiograph manufacturing. Other sources of localized argyria include prolonged contact with topical silver nitrate or silver sulfadiazine for wound care, silver-coated jewelry or piercings, acupuncture, tooth restoration procedures using dental amalgam, silver-containing surgical implants, or other silver-containing medications or wound dressings. Discontinuing contact with the source of silver minimizes further pigmentation, and excision of deposits may be helpful in some instances.³

Histopathologic findings in argyria may be subtle and diverse. Small particulate material may be apparent on careful examination at high magnification only, and the depth of deposition can depend on the etiology of absorption or implantation as well as the length of exposure. Short-term exposure may be associated with deposition of dark, brown-black, coarse granules confined to the stratum corneum.¹ Frequently, cases of argyria reveal small, extracellular, brown-black, pigmented granules in a bandlike distribution primarily around vasculature, eccrine glands, perineural tissue, hair follicles, or arrector pili muscles or free in the dermis around collagen bundles. The granules can be highlighted by dark-field microscopy that will display scattered, refractile, white particles, described as a “stars in heaven” pattern.³ Rare ochre-colored collagen bundles have been reported in some cases, described as a pseudo-ochronosis pattern of argyria.⁴

Given the clinical history in our patient, a melanocytic lesion was considered but was excluded based on the histopathologic findings. Regressed melanoma clinically may resemble cutaneous silver deposition, as tumoral melanosis can be associated with an intense blue-black presentation. Histopathology will reveal an absence of melanocytes with residual coarse melanin in melanophages (Figure 1) rather than the particulate material associated with silver deposition. Although argyria can be associated with increased melanin in the basal epidermal keratinocytes and melanophages in the papillary dermis, silver granules can be distinguished by their uniform appearance and location throughout the skin (dermis, around vasculature/adnexal structures vs melanin in melanophages and basal epidermal keratinocytes).^3,5,6

Blue nevi typically present as well-circumscribed, blue to gray or even dark brown lesions most often located on the arms, legs, head, and neck. Histopathology reveals spindle-shaped dendritic melanocytes dissecting through collagen bundles in the dermis with melanophages (Figure 2). Pigmentation may vary from extensive to little or even none. Blue nevi are demarcated and may be associated with dermal sclerosis.⁷

Drug-induced hyperpigmentation has a variable presentation both clinically and histologically depending on the type of drug implicated. Tetracyclines, particularly minocycline, are known culprits of drug-induced pigmentation, which can present as blue-gray to brown discoloration in at least 3 classically described patterns: (1) blue-black pigmentation around scars or prior inflammatory sites, (2) blue-black pigmentation on the shins or upper extremities, or (3) brown pigmentation in photosensitive areas. Histopathology reveals brown-black granules intracellularly in macrophages or fibroblasts or localized around vessels or eccrine glands (Figure 3). Special stains such as Perls Prussian blue or Fontana-Masson may highlight the pigmented granules. Widespread pigmentation in other organs, such as the thyroid, and history of long-standing tetracycline use are helpful clues to distinguish drug-induced pigmentation from other entities.⁸

Tattoo ink reaction frequently presents as an irregular pigmented lesion that can have associated features of inflammation including rash, erythema, and swelling. Histopathology reveals small clumped pigment in the dermis localized either extracellularly preferentially around vascular structures and collagen fibers or intracellularly in macrophages or fibroblasts (Figure 4). Considering the pigment is foreign material, a mixed inflammatory infiltrate can be present or more rarely the presence of pigment may induce pseudoepitheliomatous hyperplasia. The inflammatory reaction pattern on histology can vary, but granulomatous and lichenoid patterns frequently have been described. Other helpful clues to suggest tattoo pigment include refractile granules under polarized light and multiple pigmented colors.³

Dermal melanocytosis also may be considered, which consists of blue-gray irregular macules to patches on the skin that are frequently present at birth but may develop later in life. Histopathology reveals pigmented dendritic to spindle-shaped dermal melanocytes and melanophages dissecting between collagen fibers localized to the deep dermis. In addition, some hematologic or vascular disorders, including resolving hemorrhage or cyanosis, may be considered in the clinical differential. Deposition disorders such as chrysiasis and ochronosis could exhibit clinical or histopathologic similarities.^3,8

Occasionally, prolonged use of topical silver nitrate may result in a pigmented lesion that mimics a melanocytic neoplasm or other pigmented lesions. However, these conditions can be readily differentiated by their characteristic histopathologic findings along with detailed clinical history.

Ferritin is an iron storage protein crucial to human iron homeostasis. Because serum ferritin levels are in dynamic equilibrium with the body’s iron stores, ferritin often is measured as a reflection of iron status; however, ferritin also is an acute-phase reactant whose levels may be nonspecifically elevated in a wide range of inflammatory conditions. The various processes that alter serum ferritin levels complicate the clinical interpretation of this laboratory value. In this article, we review the structure and function of ferritin and provide a guide for clinical use.

Overview of Iron

Iron is an essential element of key biologic functions including DNA synthesis and repair, oxygen transport, and oxidative phosphorylation. The body’s iron stores are mainly derived from internal iron recycling following red blood cell breakdown, while 5% to 10% is supplied by dietary intake.^1-3 Iron metabolism is of particular importance in cells of the reticuloendothelial system (eg, spleen, liver, bone marrow), where excess iron must be appropriately sequestered and from which iron can be mobilized.⁴ Sufficient iron stores are necessary for proper cellular function and survival, as iron is a necessary component of hemoglobin for oxygen delivery, iron-sulfur clusters in electron transport, and enzyme cofactors in other cellular processes.

Although labile pools of biologically active free iron exist in limited amounts within cells, excess free iron can generate free radicals that damage cellular proteins, lipids, and nucleic acids.^5-7 As such, most intracellular iron is captured within ferritin molecules. The excretion of iron is unregulated and occurs through loss in sweat, menstruation, hair shedding, skin desquamation, and enterocyte turnover.⁸ The lack of regulated excretion highlights the need for a tightly regulated system of uptake, transportation, storage, and sequestration to maintain iron homeostasis.

Overview of Ferritin Structure and Function

Ferritin is a key regulator of iron homeostasis that also serves as an important clinical indicator of body iron status. Ferritin mainly is found as an intracellular cytosolic iron storage and detoxification protein structured as a hollow 24-subunit polymer shell that can sequester up to 4500 atoms of iron within its core.^9,10 The 24-mer is composed of both ferritin L (FTL) and ferritin H (FTH) subunits, with dynamic regulation of the H:L ratio dependent on the context and tissue in which ferritin is found.⁶

Ferritin H possesses ferroxidase, which facilitates oxidation of ferrous (Fe²⁺) iron into ferric (Fe³⁺) iron, which can then be incorporated into the mineral core of the ferritin heteropolymer.¹¹ Ferritin L is more abundant in the spleen and liver, while FTH is found predominantly in the heart and kidneys where the increased ferroxidase activity may confer an increased ability to oxidize Fe²⁺ and limit oxidative stress.⁶

Regulation of Ferritin Synthesis and Secretion

Ferritin synthesis is regulated by intracellular nonheme iron levels, governed mainly by an iron response element (IRE) and iron response protein (IRP) translational repression system. Both FTH and FTL messenger RNA (mRNA) contain an IRE that is a regulatory stem-loop structure in the 5´ untranslated region. When the IRE is bound by IRP1 or IRP2, mRNA translation of ferritin subunits is suppressed.⁶ In low iron conditions, IRPs have greater affinity for IRE, and binding suppresses ferritin translation.¹² In high iron conditions, IRPs have a decreased affinity for IRE, and ferritin mRNA synthesis is increased.¹³ Additionally, inflammatory cytokines such as tumor necrosis factor α and IL-1α transcriptionally induce FTH synthesis, resulting in an increased population of H-rich ferritins.^11,14-16 A study using cultured human primary skin fibroblasts demonstrated UV radiation–induced increases in free intracellular iron content.^17,18 Pourzand et al¹⁸ suggested that UV-mediated damage of lysosomal membranes results in leakage of lysosomal proteases into the cytosol, contributing to degradation of intracellular ferritin and subsequent release of iron within skin fibroblasts. The increased intracellular iron downregulates IRPs and increases ferritin mRNA synthesis,¹⁸ consistent with prior findings of increased ferritin synthesis in skin that is induced by UV radiation.¹⁹

Molecular analysis of serum ferritin in iron-overloaded mice revealed that extracellular ferritin found in the serum is composed of a greater fraction of FTL and has lower iron content than intracellular ferritin. The low iron content of serum ferritin compared with intracellular ferritin and transferrin suggests that serum ferritin is not a major pathway of systemic iron transport.¹⁰ However, locally secreted ferritins may play a greater role in iron transport and release in selected tissues. Additionally, in vitro studies of cell cultures from humans and mice have demonstrated the ability of macrophages to secrete ferritin, suggesting that macrophages are an important cellular source of serum ferritin.^10,20 As such, serum ferritin generally may reflect body iron status but more specifically reflects macrophage iron status.¹⁰ Although the exact pathways of ferritin release are unknown, it is hypothesized that ferritin secretion occurs through cytosolic autophagy followed by secretion of proteins from the lysosomal compartment.^10,18,21

Low Ferritin and Iron Deficiency—Although bone marrow biopsy with iron staining remains the gold standard for diagnosis of iron deficiency, serum ferritin is a much more accessible and less invasive tool for evaluation of iron status. A serum ferritin level below 12 μg/L is highly specific for iron depletion,²² with a higher cutoff recommended in clinical practice to improve diagnostic sensitivity.^23,24 Conditions independent of iron deficiency that may reduce serum ferritin include hypothyroidism and ascorbate deficiency, though neither condition has been reported to interfere with appropriate diagnosis of iron deficiency.²⁵ Guyatt et al²⁶ conducted a systematic review of laboratory tests used in the diagnosis of iron deficiency anemia and identified 55 studies suitable for inclusion. Based on an area under the receiver operating characteristic curve (AUROC) of 0.95, serum ferritin values were superior to transferrin saturation (AUROC, 0.74), red cell protoporphyrin (AUROC, 0.77), red cell volume distribution width (AUROC, 0.62), and mean cell volume (AUROC, 0.76) for diagnosis of IDA, verified by histologic examination of aspirated bone marrow.²⁶ The likelihood ratio of iron deficiency begins to decrease for serum ferritin values of 40 μg/L or greater. For patients with inflammatory conditions—patients with concomitant chronic renal failure, inflammatory disease, infection, rheumatoid arthritis, liver disease, inflammatory bowel disease, and malignancy—the likelihood of iron deficiency begins to decrease at serum ferritin levels of 70 μg/L or greater.²⁶ Similarly, the World Health Organization recommends that in adults with infection or inflammation, serum ferritin levels lower than 70 μg/L may be used to indicate iron deficiency.²⁴ A serum ferritin level of 41 μg/L or lower was found to have a sensitivity and specificity of 98% for discriminating between iron-deficiency anemia and anemia of chronic disease (diagnosed based on bone marrow biopsy with iron staining), with an AUROC of 0.98.²⁷ As such, we recommend using a serum ferritin level of 40 μg/L or lower in patients who are otherwise healthy as an indicator of iron deficiency.

The threshold for iron supplementation may vary based on age, sex, and race. In women, ferritin levels increase during menopause and peak after menopause; ferritin levels are higher in men than in women.^28-30 A multisite longitudinal cohort study of 70 women in the United States found that the mean (SD) ferritin valuewas 69.5 (81.7) μg/L premenopause and 128.8 (125.7) μg/L postmenopause (P<.01).³¹ A separate longitudinal survey study of 8564 patients in China found that the mean (SE) ferritin value was 201.55 (3.60) μg/L for men and 80.46 (1.64) μg/L for women (P<.0001).³² Analysis of serum ferritin levels of 3554 male patients from the third National Health and Nutrition Examination Survey demonstrated that patients who self-reported as non-Hispanic Black (n=1616) had significantly higher serum ferritin levels than non-Hispanic White patients (n=1938)(serum ferritin difference of 37.1 μg/L)(P<.0001).³³ The British Society for Haematology guidelines recommend that the threshold of serum ferritin for diagnosing iron deficiency should take into account age-, sex-, and race-based differences.³⁴ Ferritin and Hair—Cutaneous manifestations of iron deficiency include koilonychia, glossitis, pruritus, angular cheilitis, and telogen effluvium (TE).¹ A case-control study of 30 females aged 15 to 45 years demonstrated that the mean (SD) ferritin level was significantly lower in patients with TE than those with no hair loss (16.3 [12.6] ng/mL vs 60.3 [50.1] ng/mL; P<.0001). Using a threshold of 30 μg/L or lower, the investigators found that the odds ratio for TE was 21.0 (95% CI, 4.2-105.0) in patients with low serum ferritin.³⁵

Another retrospective review of 54 patients with diffuse hair loss and 55 controls compared serum vitamin B₁₂, folate, thyroid-stimulating hormone, zinc, ferritin, and 25-hydroxy vitamin D levels between the 2 groups.³⁶ Exclusion criteria were clinical diagnoses of female pattern hair loss (androgenetic alopecia), pregnancy, menopause, metabolic and endocrine disorders, hormone replacement therapy, chemotherapy, immunosuppressive therapy, vitamin and mineral supplementation, scarring alopecia, eating disorders, and restrictive diets. Compared with controls, patients with diffuse nonscarring hair loss were found to have significantly lower ferritin (mean [SD], 14.72 [10.70] ng/mL vs 25.30 [14.41] ng/mL; P<.001) and 25-hydroxy vitamin D levels (mean [SD], 14.03 [8.09] ng/mL vs 17.01 [8.59] ng/mL; P=.01).³⁶

In contrast, a separate case-control study of 381 cases and 76 controls found no increase in the rate of iron deficiency—defined as ferritin ≤15 μg/L or ≤40 μg/L—among women with female pattern hair loss or chronic TE vs controls.³⁷ Taken together, these studies suggest that iron status may play a role in TE, a process that may result from nutritional deficiency, trauma, or physical or psychological stress³⁸; however, there is insufficient evidence to suggest that low iron status impacts androgenetic alopecia, in which its multifactorial pathogenesis implicates genetic and hormonal factors.³⁹ More research is needed to clarify the potential associations between iron deficiency and types of hair loss. Additionally, it is unclear whether iron supplementation improves hair growth parameters such as density and caliber.⁴⁰

Low serum ferritin (<40 μg/L) with concurrent symptoms of iron deficiency, including fatigue, pallor, dyspnea on exertion, or hair loss, should prompt treatment with supplemental iron.^41-43 Generally, ferrous (Fe2⁺) salts are preferred to ferric (Fe3⁺) salts, as the former is more readily absorbed through the duodenal mucosa⁴⁴ and is the more common formulation in commercially available supplements in the United States.⁴⁵ Oral supplementation with ferrous sulfate 325 mg (65 mg elemental iron) tablets is the first-line therapy for iron deficiency anemia.¹ Alternatively, ferrous gluconate 324 mg (38 mg elemental iron) over-the-counter and its liquid form has demonstrated superior absorption compared to ferrous sulfate tablets in a clinical study with peritoneal dialysis patients.^1,46 One study suggested that oral iron 40 to 80 mg should be taken every other day to increase absorption.⁴⁷ Due to improved bioavailability, intravenous iron may be utilized in patients with malabsorption, renal failure, or intolerance to oral iron (including those with gastric ulcers or active inflammatory bowel disease), with the formulation chosen based on underlying comorbidities and potential risks.^1,48 The theoretical risk for potentiating bacterial growth by increasing the amount of unbound iron in the blood raises concerns of iron supplementation in patients with infection or sepsis. Although far from definitive, existing data suggest that risk for infection is greater with intravenous iron supplementation and should be carefully considered prior to use.^49,50Elevated Ferritin—Elevated ferritin may be difficult to interpret given the multitude of conditions that can cause it.^23,51,52 Elevated serum ferritin can be broadly characterized by increased synthesis due to iron overload, increased synthesis due to inflammation, or increased ferritin release from cellular damage.³⁴ Further complicating interpretation is the potential diurnal fluctuations in serum iron levels dependent on dietary intake and timing of laboratory evaluation, choice of assay, differences in reference standards, and variations in calibration procedures that can lead to analytic variability in the measurement of ferritin.^23,53,54

Among healthy patients, serum ferritin is directly proportional to iron status.^9,51 A study utilizing weekly phlebotomy of 22 healthy participants to measure serum ferritin and calculate mobilizable storage iron found a strong positive correlation between the 2 variables (r=0.83, P<.001), with each 1-μg/L increase of serum ferritin corresponding to approximately an 8-mg increase of storage iron; the initial serum ferritin values ranged from 2 to 83 μg/L in females and 36 to 224 μg/L in males.⁵⁵ The correlation of ferritin with iron status also was supported by the significant correlation between the number of transfusions received in patients with transfusion-related iron overload and serum ferritin levels (r=0.89, P<.001), with an average increase of 60 μg/L per transfusion.⁵¹

Clinical guidelines on the interpretation of serum ferritin levels by Cullis et al³⁴ recommend a normal upper limit of 200 μg/L for healthy females and 300 μg/L for healthy males. Outside of clinical syndromes associated with iron overload, Lee and Means⁵⁶ found that serum ferritin of 1000 μg/L or higher was a nonspecific marker of disease, including infection and/or neoplastic disorders. We have adapted these guidelines to propose a workflow for evaluation of serum ferritin levels (Figure). In patients with inflammatory conditions or those affected by metabolic syndrome, elevated serum ferritin does not correlate with body iron status.^57,58 It is believed that inflammatory cytokines, including tumor necrosis factor α and IL-1α, can upregulate ferritin synthesis independent of cellular iron stores.^15,16 Several studies have examined the relationship between insulin resistance and/or metabolic syndrome with serum ferritin levels.^31,32 Han et al³² found that elevated serum ferritin was significantly associated with higher risk for metabolic syndrome in men (P<.0001) but not in women.

Although cutaneous manifestations of iron overload can be seen as skin hyperpigmentation due to increased iron deposits and increased melanin production,²² the effects of elevated ferritin on the skin and hair are not well known. Iron overload is a known trigger of porphyria cutanea tarda (PCT),⁵⁹ a condition in which reduced or absent enzymatic activity of uroporphyrinogen decarboxylase (UROD) leads to build up of toxic porphyrins in various organs.⁶⁰ In the skin, PCT manifests as a blistering photosensitive eruption that may resolve as dyspigmentation, scarring, and milia.⁶¹ Phlebotomy is first-line therapy in PCT to reduce serum iron and subsequent formation of UROD inhibitors, with guidelines suggesting discontinuation of phlebotomy when serum ferritin levels reach 20 ng/mL or lower.⁶⁰ Hyperferritinemia (serum ferritin >500 μg/L) is a common finding in several inflammatory disorders often accompanied by clinically apparent cutaneous symptoms such as adult-onset Still disease,⁶² hemophagocytic lymphohistiocytosis,^63,64 and anti-melanoma differentiation-associated gene 5 dermatomyositis.⁶⁵ Among these conditions, serum ferritin levels have been reported to correlate with disease activity, raising the question of whether ferritin is a bystander or a driver of the underlying pathology.^62,66,67 However, rapid decline of serum ferritin levels with treatment and control of inflammatory cytokines suggest that ferritin is unlikely to contribute to pathology.^62,67

Final Thoughts

Many clinical studies have examined the association between hair health and body iron status, the collective findings of which suggest that iron deficiency may be associated with TE. Among commonly measured serum iron parameters, low ferritin is a highly specific and sensitive marker for diagnosing iron deficiency. Serum ferritin may be a clinically useful tool for ruling out underlying iron deficiency in patients presenting with hair loss. Despite advances in our understanding of the molecular mechanisms of ferritin synthesis and regulation, whether ferritin itself contributes to cutaneous pathology is poorly understood.^35,36,68-74 For patients who are otherwise healthy with low suspicion for inflammatory disorders, chronic systemic illnesses, or malignancy, serum ferritin can be used as an indicator of body iron status. The workup for slightly elevated serum ferritin should be interpreted in the context of other laboratory findings and should be reassessed over time. Serum ferritin levels above 1000 μg/L warrant further investigation into causes such as iron overload conditions and underlying inflammatory conditions or malignancy.

Ferritin is an iron storage protein crucial to human iron homeostasis. Because serum ferritin levels are in dynamic equilibrium with the body’s iron stores, ferritin often is measured as a reflection of iron status; however, ferritin also is an acute-phase reactant whose levels may be nonspecifically elevated in a wide range of inflammatory conditions. The various processes that alter serum ferritin levels complicate the clinical interpretation of this laboratory value. In this article, we review the structure and function of ferritin and provide a guide for clinical use.

Overview of Iron

Iron is an essential element of key biologic functions including DNA synthesis and repair, oxygen transport, and oxidative phosphorylation. The body’s iron stores are mainly derived from internal iron recycling following red blood cell breakdown, while 5% to 10% is supplied by dietary intake.^1-3 Iron metabolism is of particular importance in cells of the reticuloendothelial system (eg, spleen, liver, bone marrow), where excess iron must be appropriately sequestered and from which iron can be mobilized.⁴ Sufficient iron stores are necessary for proper cellular function and survival, as iron is a necessary component of hemoglobin for oxygen delivery, iron-sulfur clusters in electron transport, and enzyme cofactors in other cellular processes.

Although labile pools of biologically active free iron exist in limited amounts within cells, excess free iron can generate free radicals that damage cellular proteins, lipids, and nucleic acids.^5-7 As such, most intracellular iron is captured within ferritin molecules. The excretion of iron is unregulated and occurs through loss in sweat, menstruation, hair shedding, skin desquamation, and enterocyte turnover.⁸ The lack of regulated excretion highlights the need for a tightly regulated system of uptake, transportation, storage, and sequestration to maintain iron homeostasis.

Overview of Ferritin Structure and Function

Ferritin is a key regulator of iron homeostasis that also serves as an important clinical indicator of body iron status. Ferritin mainly is found as an intracellular cytosolic iron storage and detoxification protein structured as a hollow 24-subunit polymer shell that can sequester up to 4500 atoms of iron within its core.^9,10 The 24-mer is composed of both ferritin L (FTL) and ferritin H (FTH) subunits, with dynamic regulation of the H:L ratio dependent on the context and tissue in which ferritin is found.⁶

Ferritin H possesses ferroxidase, which facilitates oxidation of ferrous (Fe²⁺) iron into ferric (Fe³⁺) iron, which can then be incorporated into the mineral core of the ferritin heteropolymer.¹¹ Ferritin L is more abundant in the spleen and liver, while FTH is found predominantly in the heart and kidneys where the increased ferroxidase activity may confer an increased ability to oxidize Fe²⁺ and limit oxidative stress.⁶

Regulation of Ferritin Synthesis and Secretion

Ferritin synthesis is regulated by intracellular nonheme iron levels, governed mainly by an iron response element (IRE) and iron response protein (IRP) translational repression system. Both FTH and FTL messenger RNA (mRNA) contain an IRE that is a regulatory stem-loop structure in the 5´ untranslated region. When the IRE is bound by IRP1 or IRP2, mRNA translation of ferritin subunits is suppressed.⁶ In low iron conditions, IRPs have greater affinity for IRE, and binding suppresses ferritin translation.¹² In high iron conditions, IRPs have a decreased affinity for IRE, and ferritin mRNA synthesis is increased.¹³ Additionally, inflammatory cytokines such as tumor necrosis factor α and IL-1α transcriptionally induce FTH synthesis, resulting in an increased population of H-rich ferritins.^11,14-16 A study using cultured human primary skin fibroblasts demonstrated UV radiation–induced increases in free intracellular iron content.^17,18 Pourzand et al¹⁸ suggested that UV-mediated damage of lysosomal membranes results in leakage of lysosomal proteases into the cytosol, contributing to degradation of intracellular ferritin and subsequent release of iron within skin fibroblasts. The increased intracellular iron downregulates IRPs and increases ferritin mRNA synthesis,¹⁸ consistent with prior findings of increased ferritin synthesis in skin that is induced by UV radiation.¹⁹

Molecular analysis of serum ferritin in iron-overloaded mice revealed that extracellular ferritin found in the serum is composed of a greater fraction of FTL and has lower iron content than intracellular ferritin. The low iron content of serum ferritin compared with intracellular ferritin and transferrin suggests that serum ferritin is not a major pathway of systemic iron transport.¹⁰ However, locally secreted ferritins may play a greater role in iron transport and release in selected tissues. Additionally, in vitro studies of cell cultures from humans and mice have demonstrated the ability of macrophages to secrete ferritin, suggesting that macrophages are an important cellular source of serum ferritin.^10,20 As such, serum ferritin generally may reflect body iron status but more specifically reflects macrophage iron status.¹⁰ Although the exact pathways of ferritin release are unknown, it is hypothesized that ferritin secretion occurs through cytosolic autophagy followed by secretion of proteins from the lysosomal compartment.^10,18,21

Low Ferritin and Iron Deficiency—Although bone marrow biopsy with iron staining remains the gold standard for diagnosis of iron deficiency, serum ferritin is a much more accessible and less invasive tool for evaluation of iron status. A serum ferritin level below 12 μg/L is highly specific for iron depletion,²² with a higher cutoff recommended in clinical practice to improve diagnostic sensitivity.^23,24 Conditions independent of iron deficiency that may reduce serum ferritin include hypothyroidism and ascorbate deficiency, though neither condition has been reported to interfere with appropriate diagnosis of iron deficiency.²⁵ Guyatt et al²⁶ conducted a systematic review of laboratory tests used in the diagnosis of iron deficiency anemia and identified 55 studies suitable for inclusion. Based on an area under the receiver operating characteristic curve (AUROC) of 0.95, serum ferritin values were superior to transferrin saturation (AUROC, 0.74), red cell protoporphyrin (AUROC, 0.77), red cell volume distribution width (AUROC, 0.62), and mean cell volume (AUROC, 0.76) for diagnosis of IDA, verified by histologic examination of aspirated bone marrow.²⁶ The likelihood ratio of iron deficiency begins to decrease for serum ferritin values of 40 μg/L or greater. For patients with inflammatory conditions—patients with concomitant chronic renal failure, inflammatory disease, infection, rheumatoid arthritis, liver disease, inflammatory bowel disease, and malignancy—the likelihood of iron deficiency begins to decrease at serum ferritin levels of 70 μg/L or greater.²⁶ Similarly, the World Health Organization recommends that in adults with infection or inflammation, serum ferritin levels lower than 70 μg/L may be used to indicate iron deficiency.²⁴ A serum ferritin level of 41 μg/L or lower was found to have a sensitivity and specificity of 98% for discriminating between iron-deficiency anemia and anemia of chronic disease (diagnosed based on bone marrow biopsy with iron staining), with an AUROC of 0.98.²⁷ As such, we recommend using a serum ferritin level of 40 μg/L or lower in patients who are otherwise healthy as an indicator of iron deficiency.

The threshold for iron supplementation may vary based on age, sex, and race. In women, ferritin levels increase during menopause and peak after menopause; ferritin levels are higher in men than in women.^28-30 A multisite longitudinal cohort study of 70 women in the United States found that the mean (SD) ferritin valuewas 69.5 (81.7) μg/L premenopause and 128.8 (125.7) μg/L postmenopause (P<.01).³¹ A separate longitudinal survey study of 8564 patients in China found that the mean (SE) ferritin value was 201.55 (3.60) μg/L for men and 80.46 (1.64) μg/L for women (P<.0001).³² Analysis of serum ferritin levels of 3554 male patients from the third National Health and Nutrition Examination Survey demonstrated that patients who self-reported as non-Hispanic Black (n=1616) had significantly higher serum ferritin levels than non-Hispanic White patients (n=1938)(serum ferritin difference of 37.1 μg/L)(P<.0001).³³ The British Society for Haematology guidelines recommend that the threshold of serum ferritin for diagnosing iron deficiency should take into account age-, sex-, and race-based differences.³⁴ Ferritin and Hair—Cutaneous manifestations of iron deficiency include koilonychia, glossitis, pruritus, angular cheilitis, and telogen effluvium (TE).¹ A case-control study of 30 females aged 15 to 45 years demonstrated that the mean (SD) ferritin level was significantly lower in patients with TE than those with no hair loss (16.3 [12.6] ng/mL vs 60.3 [50.1] ng/mL; P<.0001). Using a threshold of 30 μg/L or lower, the investigators found that the odds ratio for TE was 21.0 (95% CI, 4.2-105.0) in patients with low serum ferritin.³⁵

Another retrospective review of 54 patients with diffuse hair loss and 55 controls compared serum vitamin B₁₂, folate, thyroid-stimulating hormone, zinc, ferritin, and 25-hydroxy vitamin D levels between the 2 groups.³⁶ Exclusion criteria were clinical diagnoses of female pattern hair loss (androgenetic alopecia), pregnancy, menopause, metabolic and endocrine disorders, hormone replacement therapy, chemotherapy, immunosuppressive therapy, vitamin and mineral supplementation, scarring alopecia, eating disorders, and restrictive diets. Compared with controls, patients with diffuse nonscarring hair loss were found to have significantly lower ferritin (mean [SD], 14.72 [10.70] ng/mL vs 25.30 [14.41] ng/mL; P<.001) and 25-hydroxy vitamin D levels (mean [SD], 14.03 [8.09] ng/mL vs 17.01 [8.59] ng/mL; P=.01).³⁶

In contrast, a separate case-control study of 381 cases and 76 controls found no increase in the rate of iron deficiency—defined as ferritin ≤15 μg/L or ≤40 μg/L—among women with female pattern hair loss or chronic TE vs controls.³⁷ Taken together, these studies suggest that iron status may play a role in TE, a process that may result from nutritional deficiency, trauma, or physical or psychological stress³⁸; however, there is insufficient evidence to suggest that low iron status impacts androgenetic alopecia, in which its multifactorial pathogenesis implicates genetic and hormonal factors.³⁹ More research is needed to clarify the potential associations between iron deficiency and types of hair loss. Additionally, it is unclear whether iron supplementation improves hair growth parameters such as density and caliber.⁴⁰

Low serum ferritin (<40 μg/L) with concurrent symptoms of iron deficiency, including fatigue, pallor, dyspnea on exertion, or hair loss, should prompt treatment with supplemental iron.^41-43 Generally, ferrous (Fe2⁺) salts are preferred to ferric (Fe3⁺) salts, as the former is more readily absorbed through the duodenal mucosa⁴⁴ and is the more common formulation in commercially available supplements in the United States.⁴⁵ Oral supplementation with ferrous sulfate 325 mg (65 mg elemental iron) tablets is the first-line therapy for iron deficiency anemia.¹ Alternatively, ferrous gluconate 324 mg (38 mg elemental iron) over-the-counter and its liquid form has demonstrated superior absorption compared to ferrous sulfate tablets in a clinical study with peritoneal dialysis patients.^1,46 One study suggested that oral iron 40 to 80 mg should be taken every other day to increase absorption.⁴⁷ Due to improved bioavailability, intravenous iron may be utilized in patients with malabsorption, renal failure, or intolerance to oral iron (including those with gastric ulcers or active inflammatory bowel disease), with the formulation chosen based on underlying comorbidities and potential risks.^1,48 The theoretical risk for potentiating bacterial growth by increasing the amount of unbound iron in the blood raises concerns of iron supplementation in patients with infection or sepsis. Although far from definitive, existing data suggest that risk for infection is greater with intravenous iron supplementation and should be carefully considered prior to use.^49,50Elevated Ferritin—Elevated ferritin may be difficult to interpret given the multitude of conditions that can cause it.^23,51,52 Elevated serum ferritin can be broadly characterized by increased synthesis due to iron overload, increased synthesis due to inflammation, or increased ferritin release from cellular damage.³⁴ Further complicating interpretation is the potential diurnal fluctuations in serum iron levels dependent on dietary intake and timing of laboratory evaluation, choice of assay, differences in reference standards, and variations in calibration procedures that can lead to analytic variability in the measurement of ferritin.^23,53,54

Among healthy patients, serum ferritin is directly proportional to iron status.^9,51 A study utilizing weekly phlebotomy of 22 healthy participants to measure serum ferritin and calculate mobilizable storage iron found a strong positive correlation between the 2 variables (r=0.83, P<.001), with each 1-μg/L increase of serum ferritin corresponding to approximately an 8-mg increase of storage iron; the initial serum ferritin values ranged from 2 to 83 μg/L in females and 36 to 224 μg/L in males.⁵⁵ The correlation of ferritin with iron status also was supported by the significant correlation between the number of transfusions received in patients with transfusion-related iron overload and serum ferritin levels (r=0.89, P<.001), with an average increase of 60 μg/L per transfusion.⁵¹

Clinical guidelines on the interpretation of serum ferritin levels by Cullis et al³⁴ recommend a normal upper limit of 200 μg/L for healthy females and 300 μg/L for healthy males. Outside of clinical syndromes associated with iron overload, Lee and Means⁵⁶ found that serum ferritin of 1000 μg/L or higher was a nonspecific marker of disease, including infection and/or neoplastic disorders. We have adapted these guidelines to propose a workflow for evaluation of serum ferritin levels (Figure). In patients with inflammatory conditions or those affected by metabolic syndrome, elevated serum ferritin does not correlate with body iron status.^57,58 It is believed that inflammatory cytokines, including tumor necrosis factor α and IL-1α, can upregulate ferritin synthesis independent of cellular iron stores.^15,16 Several studies have examined the relationship between insulin resistance and/or metabolic syndrome with serum ferritin levels.^31,32 Han et al³² found that elevated serum ferritin was significantly associated with higher risk for metabolic syndrome in men (P<.0001) but not in women.

Although cutaneous manifestations of iron overload can be seen as skin hyperpigmentation due to increased iron deposits and increased melanin production,²² the effects of elevated ferritin on the skin and hair are not well known. Iron overload is a known trigger of porphyria cutanea tarda (PCT),⁵⁹ a condition in which reduced or absent enzymatic activity of uroporphyrinogen decarboxylase (UROD) leads to build up of toxic porphyrins in various organs.⁶⁰ In the skin, PCT manifests as a blistering photosensitive eruption that may resolve as dyspigmentation, scarring, and milia.⁶¹ Phlebotomy is first-line therapy in PCT to reduce serum iron and subsequent formation of UROD inhibitors, with guidelines suggesting discontinuation of phlebotomy when serum ferritin levels reach 20 ng/mL or lower.⁶⁰ Hyperferritinemia (serum ferritin >500 μg/L) is a common finding in several inflammatory disorders often accompanied by clinically apparent cutaneous symptoms such as adult-onset Still disease,⁶² hemophagocytic lymphohistiocytosis,^63,64 and anti-melanoma differentiation-associated gene 5 dermatomyositis.⁶⁵ Among these conditions, serum ferritin levels have been reported to correlate with disease activity, raising the question of whether ferritin is a bystander or a driver of the underlying pathology.^62,66,67 However, rapid decline of serum ferritin levels with treatment and control of inflammatory cytokines suggest that ferritin is unlikely to contribute to pathology.^62,67

Final Thoughts

Many clinical studies have examined the association between hair health and body iron status, the collective findings of which suggest that iron deficiency may be associated with TE. Among commonly measured serum iron parameters, low ferritin is a highly specific and sensitive marker for diagnosing iron deficiency. Serum ferritin may be a clinically useful tool for ruling out underlying iron deficiency in patients presenting with hair loss. Despite advances in our understanding of the molecular mechanisms of ferritin synthesis and regulation, whether ferritin itself contributes to cutaneous pathology is poorly understood.^35,36,68-74 For patients who are otherwise healthy with low suspicion for inflammatory disorders, chronic systemic illnesses, or malignancy, serum ferritin can be used as an indicator of body iron status. The workup for slightly elevated serum ferritin should be interpreted in the context of other laboratory findings and should be reassessed over time. Serum ferritin levels above 1000 μg/L warrant further investigation into causes such as iron overload conditions and underlying inflammatory conditions or malignancy.

Ferritin is an iron storage protein crucial to human iron homeostasis. Because serum ferritin levels are in dynamic equilibrium with the body’s iron stores, ferritin often is measured as a reflection of iron status; however, ferritin also is an acute-phase reactant whose levels may be nonspecifically elevated in a wide range of inflammatory conditions. The various processes that alter serum ferritin levels complicate the clinical interpretation of this laboratory value. In this article, we review the structure and function of ferritin and provide a guide for clinical use.

Overview of Iron

Iron is an essential element of key biologic functions including DNA synthesis and repair, oxygen transport, and oxidative phosphorylation. The body’s iron stores are mainly derived from internal iron recycling following red blood cell breakdown, while 5% to 10% is supplied by dietary intake.^1-3 Iron metabolism is of particular importance in cells of the reticuloendothelial system (eg, spleen, liver, bone marrow), where excess iron must be appropriately sequestered and from which iron can be mobilized.⁴ Sufficient iron stores are necessary for proper cellular function and survival, as iron is a necessary component of hemoglobin for oxygen delivery, iron-sulfur clusters in electron transport, and enzyme cofactors in other cellular processes.

Although labile pools of biologically active free iron exist in limited amounts within cells, excess free iron can generate free radicals that damage cellular proteins, lipids, and nucleic acids.^5-7 As such, most intracellular iron is captured within ferritin molecules. The excretion of iron is unregulated and occurs through loss in sweat, menstruation, hair shedding, skin desquamation, and enterocyte turnover.⁸ The lack of regulated excretion highlights the need for a tightly regulated system of uptake, transportation, storage, and sequestration to maintain iron homeostasis.

Overview of Ferritin Structure and Function

Ferritin is a key regulator of iron homeostasis that also serves as an important clinical indicator of body iron status. Ferritin mainly is found as an intracellular cytosolic iron storage and detoxification protein structured as a hollow 24-subunit polymer shell that can sequester up to 4500 atoms of iron within its core.^9,10 The 24-mer is composed of both ferritin L (FTL) and ferritin H (FTH) subunits, with dynamic regulation of the H:L ratio dependent on the context and tissue in which ferritin is found.⁶

Ferritin H possesses ferroxidase, which facilitates oxidation of ferrous (Fe²⁺) iron into ferric (Fe³⁺) iron, which can then be incorporated into the mineral core of the ferritin heteropolymer.¹¹ Ferritin L is more abundant in the spleen and liver, while FTH is found predominantly in the heart and kidneys where the increased ferroxidase activity may confer an increased ability to oxidize Fe²⁺ and limit oxidative stress.⁶

Regulation of Ferritin Synthesis and Secretion

Ferritin synthesis is regulated by intracellular nonheme iron levels, governed mainly by an iron response element (IRE) and iron response protein (IRP) translational repression system. Both FTH and FTL messenger RNA (mRNA) contain an IRE that is a regulatory stem-loop structure in the 5´ untranslated region. When the IRE is bound by IRP1 or IRP2, mRNA translation of ferritin subunits is suppressed.⁶ In low iron conditions, IRPs have greater affinity for IRE, and binding suppresses ferritin translation.¹² In high iron conditions, IRPs have a decreased affinity for IRE, and ferritin mRNA synthesis is increased.¹³ Additionally, inflammatory cytokines such as tumor necrosis factor α and IL-1α transcriptionally induce FTH synthesis, resulting in an increased population of H-rich ferritins.^11,14-16 A study using cultured human primary skin fibroblasts demonstrated UV radiation–induced increases in free intracellular iron content.^17,18 Pourzand et al¹⁸ suggested that UV-mediated damage of lysosomal membranes results in leakage of lysosomal proteases into the cytosol, contributing to degradation of intracellular ferritin and subsequent release of iron within skin fibroblasts. The increased intracellular iron downregulates IRPs and increases ferritin mRNA synthesis,¹⁸ consistent with prior findings of increased ferritin synthesis in skin that is induced by UV radiation.¹⁹

Molecular analysis of serum ferritin in iron-overloaded mice revealed that extracellular ferritin found in the serum is composed of a greater fraction of FTL and has lower iron content than intracellular ferritin. The low iron content of serum ferritin compared with intracellular ferritin and transferrin suggests that serum ferritin is not a major pathway of systemic iron transport.¹⁰ However, locally secreted ferritins may play a greater role in iron transport and release in selected tissues. Additionally, in vitro studies of cell cultures from humans and mice have demonstrated the ability of macrophages to secrete ferritin, suggesting that macrophages are an important cellular source of serum ferritin.^10,20 As such, serum ferritin generally may reflect body iron status but more specifically reflects macrophage iron status.¹⁰ Although the exact pathways of ferritin release are unknown, it is hypothesized that ferritin secretion occurs through cytosolic autophagy followed by secretion of proteins from the lysosomal compartment.^10,18,21

Low Ferritin and Iron Deficiency—Although bone marrow biopsy with iron staining remains the gold standard for diagnosis of iron deficiency, serum ferritin is a much more accessible and less invasive tool for evaluation of iron status. A serum ferritin level below 12 μg/L is highly specific for iron depletion,²² with a higher cutoff recommended in clinical practice to improve diagnostic sensitivity.^23,24 Conditions independent of iron deficiency that may reduce serum ferritin include hypothyroidism and ascorbate deficiency, though neither condition has been reported to interfere with appropriate diagnosis of iron deficiency.²⁵ Guyatt et al²⁶ conducted a systematic review of laboratory tests used in the diagnosis of iron deficiency anemia and identified 55 studies suitable for inclusion. Based on an area under the receiver operating characteristic curve (AUROC) of 0.95, serum ferritin values were superior to transferrin saturation (AUROC, 0.74), red cell protoporphyrin (AUROC, 0.77), red cell volume distribution width (AUROC, 0.62), and mean cell volume (AUROC, 0.76) for diagnosis of IDA, verified by histologic examination of aspirated bone marrow.²⁶ The likelihood ratio of iron deficiency begins to decrease for serum ferritin values of 40 μg/L or greater. For patients with inflammatory conditions—patients with concomitant chronic renal failure, inflammatory disease, infection, rheumatoid arthritis, liver disease, inflammatory bowel disease, and malignancy—the likelihood of iron deficiency begins to decrease at serum ferritin levels of 70 μg/L or greater.²⁶ Similarly, the World Health Organization recommends that in adults with infection or inflammation, serum ferritin levels lower than 70 μg/L may be used to indicate iron deficiency.²⁴ A serum ferritin level of 41 μg/L or lower was found to have a sensitivity and specificity of 98% for discriminating between iron-deficiency anemia and anemia of chronic disease (diagnosed based on bone marrow biopsy with iron staining), with an AUROC of 0.98.²⁷ As such, we recommend using a serum ferritin level of 40 μg/L or lower in patients who are otherwise healthy as an indicator of iron deficiency.

The threshold for iron supplementation may vary based on age, sex, and race. In women, ferritin levels increase during menopause and peak after menopause; ferritin levels are higher in men than in women.^28-30 A multisite longitudinal cohort study of 70 women in the United States found that the mean (SD) ferritin valuewas 69.5 (81.7) μg/L premenopause and 128.8 (125.7) μg/L postmenopause (P<.01).³¹ A separate longitudinal survey study of 8564 patients in China found that the mean (SE) ferritin value was 201.55 (3.60) μg/L for men and 80.46 (1.64) μg/L for women (P<.0001).³² Analysis of serum ferritin levels of 3554 male patients from the third National Health and Nutrition Examination Survey demonstrated that patients who self-reported as non-Hispanic Black (n=1616) had significantly higher serum ferritin levels than non-Hispanic White patients (n=1938)(serum ferritin difference of 37.1 μg/L)(P<.0001).³³ The British Society for Haematology guidelines recommend that the threshold of serum ferritin for diagnosing iron deficiency should take into account age-, sex-, and race-based differences.³⁴ Ferritin and Hair—Cutaneous manifestations of iron deficiency include koilonychia, glossitis, pruritus, angular cheilitis, and telogen effluvium (TE).¹ A case-control study of 30 females aged 15 to 45 years demonstrated that the mean (SD) ferritin level was significantly lower in patients with TE than those with no hair loss (16.3 [12.6] ng/mL vs 60.3 [50.1] ng/mL; P<.0001). Using a threshold of 30 μg/L or lower, the investigators found that the odds ratio for TE was 21.0 (95% CI, 4.2-105.0) in patients with low serum ferritin.³⁵

Another retrospective review of 54 patients with diffuse hair loss and 55 controls compared serum vitamin B₁₂, folate, thyroid-stimulating hormone, zinc, ferritin, and 25-hydroxy vitamin D levels between the 2 groups.³⁶ Exclusion criteria were clinical diagnoses of female pattern hair loss (androgenetic alopecia), pregnancy, menopause, metabolic and endocrine disorders, hormone replacement therapy, chemotherapy, immunosuppressive therapy, vitamin and mineral supplementation, scarring alopecia, eating disorders, and restrictive diets. Compared with controls, patients with diffuse nonscarring hair loss were found to have significantly lower ferritin (mean [SD], 14.72 [10.70] ng/mL vs 25.30 [14.41] ng/mL; P<.001) and 25-hydroxy vitamin D levels (mean [SD], 14.03 [8.09] ng/mL vs 17.01 [8.59] ng/mL; P=.01).³⁶

In contrast, a separate case-control study of 381 cases and 76 controls found no increase in the rate of iron deficiency—defined as ferritin ≤15 μg/L or ≤40 μg/L—among women with female pattern hair loss or chronic TE vs controls.³⁷ Taken together, these studies suggest that iron status may play a role in TE, a process that may result from nutritional deficiency, trauma, or physical or psychological stress³⁸; however, there is insufficient evidence to suggest that low iron status impacts androgenetic alopecia, in which its multifactorial pathogenesis implicates genetic and hormonal factors.³⁹ More research is needed to clarify the potential associations between iron deficiency and types of hair loss. Additionally, it is unclear whether iron supplementation improves hair growth parameters such as density and caliber.⁴⁰

Low serum ferritin (<40 μg/L) with concurrent symptoms of iron deficiency, including fatigue, pallor, dyspnea on exertion, or hair loss, should prompt treatment with supplemental iron.^41-43 Generally, ferrous (Fe2⁺) salts are preferred to ferric (Fe3⁺) salts, as the former is more readily absorbed through the duodenal mucosa⁴⁴ and is the more common formulation in commercially available supplements in the United States.⁴⁵ Oral supplementation with ferrous sulfate 325 mg (65 mg elemental iron) tablets is the first-line therapy for iron deficiency anemia.¹ Alternatively, ferrous gluconate 324 mg (38 mg elemental iron) over-the-counter and its liquid form has demonstrated superior absorption compared to ferrous sulfate tablets in a clinical study with peritoneal dialysis patients.^1,46 One study suggested that oral iron 40 to 80 mg should be taken every other day to increase absorption.⁴⁷ Due to improved bioavailability, intravenous iron may be utilized in patients with malabsorption, renal failure, or intolerance to oral iron (including those with gastric ulcers or active inflammatory bowel disease), with the formulation chosen based on underlying comorbidities and potential risks.^1,48 The theoretical risk for potentiating bacterial growth by increasing the amount of unbound iron in the blood raises concerns of iron supplementation in patients with infection or sepsis. Although far from definitive, existing data suggest that risk for infection is greater with intravenous iron supplementation and should be carefully considered prior to use.^49,50Elevated Ferritin—Elevated ferritin may be difficult to interpret given the multitude of conditions that can cause it.^23,51,52 Elevated serum ferritin can be broadly characterized by increased synthesis due to iron overload, increased synthesis due to inflammation, or increased ferritin release from cellular damage.³⁴ Further complicating interpretation is the potential diurnal fluctuations in serum iron levels dependent on dietary intake and timing of laboratory evaluation, choice of assay, differences in reference standards, and variations in calibration procedures that can lead to analytic variability in the measurement of ferritin.^23,53,54

Among healthy patients, serum ferritin is directly proportional to iron status.^9,51 A study utilizing weekly phlebotomy of 22 healthy participants to measure serum ferritin and calculate mobilizable storage iron found a strong positive correlation between the 2 variables (r=0.83, P<.001), with each 1-μg/L increase of serum ferritin corresponding to approximately an 8-mg increase of storage iron; the initial serum ferritin values ranged from 2 to 83 μg/L in females and 36 to 224 μg/L in males.⁵⁵ The correlation of ferritin with iron status also was supported by the significant correlation between the number of transfusions received in patients with transfusion-related iron overload and serum ferritin levels (r=0.89, P<.001), with an average increase of 60 μg/L per transfusion.⁵¹

Clinical guidelines on the interpretation of serum ferritin levels by Cullis et al³⁴ recommend a normal upper limit of 200 μg/L for healthy females and 300 μg/L for healthy males. Outside of clinical syndromes associated with iron overload, Lee and Means⁵⁶ found that serum ferritin of 1000 μg/L or higher was a nonspecific marker of disease, including infection and/or neoplastic disorders. We have adapted these guidelines to propose a workflow for evaluation of serum ferritin levels (Figure). In patients with inflammatory conditions or those affected by metabolic syndrome, elevated serum ferritin does not correlate with body iron status.^57,58 It is believed that inflammatory cytokines, including tumor necrosis factor α and IL-1α, can upregulate ferritin synthesis independent of cellular iron stores.^15,16 Several studies have examined the relationship between insulin resistance and/or metabolic syndrome with serum ferritin levels.^31,32 Han et al³² found that elevated serum ferritin was significantly associated with higher risk for metabolic syndrome in men (P<.0001) but not in women.

Although cutaneous manifestations of iron overload can be seen as skin hyperpigmentation due to increased iron deposits and increased melanin production,²² the effects of elevated ferritin on the skin and hair are not well known. Iron overload is a known trigger of porphyria cutanea tarda (PCT),⁵⁹ a condition in which reduced or absent enzymatic activity of uroporphyrinogen decarboxylase (UROD) leads to build up of toxic porphyrins in various organs.⁶⁰ In the skin, PCT manifests as a blistering photosensitive eruption that may resolve as dyspigmentation, scarring, and milia.⁶¹ Phlebotomy is first-line therapy in PCT to reduce serum iron and subsequent formation of UROD inhibitors, with guidelines suggesting discontinuation of phlebotomy when serum ferritin levels reach 20 ng/mL or lower.⁶⁰ Hyperferritinemia (serum ferritin >500 μg/L) is a common finding in several inflammatory disorders often accompanied by clinically apparent cutaneous symptoms such as adult-onset Still disease,⁶² hemophagocytic lymphohistiocytosis,^63,64 and anti-melanoma differentiation-associated gene 5 dermatomyositis.⁶⁵ Among these conditions, serum ferritin levels have been reported to correlate with disease activity, raising the question of whether ferritin is a bystander or a driver of the underlying pathology.^62,66,67 However, rapid decline of serum ferritin levels with treatment and control of inflammatory cytokines suggest that ferritin is unlikely to contribute to pathology.^62,67

Final Thoughts

Many clinical studies have examined the association between hair health and body iron status, the collective findings of which suggest that iron deficiency may be associated with TE. Among commonly measured serum iron parameters, low ferritin is a highly specific and sensitive marker for diagnosing iron deficiency. Serum ferritin may be a clinically useful tool for ruling out underlying iron deficiency in patients presenting with hair loss. Despite advances in our understanding of the molecular mechanisms of ferritin synthesis and regulation, whether ferritin itself contributes to cutaneous pathology is poorly understood.^35,36,68-74 For patients who are otherwise healthy with low suspicion for inflammatory disorders, chronic systemic illnesses, or malignancy, serum ferritin can be used as an indicator of body iron status. The workup for slightly elevated serum ferritin should be interpreted in the context of other laboratory findings and should be reassessed over time. Serum ferritin levels above 1000 μg/L warrant further investigation into causes such as iron overload conditions and underlying inflammatory conditions or malignancy.

Nail surgical procedures including biopsies, correction of onychocryptosis and other deformities, and excision of tumors are essential for diagnosing and treating nail disorders. Nail surgery often is perceived by dermatologists as a difficult-to-perform, high-risk procedure associated with patient anxiety, pain, and permanent scarring, which may limit implementation. Misconceptions about nail surgical techniques, aftercare, and patient outcomes are prevalent, and a paucity of nail surgery randomized clinical trials hinder formulation of standardized guidelines.¹ In a survey-based study of 95 dermatology residency programs (240 total respondents), 58% of residents said they performed 10 or fewer nail procedures, 10% performed more than 10 procedures, 25% only observed nail procedures, 4% were exposed by lecture only, and 1% had no exposure; 30% said they felt incompetent performing nail biopsies.² In a retrospective study of nail biopsies performed from 2012 to 2017 in the Medicare Provider Utilization and Payment Database, only 0.28% and 1.01% of all general dermatologists and Mohs surgeons, respectively, performed nail biopsies annually.³ A minimally invasive nail surgery technique is essential to alleviating dermatologist and patient apprehension, which may lead to greater adoption and improved outcomes.

Reduce Patient Anxiety During Nail Surgery

The prospect of undergoing nail surgery can be psychologically distressing to patients because the nail unit is highly sensitive, intraoperative and postoperative pain are common concerns, patient education materials generally are scarce and inaccurate,⁴ and procedures are performed under local anesthesia with the patient fully awake. In a prospective study of 48 patients undergoing nail surgery, the median preoperative Spielberger State-Trait Anxiety Inventory level was 42.00 (IQR, 6.50).⁵ Patient distress may be minimized by providing verbal and written educational materials, discussing expectations, and preoperatively using fast-acting benzodiazepines when necessary.⁶ Utilizing a sleep mask,⁷ stress ball,⁸ music,⁹ and/or virtual reality¹⁰ also may reduce patient anxiety during nail surgery.

Use Proper Anesthetic Techniques

Proper anesthetic technique is crucial to achieve the optimal patient experience during nail surgery. With a wing block, the anesthetic is injected into 3 points: (1) the proximal nail fold, (2) the medial/lateral fold, and (3) the hyponychium. The wing block is the preferred technique by many nail surgeons because the second and third injections are given in skin that is already anesthetized, reducing patient discomfort to a single pinprick¹¹; additionally, there is lower postoperative paresthesia risk with the wing block compared with other digital nerve blocks.¹² Ropivacaine, a fast-acting and long-acting anesthetic, is preferred over lidocaine to minimize immediate postoperative pain. Buffering the anesthetic solution to physiologic pH and slow infiltration can reduce pain during infiltration.¹² Distraction¹² provided by ethyl chloride refrigerant spray, an air-cooling device,¹³ or vibration also can reduce pain during anesthesia.

Punch Biopsy and Excision Tips

The punch biopsy is a minimally invasive method for diagnosing various neoplastic and inflammatory nail unit conditions, except for pigmented lesions.¹² For polydactylous nail conditions requiring biopsy, a digit on the nondominant hand should be selected if possible. The punch is applied directly to the nail plate and twisted with downward pressure until the bone is reached, with the instrument withdrawn slowly to prevent surrounding nail plate detachment. Hemostasis is easily achieved with direct pressure and/or use of epinephrine or ropivacaine during anesthesia, and a digital tourniquet generally is not required. Applying microporous polysaccharide hemospheres powder¹⁴ or kaolin-impregnated gauze¹⁵ with direct pressure is helpful in managing continued bleeding following nail surgery. Punching through the proximal nail matrix should be avoided to prevent permanent onychodystrophy.

A tangential matrix shave biopsy requires a more practiced technique and is preferred for sampling longitudinal melanonychia. A partial proximal nail plate avulsion adequately exposes the origin of pigment and avoids complete avulsion, which may cause more onychodystrophy.¹⁶ For broad erythronychia, a total nail avulsion may be necessary. For narrow, well-defined erythronychia, a less-invasive approach such as trap-door avulsion, longitudinal nail strip, or lateral nail plate curl, depending on the etiology, often is sufficient. Tissue excision should be tailored to the specific etiology, with localized excision sufficient for glomus tumors; onychopapillomas require tangential excision of the distal matrix, entire nail bed, and hyperkeratotic papule at the hyponychium. Pushing the cuticle with an elevator/spatula instead of making 2 tangential incisions on the proximal nail fold has been suggested to decrease postoperative paronychia risk.¹² A Teflon-coated blade is used to achieve a smooth cut with minimal drag, enabling collection of specimens less than 1 mm thick, which provides sufficient nail matrix epithelium and dermis for histologic examination.¹⁶ After obtaining the specimen, the avulsed nail plate may be sutured back to the nail bed using a rapidly absorbable suture such as polyglactin 910, serving as a temporary biological dressing and splint for the nail unit during healing.¹² In a retrospective study of 30 patients with longitudinal melanonychia undergoing tangential matrix excision, 27% (8/30) developed postoperative onychodystrophy.¹⁷ Although this technique carries relatively lower risk of permanent onychodystrophy compared to other methods, it still is important to acknowledge during the preoperative consent process.¹²

The lateral longitudinal excision is a valuable technique for diagnosing nail unit inflammatory conditions. Classically, a longitudinal sample including the proximal nail fold, complete matrix, lateral plate, lateral nail fold, hyponychium, and distal tip skin is obtained, with a 10% narrowing of the nail plate expected. If the lateral horn of the nail matrix is missed, permanent lateral malalignment and spicule formation are potential risks. To minimize narrowing of the nail plate and postoperative paronychia, a longitudinal nail strip—where the proximal nail fold and matrix are left intact—is an alternative technique.¹⁸

Pain Management Approaches

Appropriate postoperative pain management is crucial for optimizing patient outcomes. In a prospective study of 20 patients undergoing nail biopsy, the mean pain score 6 to 12 hours postprocedure was 5.7 on a scale of 0 to 10. Patients with presurgery pain vs those without experienced significantly higher pain levels both during anesthesia and after surgery (both P<.05).¹⁹ Therefore, a personalized approach to pain management based on presence of presurgical pain is warranted. In a randomized clinical trial of 16 patients anesthetized with lidocaine 2% and intraoperative infiltration with a combination of ropivacaine 0.5 mL and triamcinolone (10 mg/mL [0.5 mL]) vs lidocaine 2% alone, the intraoperative mixture reduced postoperative pain (mean pain score, 2 of 10 at 48 hours postprocedure vs 7.88 of 10 in the control group [P<.001]).²⁰

A Cochrane review of 4 unpublished dental and orthopedic surgery studies showed that gabapentin is superior to placebo in the treatment of acute postoperative pain. Therefore, a single dose of gabapentin (250 mg) may be considered in patients at risk for high postoperative pain.²¹ In a randomized double-blind trial of 210 Mohs micrographic surgery patients, those receiving acetaminophen and ibuprofen reported lower pain scores at 2, 4, 8, and 12 hours postprocedure compared with patients taking acetaminophen and codeine or acetaminophen alone.²² However, the role of opioids in pain management following nail surgery has not been adequately studied.

Wound Care

An efficient dressing protects the surgical wound, facilitates healing, and provides comfort. In our experience, an initial layer of petrolatum-impregnated gauze followed by a pressure-padded bandage consisting of folded dry gauze secured in place with longitudinally applied tape to avoid a tourniquet effect is effective for nail surgical wounds. As the last step, self-adherent elastic wrap is applied around the digit and extended proximally to prevent a tourniquet effect.²³

Final Thoughts

Due to the intricate anatomy of the nail unit, nail surgeries are inherently more invasive than most dermatologic surgical procedures. It is crucial to adopt a minimally invasive approach to reduce tissue damage and potential complications in both the short-term and long-term. Adopting this approach may substantially improve patient outcomes and enhance diagnostic and treatment efficacy.

Nail surgical procedures including biopsies, correction of onychocryptosis and other deformities, and excision of tumors are essential for diagnosing and treating nail disorders. Nail surgery often is perceived by dermatologists as a difficult-to-perform, high-risk procedure associated with patient anxiety, pain, and permanent scarring, which may limit implementation. Misconceptions about nail surgical techniques, aftercare, and patient outcomes are prevalent, and a paucity of nail surgery randomized clinical trials hinder formulation of standardized guidelines.¹ In a survey-based study of 95 dermatology residency programs (240 total respondents), 58% of residents said they performed 10 or fewer nail procedures, 10% performed more than 10 procedures, 25% only observed nail procedures, 4% were exposed by lecture only, and 1% had no exposure; 30% said they felt incompetent performing nail biopsies.² In a retrospective study of nail biopsies performed from 2012 to 2017 in the Medicare Provider Utilization and Payment Database, only 0.28% and 1.01% of all general dermatologists and Mohs surgeons, respectively, performed nail biopsies annually.³ A minimally invasive nail surgery technique is essential to alleviating dermatologist and patient apprehension, which may lead to greater adoption and improved outcomes.

Reduce Patient Anxiety During Nail Surgery

The prospect of undergoing nail surgery can be psychologically distressing to patients because the nail unit is highly sensitive, intraoperative and postoperative pain are common concerns, patient education materials generally are scarce and inaccurate,⁴ and procedures are performed under local anesthesia with the patient fully awake. In a prospective study of 48 patients undergoing nail surgery, the median preoperative Spielberger State-Trait Anxiety Inventory level was 42.00 (IQR, 6.50).⁵ Patient distress may be minimized by providing verbal and written educational materials, discussing expectations, and preoperatively using fast-acting benzodiazepines when necessary.⁶ Utilizing a sleep mask,⁷ stress ball,⁸ music,⁹ and/or virtual reality¹⁰ also may reduce patient anxiety during nail surgery.

Use Proper Anesthetic Techniques

Proper anesthetic technique is crucial to achieve the optimal patient experience during nail surgery. With a wing block, the anesthetic is injected into 3 points: (1) the proximal nail fold, (2) the medial/lateral fold, and (3) the hyponychium. The wing block is the preferred technique by many nail surgeons because the second and third injections are given in skin that is already anesthetized, reducing patient discomfort to a single pinprick¹¹; additionally, there is lower postoperative paresthesia risk with the wing block compared with other digital nerve blocks.¹² Ropivacaine, a fast-acting and long-acting anesthetic, is preferred over lidocaine to minimize immediate postoperative pain. Buffering the anesthetic solution to physiologic pH and slow infiltration can reduce pain during infiltration.¹² Distraction¹² provided by ethyl chloride refrigerant spray, an air-cooling device,¹³ or vibration also can reduce pain during anesthesia.

Punch Biopsy and Excision Tips

The punch biopsy is a minimally invasive method for diagnosing various neoplastic and inflammatory nail unit conditions, except for pigmented lesions.¹² For polydactylous nail conditions requiring biopsy, a digit on the nondominant hand should be selected if possible. The punch is applied directly to the nail plate and twisted with downward pressure until the bone is reached, with the instrument withdrawn slowly to prevent surrounding nail plate detachment. Hemostasis is easily achieved with direct pressure and/or use of epinephrine or ropivacaine during anesthesia, and a digital tourniquet generally is not required. Applying microporous polysaccharide hemospheres powder¹⁴ or kaolin-impregnated gauze¹⁵ with direct pressure is helpful in managing continued bleeding following nail surgery. Punching through the proximal nail matrix should be avoided to prevent permanent onychodystrophy.

A tangential matrix shave biopsy requires a more practiced technique and is preferred for sampling longitudinal melanonychia. A partial proximal nail plate avulsion adequately exposes the origin of pigment and avoids complete avulsion, which may cause more onychodystrophy.¹⁶ For broad erythronychia, a total nail avulsion may be necessary. For narrow, well-defined erythronychia, a less-invasive approach such as trap-door avulsion, longitudinal nail strip, or lateral nail plate curl, depending on the etiology, often is sufficient. Tissue excision should be tailored to the specific etiology, with localized excision sufficient for glomus tumors; onychopapillomas require tangential excision of the distal matrix, entire nail bed, and hyperkeratotic papule at the hyponychium. Pushing the cuticle with an elevator/spatula instead of making 2 tangential incisions on the proximal nail fold has been suggested to decrease postoperative paronychia risk.¹² A Teflon-coated blade is used to achieve a smooth cut with minimal drag, enabling collection of specimens less than 1 mm thick, which provides sufficient nail matrix epithelium and dermis for histologic examination.¹⁶ After obtaining the specimen, the avulsed nail plate may be sutured back to the nail bed using a rapidly absorbable suture such as polyglactin 910, serving as a temporary biological dressing and splint for the nail unit during healing.¹² In a retrospective study of 30 patients with longitudinal melanonychia undergoing tangential matrix excision, 27% (8/30) developed postoperative onychodystrophy.¹⁷ Although this technique carries relatively lower risk of permanent onychodystrophy compared to other methods, it still is important to acknowledge during the preoperative consent process.¹²

The lateral longitudinal excision is a valuable technique for diagnosing nail unit inflammatory conditions. Classically, a longitudinal sample including the proximal nail fold, complete matrix, lateral plate, lateral nail fold, hyponychium, and distal tip skin is obtained, with a 10% narrowing of the nail plate expected. If the lateral horn of the nail matrix is missed, permanent lateral malalignment and spicule formation are potential risks. To minimize narrowing of the nail plate and postoperative paronychia, a longitudinal nail strip—where the proximal nail fold and matrix are left intact—is an alternative technique.¹⁸

Pain Management Approaches

Appropriate postoperative pain management is crucial for optimizing patient outcomes. In a prospective study of 20 patients undergoing nail biopsy, the mean pain score 6 to 12 hours postprocedure was 5.7 on a scale of 0 to 10. Patients with presurgery pain vs those without experienced significantly higher pain levels both during anesthesia and after surgery (both P<.05).¹⁹ Therefore, a personalized approach to pain management based on presence of presurgical pain is warranted. In a randomized clinical trial of 16 patients anesthetized with lidocaine 2% and intraoperative infiltration with a combination of ropivacaine 0.5 mL and triamcinolone (10 mg/mL [0.5 mL]) vs lidocaine 2% alone, the intraoperative mixture reduced postoperative pain (mean pain score, 2 of 10 at 48 hours postprocedure vs 7.88 of 10 in the control group [P<.001]).²⁰

A Cochrane review of 4 unpublished dental and orthopedic surgery studies showed that gabapentin is superior to placebo in the treatment of acute postoperative pain. Therefore, a single dose of gabapentin (250 mg) may be considered in patients at risk for high postoperative pain.²¹ In a randomized double-blind trial of 210 Mohs micrographic surgery patients, those receiving acetaminophen and ibuprofen reported lower pain scores at 2, 4, 8, and 12 hours postprocedure compared with patients taking acetaminophen and codeine or acetaminophen alone.²² However, the role of opioids in pain management following nail surgery has not been adequately studied.

Wound Care

An efficient dressing protects the surgical wound, facilitates healing, and provides comfort. In our experience, an initial layer of petrolatum-impregnated gauze followed by a pressure-padded bandage consisting of folded dry gauze secured in place with longitudinally applied tape to avoid a tourniquet effect is effective for nail surgical wounds. As the last step, self-adherent elastic wrap is applied around the digit and extended proximally to prevent a tourniquet effect.²³

Final Thoughts

Due to the intricate anatomy of the nail unit, nail surgeries are inherently more invasive than most dermatologic surgical procedures. It is crucial to adopt a minimally invasive approach to reduce tissue damage and potential complications in both the short-term and long-term. Adopting this approach may substantially improve patient outcomes and enhance diagnostic and treatment efficacy.

Nail surgical procedures including biopsies, correction of onychocryptosis and other deformities, and excision of tumors are essential for diagnosing and treating nail disorders. Nail surgery often is perceived by dermatologists as a difficult-to-perform, high-risk procedure associated with patient anxiety, pain, and permanent scarring, which may limit implementation. Misconceptions about nail surgical techniques, aftercare, and patient outcomes are prevalent, and a paucity of nail surgery randomized clinical trials hinder formulation of standardized guidelines.¹ In a survey-based study of 95 dermatology residency programs (240 total respondents), 58% of residents said they performed 10 or fewer nail procedures, 10% performed more than 10 procedures, 25% only observed nail procedures, 4% were exposed by lecture only, and 1% had no exposure; 30% said they felt incompetent performing nail biopsies.² In a retrospective study of nail biopsies performed from 2012 to 2017 in the Medicare Provider Utilization and Payment Database, only 0.28% and 1.01% of all general dermatologists and Mohs surgeons, respectively, performed nail biopsies annually.³ A minimally invasive nail surgery technique is essential to alleviating dermatologist and patient apprehension, which may lead to greater adoption and improved outcomes.

Reduce Patient Anxiety During Nail Surgery

The prospect of undergoing nail surgery can be psychologically distressing to patients because the nail unit is highly sensitive, intraoperative and postoperative pain are common concerns, patient education materials generally are scarce and inaccurate,⁴ and procedures are performed under local anesthesia with the patient fully awake. In a prospective study of 48 patients undergoing nail surgery, the median preoperative Spielberger State-Trait Anxiety Inventory level was 42.00 (IQR, 6.50).⁵ Patient distress may be minimized by providing verbal and written educational materials, discussing expectations, and preoperatively using fast-acting benzodiazepines when necessary.⁶ Utilizing a sleep mask,⁷ stress ball,⁸ music,⁹ and/or virtual reality¹⁰ also may reduce patient anxiety during nail surgery.

Use Proper Anesthetic Techniques

Proper anesthetic technique is crucial to achieve the optimal patient experience during nail surgery. With a wing block, the anesthetic is injected into 3 points: (1) the proximal nail fold, (2) the medial/lateral fold, and (3) the hyponychium. The wing block is the preferred technique by many nail surgeons because the second and third injections are given in skin that is already anesthetized, reducing patient discomfort to a single pinprick¹¹; additionally, there is lower postoperative paresthesia risk with the wing block compared with other digital nerve blocks.¹² Ropivacaine, a fast-acting and long-acting anesthetic, is preferred over lidocaine to minimize immediate postoperative pain. Buffering the anesthetic solution to physiologic pH and slow infiltration can reduce pain during infiltration.¹² Distraction¹² provided by ethyl chloride refrigerant spray, an air-cooling device,¹³ or vibration also can reduce pain during anesthesia.

Punch Biopsy and Excision Tips

The punch biopsy is a minimally invasive method for diagnosing various neoplastic and inflammatory nail unit conditions, except for pigmented lesions.¹² For polydactylous nail conditions requiring biopsy, a digit on the nondominant hand should be selected if possible. The punch is applied directly to the nail plate and twisted with downward pressure until the bone is reached, with the instrument withdrawn slowly to prevent surrounding nail plate detachment. Hemostasis is easily achieved with direct pressure and/or use of epinephrine or ropivacaine during anesthesia, and a digital tourniquet generally is not required. Applying microporous polysaccharide hemospheres powder¹⁴ or kaolin-impregnated gauze¹⁵ with direct pressure is helpful in managing continued bleeding following nail surgery. Punching through the proximal nail matrix should be avoided to prevent permanent onychodystrophy.

A tangential matrix shave biopsy requires a more practiced technique and is preferred for sampling longitudinal melanonychia. A partial proximal nail plate avulsion adequately exposes the origin of pigment and avoids complete avulsion, which may cause more onychodystrophy.¹⁶ For broad erythronychia, a total nail avulsion may be necessary. For narrow, well-defined erythronychia, a less-invasive approach such as trap-door avulsion, longitudinal nail strip, or lateral nail plate curl, depending on the etiology, often is sufficient. Tissue excision should be tailored to the specific etiology, with localized excision sufficient for glomus tumors; onychopapillomas require tangential excision of the distal matrix, entire nail bed, and hyperkeratotic papule at the hyponychium. Pushing the cuticle with an elevator/spatula instead of making 2 tangential incisions on the proximal nail fold has been suggested to decrease postoperative paronychia risk.¹² A Teflon-coated blade is used to achieve a smooth cut with minimal drag, enabling collection of specimens less than 1 mm thick, which provides sufficient nail matrix epithelium and dermis for histologic examination.¹⁶ After obtaining the specimen, the avulsed nail plate may be sutured back to the nail bed using a rapidly absorbable suture such as polyglactin 910, serving as a temporary biological dressing and splint for the nail unit during healing.¹² In a retrospective study of 30 patients with longitudinal melanonychia undergoing tangential matrix excision, 27% (8/30) developed postoperative onychodystrophy.¹⁷ Although this technique carries relatively lower risk of permanent onychodystrophy compared to other methods, it still is important to acknowledge during the preoperative consent process.¹²

The lateral longitudinal excision is a valuable technique for diagnosing nail unit inflammatory conditions. Classically, a longitudinal sample including the proximal nail fold, complete matrix, lateral plate, lateral nail fold, hyponychium, and distal tip skin is obtained, with a 10% narrowing of the nail plate expected. If the lateral horn of the nail matrix is missed, permanent lateral malalignment and spicule formation are potential risks. To minimize narrowing of the nail plate and postoperative paronychia, a longitudinal nail strip—where the proximal nail fold and matrix are left intact—is an alternative technique.¹⁸

Pain Management Approaches

Appropriate postoperative pain management is crucial for optimizing patient outcomes. In a prospective study of 20 patients undergoing nail biopsy, the mean pain score 6 to 12 hours postprocedure was 5.7 on a scale of 0 to 10. Patients with presurgery pain vs those without experienced significantly higher pain levels both during anesthesia and after surgery (both P<.05).¹⁹ Therefore, a personalized approach to pain management based on presence of presurgical pain is warranted. In a randomized clinical trial of 16 patients anesthetized with lidocaine 2% and intraoperative infiltration with a combination of ropivacaine 0.5 mL and triamcinolone (10 mg/mL [0.5 mL]) vs lidocaine 2% alone, the intraoperative mixture reduced postoperative pain (mean pain score, 2 of 10 at 48 hours postprocedure vs 7.88 of 10 in the control group [P<.001]).²⁰

A Cochrane review of 4 unpublished dental and orthopedic surgery studies showed that gabapentin is superior to placebo in the treatment of acute postoperative pain. Therefore, a single dose of gabapentin (250 mg) may be considered in patients at risk for high postoperative pain.²¹ In a randomized double-blind trial of 210 Mohs micrographic surgery patients, those receiving acetaminophen and ibuprofen reported lower pain scores at 2, 4, 8, and 12 hours postprocedure compared with patients taking acetaminophen and codeine or acetaminophen alone.²² However, the role of opioids in pain management following nail surgery has not been adequately studied.

Wound Care

An efficient dressing protects the surgical wound, facilitates healing, and provides comfort. In our experience, an initial layer of petrolatum-impregnated gauze followed by a pressure-padded bandage consisting of folded dry gauze secured in place with longitudinally applied tape to avoid a tourniquet effect is effective for nail surgical wounds. As the last step, self-adherent elastic wrap is applied around the digit and extended proximally to prevent a tourniquet effect.²³

Final Thoughts

Due to the intricate anatomy of the nail unit, nail surgeries are inherently more invasive than most dermatologic surgical procedures. It is crucial to adopt a minimally invasive approach to reduce tissue damage and potential complications in both the short-term and long-term. Adopting this approach may substantially improve patient outcomes and enhance diagnostic and treatment efficacy.

Physicians have some of the highest rates of burnout among all professions.¹ Complicating matters is that clinicians (including residents)² may avoid seeking treatment out of fear it will affect their license or privileges.³ In this article, we consider burnout in greater detail, as well as ways of successfully addressing the level of burnout in the profession (FIGURE 1), including steps individual practitioners, health care entities, and regulators should consider to reduce burnout and its harmful effects.

How burnout becomes a problem

Six general factors are commonly identified as leading to clinician career dissatisfaction and burnout:⁴

1. work overload

2. lack of autonomy and control

3. inadequate rewards, financial and  otherwise

4. work-home schedules

5. perception of lack of fairness

6. values conflict between the clinician and employer (including a breakdown of professional community). 

At the top of the list of causes of burnout is often “administrative and bureaucratic headaches.”⁵ More specifically, electronic health records (EHRs), including computerized order entry, is commonly cited as a major cause of burnout.^6,7 According to some studies, clinicians spend as much as 49% of working time doing clerical work,⁸ and studies found the extension of work into home life.⁹

Increased measurement of performance metrics in health care services are a significant contributor to physician burnout.¹⁰ These include pressure to see more patients, perform more procedures, and respond quickly to patient requests (eg, through email).⁷ As we will see, medical malpractice cases, or the risk of such cases, have also played a role in burnout in some medical specialties.¹¹ The pandemic also contributed, at least temporarily, to burnout.^12,13

Rates of burnout among physicians are notably higher than among the general population¹⁴ or other professions.⁶ Although physicians have generally entered clinical practice with lower rates of burnout than the general population,¹⁵ The American College of Obstetricians and Gynecologists (ACOG) reports that 40% to 75% of ObGyns “experience some form of professional burnout.”^16,17 Other source(s) cite that 53% of ObGyns report burnout (TABLE 1).

Burnout undoubtedly contributes to professionals leaving practice, leading to a significant shortage of ObGyns.¹⁸ It also raises several significant legal concerns. Despite the enormity and seriousness of the problem, there is considerable optimism and assurance that the epidemic of burnout is solvable on the individual, specialty, and profession-wide levels. ACOG and other organizations have made suggestions for physicians, the profession, and to health care institutions for reducing burnout.¹⁹ This is not to say that solutions are simple or easy for individual professionals or institutions, but they are within the reach of the profession (FIGURE 2).

Costs of clinician burnout

Burnout is endemic among health care providers, with numerous studies detailing the professional, emotional, and financial costs. Prior to the pandemic, one analysis of nationwide fiscal costs associated with burnout estimated an annual cost of $4.6B due to physician turnover and reduced clinical hours.²¹ The COVID-19 epidemic has by all accounts worsened rates of health care worker burnout, particularly for those in high patient-contact positions.²²

Female clinicians appear to be differentially affected; in one recent study women reported symptoms of burnout at twice the rate of their male counterparts.²³ Whether burnout rates will return to pre-pandemic levels remains an open question, but since burnout is frequently related to one’s own assessment of work-life balance, it is possible that a longer term shift in burnout rates associated with post-pandemic occupational attitudes will be observed.

Combining factors contribute to burnout

Burnout is a universal occupational hazard, but extant data suggest that physicians and other health care providers may be at higher risk. Among physicians, younger age, female gender, and front-line specialty status appear associated with higher burnout rates.²⁴ Given that ObGyn physicians are overwhelmingly female (60% of physicians and 86% of residents),^25,26 gender-related burnout factors exist alongside other specific occupational burnout risks. While gender parity has been achieved among health care providers, gender disparities persist in terms of those in leadership positions, compensation, and other factors.²²

The smattering of evidence suggesting that ObGyns have higher rates of burnout than many other specialties is understandable given the unique legal challenges confronting ObGyn practice. This may be of special significance because ObGyn malpractice insurance rates are among the highest of all specialties.²⁷ The overall shortage of ObGyns has been exacerbated by the demonstrated negative effects on training and workforce representation stemming from recent legislation that has the effect of criminalizing certain aspects of ObGyn practice;²⁸ for instance, uncertainty regarding abortion regulations.

These negative effects are particularly heightened in states in which the law is in flux or where there are continuing efforts to substantially limit access to abortion. The efforts to increase civil and even criminal penalties related to abortion care challenge ObGyns’ professional practices, as legal rules are frequently changing. In some states, ObGyns may face additional workloads secondary to a flight of ObGyns from restrictive jurisdictions in addition to legal and professional repercussions. In a small study of 19 genetic counselors dealing with restrictive legislation in the state of Ohio,²⁹ increased stress and burnout rates were identified as a consequence of practice uncertainties under this legislation. It is certain that other professionals working in reproductive health care are similarly affected.³⁰

Continue to: Assessment of burnout...

Numerous scales for the assessment of burnout exist. Of these, the 22-item Maslach Burnout Inventory (MBI) is the best studied. The MBI is a well-investigated tool for assessing burnout. The MBI consists of 3 major subscales measuring overall burnout, emotional exhaustion, depersonalization, and low personal accomplishment. It exists in numerous forms. For instance, the MBI-HSS (MP), adapted for medical personnel, is available. However, the most commonly used form for assessing burnout in clinicians is the MBI-HHS (Human Services Survey); approximately 85% of all burnout studies examined in a recent meta-analysis used this survey version.³¹ As those authors commented, while burnout is a recognized phenomenon, a great deal of variability in study design, interpretation of subscale scores, and sample selection makes generalizations regarding burnout difficult to assess.

The MBI in various forms has been extensively used over the past 40 years to assess burnout amongst physicians and physicians in training. While not the only instrument designed to measure such factors, it is by far the most prevalent. Williamson and colleagues³² compared the MBI with several other measures of quality of life and found good correlation between the various instruments used, a finding replicated by other studies.³³ Brady and colleagues compared item responses to the Stanford Professional Fulfillment Index and the Min-Z Single-item Burnout scale (a 1-item screening measure) to MBI’s Emotional Exhaustion and Depersonalization subscales. Basing their findings on a survey of more than 1,300 physicians, they found that all analyzed scales were significantly correlated with such adverse outcomes as depression, distress, or intent to leave the profession.

It is important to note that most surveys of clinician burnout were conducted prior to the pandemic. While the psychometric analyses of the MBI and other scales are likely still germane, observed rates of clinician burnout have likely increased. Thus, comparisons of pre- and post-pandemic studies should factor in an increase in the incidence and prevalence of burnout.

Management strategies

In general, there are several interventions for managing burnout³⁴:

• individual-focused (including self-care and communications-skills workshops)
• mindfulness training
• yoga
• meditation
• organizational/structural (workload reduction, schedule realignment, teamwork training, and group-delivered stress management interventions)
• combination(s) of the above.

There is little evidence to suggest that any particular individual intervention (whether delivered in individual or group-based formats) is superior to any other in treating clinician burnout. A recent analysis of 24 studies employing mindfulness-based interventions demonstrated generally positive results for such interventions.³⁵ Other studies have also found general support for mindfulness-based interventions, although mindfulness is often integrated with other stress-reduction techniques, such as meditation, yoga, and communication skills. Such interventions are nonspecific but generally effective.

An accumulation of evidence to date suggests that a combination of individual and organizational interventions is most effective in combatting clinician burnout. No individual intervention can be successful without addressing root causes, such as overscheduling, lack of organizational support, and the effect of restrictive legislation on practice.

Several large teaching hospitals have established programs to address physician and health care provider burnout. Notable among these is the Stanford University School of Medicine’s WellMD and WellPhD programs (https://wellmd.stanford.edu/about.html). These programs were described by Olson and colleagues³⁶ as using a model focused on practice efficiency, organizational culture, and personal resilience to enhance physicians’ well-being. (See “Aspects of the WellMD and WellPhD programs from Stanford University.”)

A growing number of institutions have established burnout programs to support physicians experiencing work/life imbalances and other aspects of burnout.³⁷ In general, these share common features of assessment, individual and/or group intervention, and organizational change. Fear of repercussion may be one factor preventing physicians from seeking individual treatment for burnout.³⁸ Importantly, they emphasize the need for professional confidentiality when offering treatment to patients within organizational settings. Those authors also reported that a focus on organizational engagement may be an important factor in addressing burnout in female physicians, as they tend to report lower levels of organizational engagement.

Continue to: Legal considerations...

Legal considerations

Until recently, physician burnout “received little notice in the legal literature.”³⁹ Although there have been burnout legal consequences in the past, the legal issues are now becoming more visible.⁴⁰

Medical malpractice

A well-documented consequence of burnout is an increase in errors.¹⁴ Medical errors, of course, are at the heart of malpractice claims. Technically, malpractice is medical or professional negligence. It is the breach of a duty owed by the physician, or other provider, or organization (defendant) to the patient, which causes injury to the plaintiff/patient.⁴¹

“Medical error” is generally a meaningful deviation from the “standard of care” or accepted medical practice.⁴² Many medical errors do not cause injury to the patient; in those cases, the negligence does not result in liability. In instances in which the negligence causes harm, the clinician and health care facility may be subject to liability for that injury. Fortunately, however, for a variety of reasons, most harmful medical errors do not result in a medical malpractice claim or lawsuit. The absence of a good clinician-patient relationship is likely associated with an increased inclination of a patient to file a malpractice action.⁴³Clinician burnout may, therefore, contribute to increased malpractice claims in two ways. First, burnout likely leads to increased medical errors, perhaps because burnout is associated with lower concentration, inattention, reduced cognitive vigilance, and fatigue.^8,44 It may also lead to less time with patients, reduced patient empathy, and lower patient rapport, which may make injured patients more likely to file a claim or lawsuit.⁴⁵ Because the relationshipbetween burnout and medical error is bidirectional, malpractice claims tend to increase burnout, which increases error. Given the time it takes to resolve most malpractice claims, the uncertainty of medical malpractice may be especially stressful for health care providers.^46,47

Burnout is not a mitigating factor in malpractice. Our sympathies may go out to a professional suffering from burnout, but it does not excuse or reduce liability—it may, indeed, be an aggravating factor. Clinicians who can diagnose burnout and know its negative consequences but fail to deal with their own burnout may be demonstrating negligence if there has been harm to a patient related to the burnout.⁴⁸

Institutional or corporate liability to patients

Health care institutions have obligations to avoid injury to patients. Just as poorly maintained medical equipment may harm patients, so may burned-out professionals. Therefore, institutions have some obligation to supervise and avoid the increased risks to patients posed by professionals suffering from burnout.

Respondeat superior and institutional negligence. Institutional liability may arise in two ways, the first through agency, or respondeat superior. That is, if the physician or other professional is an employee (or similar agent) of the health care institution, that institution is generally responsible for the physician’s negligence during the employment.⁴⁹ Even if the physician is not an employee (for example, an independent contractor providing care or using the hospital facilities), the health care facility may be liable for the physician’s negligence.⁵⁰ Liability may occur, for example, if the health care facility was aware that the physician was engaged in careless practice or was otherwise a risk to patients but the facility did not take steps to avoid those risks.⁵¹ The basis for liability is that the health care organization owes a duty to patients to take reasonable care to ensure that its facilities are not used to injure patients negligently.⁵² Just as it must take care that unqualified physicians are not granted privileges to practice, it also must take reasonable steps to protect patients when it is aware (through nurses or other agents) of a physician’s negligent practice.

In one case, for example, the court found liability where a staff member had “severe” burnout in a physician’s office and failed to read fetal monitoring strips. The physician was found negligent for relying on the staff member who was obviously making errors in interpretation of fetal distress.⁵³

Continue to: Legal obligations of health care organizations to physicians and others...

In addition to obligations to patients, health care organizations may have obligations to employees (and others) at risk for injury. For example, assume a patient is diagnosed with a highly contagious disease. The health care organization would be obligated to warn, and take reasonable steps to protect, the staff (employees and independent contractors) from being harmed from exposure to the disease. This principle may apply to coworkers of employees with significant burnout, thereby presenting a danger in the workplace. The liability issue is more difficult for employees experiencing job-related burnout themselves. Organizations generally compensate injured employees through no-fault workers’ compensation (an insurance-like system); for independent contractors, the liability is usually through a tort claim (negligence).⁵⁴

In modern times, a focus has been on preventing those injuries, not just providing compensation after injuries have occurred. Notably, federal and state occupational health and safety laws (particularly the Occupational Safety and Health Administration [OSHA]) require most organizations (including those employing health care providers) to take steps to mitigate various kinds of worker injuries.⁵⁵

Although these worker protections have commonly been applied to hospitals and other health care providers, burnout has not traditionally been a significant concern in federal or state OSHA enforcement. For example, no formal federal OSHA regulations govern work-related burnout. Regulators, including OSHA, are increasingly interested in burnout that may affect many employees. OSHA has several recommendations for reducing health care work burnout.⁵⁶ The Surgeon General has expressed similar concerns.⁵⁷ The federal government recently allocated $103 million from the American Rescue Plan to address burnout among health care workers.⁵⁸ Also, OSHA appears to be increasing its oversight of healthcare-institution-worker injuries.⁵⁵

Is burnout a “disability”?

The federal Americans with Disabilities Act (ADA) and similar state laws prohibit discrimination based on disability.⁵⁹ A disability is defined as a “physical or mental impairment that substantially limits one or more major life activities” or “perceived as having such an impairment.”⁶⁰ The initial issue is whether burnout is a “mental impairment.” As noted earlier, it is not officially a “medical condition.”⁶¹ To date, the United Nations has classified it as an “occupational phenomenon.”⁶² It may, therefore, not qualify under the ADA, even if it “interferes with a major life activity.” There is, however, some movement toward defining burnout as a mental condition. Even if defined as a disability, there would still be legal issues of how severe it must be to qualify as a disability and the proper accommodation. Apart from the legal definition of an ADA disability, as a practical matter it likely is in the best interest of health care facilities to provide accommodations that reduce burnout. A number of strategies to decrease the incidence of burnout include the role of health care systems (FIGURE 2).

In conclusion we look at several things that can be done to “treat” or reduce burnout. That effort requires the cooperation of physicians and other providers, health care facilities, training programs, licensing authorities, and professional organizations. See suggestions below.

Conclusion

There are many excellent suggestions for reducing burnout and improving patient care and practitioner satisfaction.^63-65 We conclude with a summary of some of these suggestions for individual practitioners, health care organizations, the profession, and licensing. It is worth remembering, however, that it will require the efforts of each area to reduce burnout substantially.

For practitioners:

• Engage in quality coaching/therapy on mindfulness and stress management.
• Practice self-care, including exercise and relaxation techniques.
• Make work-life balance a priority.
• Take opportunities for collegial social and professional discussions.
• Prioritize (and periodically assess) your own professional satisfaction and burnout risk.
• Smile—enjoy a sense of humor (endorphins and cortisol).

For health care organizations:

• Urgently work with vendors and regulators to revise electronic health records to reduce their substantial impact on burnout.
• Reduce physicians’ time on clerical and administrative tasks (eg, by enhancing the use of quality AI, scribes, and automated notes from appointments. (This may increase the time they spend with patients.) Eliminate “pajama-time” charting.
• Provide various kinds of confidential professional counseling, therapy, and support related to burnout prevention and treatment, and avoid any penalty or stigma related to their use.
• Provide reasonable flexibility in scheduling.
• Routinely provide employees with information about burnout prevention and services.
• Appoint a wellness officer with authority to ensure the organization maximizes its prevention and treatment services.
• Constantly seek input from practitioners on how to improve the atmosphere for practice to maximize patient care and practitioner satisfaction.
• Provide ample professional and social opportunities for discussing and learning about work-life balance, resilience, intellectual stimulation, and career development.

For regulators, licensors, and professional organizations:

• Work with health care organizations and EHR vendors to substantially reduce the complexity, physician effort, and stress associated with those record systems. Streamlining should, in the future, be part of formally certifying EHR systems.
• Reduce the administrative burden on physicians by modifying complex regulations and using AI and other technology to the extent possible to obtain necessary reimbursement information.
• Eliminate unnecessary data gathering that requires practitioner time or attention.
• Licensing, educational, and certifying bodies should eliminate any questions regarding the diagnosis or treatment of mental health and focus on current (or very recent) impairments.
• Seek funding for research on burnout prevention and treatment.

Physicians have some of the highest rates of burnout among all professions.¹ Complicating matters is that clinicians (including residents)² may avoid seeking treatment out of fear it will affect their license or privileges.³ In this article, we consider burnout in greater detail, as well as ways of successfully addressing the level of burnout in the profession (FIGURE 1), including steps individual practitioners, health care entities, and regulators should consider to reduce burnout and its harmful effects.

How burnout becomes a problem

Six general factors are commonly identified as leading to clinician career dissatisfaction and burnout:⁴

1. work overload

2. lack of autonomy and control

3. inadequate rewards, financial and  otherwise

4. work-home schedules

5. perception of lack of fairness

6. values conflict between the clinician and employer (including a breakdown of professional community). 

At the top of the list of causes of burnout is often “administrative and bureaucratic headaches.”⁵ More specifically, electronic health records (EHRs), including computerized order entry, is commonly cited as a major cause of burnout.^6,7 According to some studies, clinicians spend as much as 49% of working time doing clerical work,⁸ and studies found the extension of work into home life.⁹

Increased measurement of performance metrics in health care services are a significant contributor to physician burnout.¹⁰ These include pressure to see more patients, perform more procedures, and respond quickly to patient requests (eg, through email).⁷ As we will see, medical malpractice cases, or the risk of such cases, have also played a role in burnout in some medical specialties.¹¹ The pandemic also contributed, at least temporarily, to burnout.^12,13

Rates of burnout among physicians are notably higher than among the general population¹⁴ or other professions.⁶ Although physicians have generally entered clinical practice with lower rates of burnout than the general population,¹⁵ The American College of Obstetricians and Gynecologists (ACOG) reports that 40% to 75% of ObGyns “experience some form of professional burnout.”^16,17 Other source(s) cite that 53% of ObGyns report burnout (TABLE 1).

Burnout undoubtedly contributes to professionals leaving practice, leading to a significant shortage of ObGyns.¹⁸ It also raises several significant legal concerns. Despite the enormity and seriousness of the problem, there is considerable optimism and assurance that the epidemic of burnout is solvable on the individual, specialty, and profession-wide levels. ACOG and other organizations have made suggestions for physicians, the profession, and to health care institutions for reducing burnout.¹⁹ This is not to say that solutions are simple or easy for individual professionals or institutions, but they are within the reach of the profession (FIGURE 2).

Costs of clinician burnout

Burnout is endemic among health care providers, with numerous studies detailing the professional, emotional, and financial costs. Prior to the pandemic, one analysis of nationwide fiscal costs associated with burnout estimated an annual cost of $4.6B due to physician turnover and reduced clinical hours.²¹ The COVID-19 epidemic has by all accounts worsened rates of health care worker burnout, particularly for those in high patient-contact positions.²²

Female clinicians appear to be differentially affected; in one recent study women reported symptoms of burnout at twice the rate of their male counterparts.²³ Whether burnout rates will return to pre-pandemic levels remains an open question, but since burnout is frequently related to one’s own assessment of work-life balance, it is possible that a longer term shift in burnout rates associated with post-pandemic occupational attitudes will be observed.

Combining factors contribute to burnout

Burnout is a universal occupational hazard, but extant data suggest that physicians and other health care providers may be at higher risk. Among physicians, younger age, female gender, and front-line specialty status appear associated with higher burnout rates.²⁴ Given that ObGyn physicians are overwhelmingly female (60% of physicians and 86% of residents),^25,26 gender-related burnout factors exist alongside other specific occupational burnout risks. While gender parity has been achieved among health care providers, gender disparities persist in terms of those in leadership positions, compensation, and other factors.²²

The smattering of evidence suggesting that ObGyns have higher rates of burnout than many other specialties is understandable given the unique legal challenges confronting ObGyn practice. This may be of special significance because ObGyn malpractice insurance rates are among the highest of all specialties.²⁷ The overall shortage of ObGyns has been exacerbated by the demonstrated negative effects on training and workforce representation stemming from recent legislation that has the effect of criminalizing certain aspects of ObGyn practice;²⁸ for instance, uncertainty regarding abortion regulations.

These negative effects are particularly heightened in states in which the law is in flux or where there are continuing efforts to substantially limit access to abortion. The efforts to increase civil and even criminal penalties related to abortion care challenge ObGyns’ professional practices, as legal rules are frequently changing. In some states, ObGyns may face additional workloads secondary to a flight of ObGyns from restrictive jurisdictions in addition to legal and professional repercussions. In a small study of 19 genetic counselors dealing with restrictive legislation in the state of Ohio,²⁹ increased stress and burnout rates were identified as a consequence of practice uncertainties under this legislation. It is certain that other professionals working in reproductive health care are similarly affected.³⁰

Continue to: Assessment of burnout...

Numerous scales for the assessment of burnout exist. Of these, the 22-item Maslach Burnout Inventory (MBI) is the best studied. The MBI is a well-investigated tool for assessing burnout. The MBI consists of 3 major subscales measuring overall burnout, emotional exhaustion, depersonalization, and low personal accomplishment. It exists in numerous forms. For instance, the MBI-HSS (MP), adapted for medical personnel, is available. However, the most commonly used form for assessing burnout in clinicians is the MBI-HHS (Human Services Survey); approximately 85% of all burnout studies examined in a recent meta-analysis used this survey version.³¹ As those authors commented, while burnout is a recognized phenomenon, a great deal of variability in study design, interpretation of subscale scores, and sample selection makes generalizations regarding burnout difficult to assess.

The MBI in various forms has been extensively used over the past 40 years to assess burnout amongst physicians and physicians in training. While not the only instrument designed to measure such factors, it is by far the most prevalent. Williamson and colleagues³² compared the MBI with several other measures of quality of life and found good correlation between the various instruments used, a finding replicated by other studies.³³ Brady and colleagues compared item responses to the Stanford Professional Fulfillment Index and the Min-Z Single-item Burnout scale (a 1-item screening measure) to MBI’s Emotional Exhaustion and Depersonalization subscales. Basing their findings on a survey of more than 1,300 physicians, they found that all analyzed scales were significantly correlated with such adverse outcomes as depression, distress, or intent to leave the profession.

It is important to note that most surveys of clinician burnout were conducted prior to the pandemic. While the psychometric analyses of the MBI and other scales are likely still germane, observed rates of clinician burnout have likely increased. Thus, comparisons of pre- and post-pandemic studies should factor in an increase in the incidence and prevalence of burnout.

Management strategies

In general, there are several interventions for managing burnout³⁴:

• individual-focused (including self-care and communications-skills workshops)
• mindfulness training
• yoga
• meditation
• organizational/structural (workload reduction, schedule realignment, teamwork training, and group-delivered stress management interventions)
• combination(s) of the above.

There is little evidence to suggest that any particular individual intervention (whether delivered in individual or group-based formats) is superior to any other in treating clinician burnout. A recent analysis of 24 studies employing mindfulness-based interventions demonstrated generally positive results for such interventions.³⁵ Other studies have also found general support for mindfulness-based interventions, although mindfulness is often integrated with other stress-reduction techniques, such as meditation, yoga, and communication skills. Such interventions are nonspecific but generally effective.

An accumulation of evidence to date suggests that a combination of individual and organizational interventions is most effective in combatting clinician burnout. No individual intervention can be successful without addressing root causes, such as overscheduling, lack of organizational support, and the effect of restrictive legislation on practice.

Several large teaching hospitals have established programs to address physician and health care provider burnout. Notable among these is the Stanford University School of Medicine’s WellMD and WellPhD programs (https://wellmd.stanford.edu/about.html). These programs were described by Olson and colleagues³⁶ as using a model focused on practice efficiency, organizational culture, and personal resilience to enhance physicians’ well-being. (See “Aspects of the WellMD and WellPhD programs from Stanford University.”)

A growing number of institutions have established burnout programs to support physicians experiencing work/life imbalances and other aspects of burnout.³⁷ In general, these share common features of assessment, individual and/or group intervention, and organizational change. Fear of repercussion may be one factor preventing physicians from seeking individual treatment for burnout.³⁸ Importantly, they emphasize the need for professional confidentiality when offering treatment to patients within organizational settings. Those authors also reported that a focus on organizational engagement may be an important factor in addressing burnout in female physicians, as they tend to report lower levels of organizational engagement.

Continue to: Legal considerations...

Legal considerations

Until recently, physician burnout “received little notice in the legal literature.”³⁹ Although there have been burnout legal consequences in the past, the legal issues are now becoming more visible.⁴⁰

Medical malpractice

A well-documented consequence of burnout is an increase in errors.¹⁴ Medical errors, of course, are at the heart of malpractice claims. Technically, malpractice is medical or professional negligence. It is the breach of a duty owed by the physician, or other provider, or organization (defendant) to the patient, which causes injury to the plaintiff/patient.⁴¹

“Medical error” is generally a meaningful deviation from the “standard of care” or accepted medical practice.⁴² Many medical errors do not cause injury to the patient; in those cases, the negligence does not result in liability. In instances in which the negligence causes harm, the clinician and health care facility may be subject to liability for that injury. Fortunately, however, for a variety of reasons, most harmful medical errors do not result in a medical malpractice claim or lawsuit. The absence of a good clinician-patient relationship is likely associated with an increased inclination of a patient to file a malpractice action.⁴³Clinician burnout may, therefore, contribute to increased malpractice claims in two ways. First, burnout likely leads to increased medical errors, perhaps because burnout is associated with lower concentration, inattention, reduced cognitive vigilance, and fatigue.^8,44 It may also lead to less time with patients, reduced patient empathy, and lower patient rapport, which may make injured patients more likely to file a claim or lawsuit.⁴⁵ Because the relationshipbetween burnout and medical error is bidirectional, malpractice claims tend to increase burnout, which increases error. Given the time it takes to resolve most malpractice claims, the uncertainty of medical malpractice may be especially stressful for health care providers.^46,47

Burnout is not a mitigating factor in malpractice. Our sympathies may go out to a professional suffering from burnout, but it does not excuse or reduce liability—it may, indeed, be an aggravating factor. Clinicians who can diagnose burnout and know its negative consequences but fail to deal with their own burnout may be demonstrating negligence if there has been harm to a patient related to the burnout.⁴⁸

Institutional or corporate liability to patients

Health care institutions have obligations to avoid injury to patients. Just as poorly maintained medical equipment may harm patients, so may burned-out professionals. Therefore, institutions have some obligation to supervise and avoid the increased risks to patients posed by professionals suffering from burnout.

Respondeat superior and institutional negligence. Institutional liability may arise in two ways, the first through agency, or respondeat superior. That is, if the physician or other professional is an employee (or similar agent) of the health care institution, that institution is generally responsible for the physician’s negligence during the employment.⁴⁹ Even if the physician is not an employee (for example, an independent contractor providing care or using the hospital facilities), the health care facility may be liable for the physician’s negligence.⁵⁰ Liability may occur, for example, if the health care facility was aware that the physician was engaged in careless practice or was otherwise a risk to patients but the facility did not take steps to avoid those risks.⁵¹ The basis for liability is that the health care organization owes a duty to patients to take reasonable care to ensure that its facilities are not used to injure patients negligently.⁵² Just as it must take care that unqualified physicians are not granted privileges to practice, it also must take reasonable steps to protect patients when it is aware (through nurses or other agents) of a physician’s negligent practice.

In one case, for example, the court found liability where a staff member had “severe” burnout in a physician’s office and failed to read fetal monitoring strips. The physician was found negligent for relying on the staff member who was obviously making errors in interpretation of fetal distress.⁵³

Continue to: Legal obligations of health care organizations to physicians and others...

In addition to obligations to patients, health care organizations may have obligations to employees (and others) at risk for injury. For example, assume a patient is diagnosed with a highly contagious disease. The health care organization would be obligated to warn, and take reasonable steps to protect, the staff (employees and independent contractors) from being harmed from exposure to the disease. This principle may apply to coworkers of employees with significant burnout, thereby presenting a danger in the workplace. The liability issue is more difficult for employees experiencing job-related burnout themselves. Organizations generally compensate injured employees through no-fault workers’ compensation (an insurance-like system); for independent contractors, the liability is usually through a tort claim (negligence).⁵⁴

In modern times, a focus has been on preventing those injuries, not just providing compensation after injuries have occurred. Notably, federal and state occupational health and safety laws (particularly the Occupational Safety and Health Administration [OSHA]) require most organizations (including those employing health care providers) to take steps to mitigate various kinds of worker injuries.⁵⁵

Although these worker protections have commonly been applied to hospitals and other health care providers, burnout has not traditionally been a significant concern in federal or state OSHA enforcement. For example, no formal federal OSHA regulations govern work-related burnout. Regulators, including OSHA, are increasingly interested in burnout that may affect many employees. OSHA has several recommendations for reducing health care work burnout.⁵⁶ The Surgeon General has expressed similar concerns.⁵⁷ The federal government recently allocated $103 million from the American Rescue Plan to address burnout among health care workers.⁵⁸ Also, OSHA appears to be increasing its oversight of healthcare-institution-worker injuries.⁵⁵

Is burnout a “disability”?

The federal Americans with Disabilities Act (ADA) and similar state laws prohibit discrimination based on disability.⁵⁹ A disability is defined as a “physical or mental impairment that substantially limits one or more major life activities” or “perceived as having such an impairment.”⁶⁰ The initial issue is whether burnout is a “mental impairment.” As noted earlier, it is not officially a “medical condition.”⁶¹ To date, the United Nations has classified it as an “occupational phenomenon.”⁶² It may, therefore, not qualify under the ADA, even if it “interferes with a major life activity.” There is, however, some movement toward defining burnout as a mental condition. Even if defined as a disability, there would still be legal issues of how severe it must be to qualify as a disability and the proper accommodation. Apart from the legal definition of an ADA disability, as a practical matter it likely is in the best interest of health care facilities to provide accommodations that reduce burnout. A number of strategies to decrease the incidence of burnout include the role of health care systems (FIGURE 2).

In conclusion we look at several things that can be done to “treat” or reduce burnout. That effort requires the cooperation of physicians and other providers, health care facilities, training programs, licensing authorities, and professional organizations. See suggestions below.

Conclusion

There are many excellent suggestions for reducing burnout and improving patient care and practitioner satisfaction.^63-65 We conclude with a summary of some of these suggestions for individual practitioners, health care organizations, the profession, and licensing. It is worth remembering, however, that it will require the efforts of each area to reduce burnout substantially.

For practitioners:

• Engage in quality coaching/therapy on mindfulness and stress management.
• Practice self-care, including exercise and relaxation techniques.
• Make work-life balance a priority.
• Take opportunities for collegial social and professional discussions.
• Prioritize (and periodically assess) your own professional satisfaction and burnout risk.
• Smile—enjoy a sense of humor (endorphins and cortisol).

For health care organizations:

• Urgently work with vendors and regulators to revise electronic health records to reduce their substantial impact on burnout.
• Reduce physicians’ time on clerical and administrative tasks (eg, by enhancing the use of quality AI, scribes, and automated notes from appointments. (This may increase the time they spend with patients.) Eliminate “pajama-time” charting.
• Provide various kinds of confidential professional counseling, therapy, and support related to burnout prevention and treatment, and avoid any penalty or stigma related to their use.
• Provide reasonable flexibility in scheduling.
• Routinely provide employees with information about burnout prevention and services.
• Appoint a wellness officer with authority to ensure the organization maximizes its prevention and treatment services.
• Constantly seek input from practitioners on how to improve the atmosphere for practice to maximize patient care and practitioner satisfaction.
• Provide ample professional and social opportunities for discussing and learning about work-life balance, resilience, intellectual stimulation, and career development.

For regulators, licensors, and professional organizations:

• Work with health care organizations and EHR vendors to substantially reduce the complexity, physician effort, and stress associated with those record systems. Streamlining should, in the future, be part of formally certifying EHR systems.
• Reduce the administrative burden on physicians by modifying complex regulations and using AI and other technology to the extent possible to obtain necessary reimbursement information.
• Eliminate unnecessary data gathering that requires practitioner time or attention.
• Licensing, educational, and certifying bodies should eliminate any questions regarding the diagnosis or treatment of mental health and focus on current (or very recent) impairments.
• Seek funding for research on burnout prevention and treatment.

Physicians have some of the highest rates of burnout among all professions.¹ Complicating matters is that clinicians (including residents)² may avoid seeking treatment out of fear it will affect their license or privileges.³ In this article, we consider burnout in greater detail, as well as ways of successfully addressing the level of burnout in the profession (FIGURE 1), including steps individual practitioners, health care entities, and regulators should consider to reduce burnout and its harmful effects.

How burnout becomes a problem

Six general factors are commonly identified as leading to clinician career dissatisfaction and burnout:⁴

1. work overload

2. lack of autonomy and control

3. inadequate rewards, financial and  otherwise

4. work-home schedules

5. perception of lack of fairness

6. values conflict between the clinician and employer (including a breakdown of professional community). 

At the top of the list of causes of burnout is often “administrative and bureaucratic headaches.”⁵ More specifically, electronic health records (EHRs), including computerized order entry, is commonly cited as a major cause of burnout.^6,7 According to some studies, clinicians spend as much as 49% of working time doing clerical work,⁸ and studies found the extension of work into home life.⁹

Increased measurement of performance metrics in health care services are a significant contributor to physician burnout.¹⁰ These include pressure to see more patients, perform more procedures, and respond quickly to patient requests (eg, through email).⁷ As we will see, medical malpractice cases, or the risk of such cases, have also played a role in burnout in some medical specialties.¹¹ The pandemic also contributed, at least temporarily, to burnout.^12,13

Rates of burnout among physicians are notably higher than among the general population¹⁴ or other professions.⁶ Although physicians have generally entered clinical practice with lower rates of burnout than the general population,¹⁵ The American College of Obstetricians and Gynecologists (ACOG) reports that 40% to 75% of ObGyns “experience some form of professional burnout.”^16,17 Other source(s) cite that 53% of ObGyns report burnout (TABLE 1).

Burnout undoubtedly contributes to professionals leaving practice, leading to a significant shortage of ObGyns.¹⁸ It also raises several significant legal concerns. Despite the enormity and seriousness of the problem, there is considerable optimism and assurance that the epidemic of burnout is solvable on the individual, specialty, and profession-wide levels. ACOG and other organizations have made suggestions for physicians, the profession, and to health care institutions for reducing burnout.¹⁹ This is not to say that solutions are simple or easy for individual professionals or institutions, but they are within the reach of the profession (FIGURE 2).

Costs of clinician burnout

Burnout is endemic among health care providers, with numerous studies detailing the professional, emotional, and financial costs. Prior to the pandemic, one analysis of nationwide fiscal costs associated with burnout estimated an annual cost of $4.6B due to physician turnover and reduced clinical hours.²¹ The COVID-19 epidemic has by all accounts worsened rates of health care worker burnout, particularly for those in high patient-contact positions.²²

Female clinicians appear to be differentially affected; in one recent study women reported symptoms of burnout at twice the rate of their male counterparts.²³ Whether burnout rates will return to pre-pandemic levels remains an open question, but since burnout is frequently related to one’s own assessment of work-life balance, it is possible that a longer term shift in burnout rates associated with post-pandemic occupational attitudes will be observed.

Combining factors contribute to burnout

Burnout is a universal occupational hazard, but extant data suggest that physicians and other health care providers may be at higher risk. Among physicians, younger age, female gender, and front-line specialty status appear associated with higher burnout rates.²⁴ Given that ObGyn physicians are overwhelmingly female (60% of physicians and 86% of residents),^25,26 gender-related burnout factors exist alongside other specific occupational burnout risks. While gender parity has been achieved among health care providers, gender disparities persist in terms of those in leadership positions, compensation, and other factors.²²

The smattering of evidence suggesting that ObGyns have higher rates of burnout than many other specialties is understandable given the unique legal challenges confronting ObGyn practice. This may be of special significance because ObGyn malpractice insurance rates are among the highest of all specialties.²⁷ The overall shortage of ObGyns has been exacerbated by the demonstrated negative effects on training and workforce representation stemming from recent legislation that has the effect of criminalizing certain aspects of ObGyn practice;²⁸ for instance, uncertainty regarding abortion regulations.

These negative effects are particularly heightened in states in which the law is in flux or where there are continuing efforts to substantially limit access to abortion. The efforts to increase civil and even criminal penalties related to abortion care challenge ObGyns’ professional practices, as legal rules are frequently changing. In some states, ObGyns may face additional workloads secondary to a flight of ObGyns from restrictive jurisdictions in addition to legal and professional repercussions. In a small study of 19 genetic counselors dealing with restrictive legislation in the state of Ohio,²⁹ increased stress and burnout rates were identified as a consequence of practice uncertainties under this legislation. It is certain that other professionals working in reproductive health care are similarly affected.³⁰

Continue to: Assessment of burnout...

Numerous scales for the assessment of burnout exist. Of these, the 22-item Maslach Burnout Inventory (MBI) is the best studied. The MBI is a well-investigated tool for assessing burnout. The MBI consists of 3 major subscales measuring overall burnout, emotional exhaustion, depersonalization, and low personal accomplishment. It exists in numerous forms. For instance, the MBI-HSS (MP), adapted for medical personnel, is available. However, the most commonly used form for assessing burnout in clinicians is the MBI-HHS (Human Services Survey); approximately 85% of all burnout studies examined in a recent meta-analysis used this survey version.³¹ As those authors commented, while burnout is a recognized phenomenon, a great deal of variability in study design, interpretation of subscale scores, and sample selection makes generalizations regarding burnout difficult to assess.

The MBI in various forms has been extensively used over the past 40 years to assess burnout amongst physicians and physicians in training. While not the only instrument designed to measure such factors, it is by far the most prevalent. Williamson and colleagues³² compared the MBI with several other measures of quality of life and found good correlation between the various instruments used, a finding replicated by other studies.³³ Brady and colleagues compared item responses to the Stanford Professional Fulfillment Index and the Min-Z Single-item Burnout scale (a 1-item screening measure) to MBI’s Emotional Exhaustion and Depersonalization subscales. Basing their findings on a survey of more than 1,300 physicians, they found that all analyzed scales were significantly correlated with such adverse outcomes as depression, distress, or intent to leave the profession.

It is important to note that most surveys of clinician burnout were conducted prior to the pandemic. While the psychometric analyses of the MBI and other scales are likely still germane, observed rates of clinician burnout have likely increased. Thus, comparisons of pre- and post-pandemic studies should factor in an increase in the incidence and prevalence of burnout.

Management strategies

In general, there are several interventions for managing burnout³⁴:

• individual-focused (including self-care and communications-skills workshops)
• mindfulness training
• yoga
• meditation
• organizational/structural (workload reduction, schedule realignment, teamwork training, and group-delivered stress management interventions)
• combination(s) of the above.

There is little evidence to suggest that any particular individual intervention (whether delivered in individual or group-based formats) is superior to any other in treating clinician burnout. A recent analysis of 24 studies employing mindfulness-based interventions demonstrated generally positive results for such interventions.³⁵ Other studies have also found general support for mindfulness-based interventions, although mindfulness is often integrated with other stress-reduction techniques, such as meditation, yoga, and communication skills. Such interventions are nonspecific but generally effective.

An accumulation of evidence to date suggests that a combination of individual and organizational interventions is most effective in combatting clinician burnout. No individual intervention can be successful without addressing root causes, such as overscheduling, lack of organizational support, and the effect of restrictive legislation on practice.

Several large teaching hospitals have established programs to address physician and health care provider burnout. Notable among these is the Stanford University School of Medicine’s WellMD and WellPhD programs (https://wellmd.stanford.edu/about.html). These programs were described by Olson and colleagues³⁶ as using a model focused on practice efficiency, organizational culture, and personal resilience to enhance physicians’ well-being. (See “Aspects of the WellMD and WellPhD programs from Stanford University.”)

A growing number of institutions have established burnout programs to support physicians experiencing work/life imbalances and other aspects of burnout.³⁷ In general, these share common features of assessment, individual and/or group intervention, and organizational change. Fear of repercussion may be one factor preventing physicians from seeking individual treatment for burnout.³⁸ Importantly, they emphasize the need for professional confidentiality when offering treatment to patients within organizational settings. Those authors also reported that a focus on organizational engagement may be an important factor in addressing burnout in female physicians, as they tend to report lower levels of organizational engagement.

Continue to: Legal considerations...

Legal considerations

Until recently, physician burnout “received little notice in the legal literature.”³⁹ Although there have been burnout legal consequences in the past, the legal issues are now becoming more visible.⁴⁰

Medical malpractice

A well-documented consequence of burnout is an increase in errors.¹⁴ Medical errors, of course, are at the heart of malpractice claims. Technically, malpractice is medical or professional negligence. It is the breach of a duty owed by the physician, or other provider, or organization (defendant) to the patient, which causes injury to the plaintiff/patient.⁴¹

“Medical error” is generally a meaningful deviation from the “standard of care” or accepted medical practice.⁴² Many medical errors do not cause injury to the patient; in those cases, the negligence does not result in liability. In instances in which the negligence causes harm, the clinician and health care facility may be subject to liability for that injury. Fortunately, however, for a variety of reasons, most harmful medical errors do not result in a medical malpractice claim or lawsuit. The absence of a good clinician-patient relationship is likely associated with an increased inclination of a patient to file a malpractice action.⁴³Clinician burnout may, therefore, contribute to increased malpractice claims in two ways. First, burnout likely leads to increased medical errors, perhaps because burnout is associated with lower concentration, inattention, reduced cognitive vigilance, and fatigue.^8,44 It may also lead to less time with patients, reduced patient empathy, and lower patient rapport, which may make injured patients more likely to file a claim or lawsuit.⁴⁵ Because the relationshipbetween burnout and medical error is bidirectional, malpractice claims tend to increase burnout, which increases error. Given the time it takes to resolve most malpractice claims, the uncertainty of medical malpractice may be especially stressful for health care providers.^46,47

Burnout is not a mitigating factor in malpractice. Our sympathies may go out to a professional suffering from burnout, but it does not excuse or reduce liability—it may, indeed, be an aggravating factor. Clinicians who can diagnose burnout and know its negative consequences but fail to deal with their own burnout may be demonstrating negligence if there has been harm to a patient related to the burnout.⁴⁸

Institutional or corporate liability to patients

Health care institutions have obligations to avoid injury to patients. Just as poorly maintained medical equipment may harm patients, so may burned-out professionals. Therefore, institutions have some obligation to supervise and avoid the increased risks to patients posed by professionals suffering from burnout.

Respondeat superior and institutional negligence. Institutional liability may arise in two ways, the first through agency, or respondeat superior. That is, if the physician or other professional is an employee (or similar agent) of the health care institution, that institution is generally responsible for the physician’s negligence during the employment.⁴⁹ Even if the physician is not an employee (for example, an independent contractor providing care or using the hospital facilities), the health care facility may be liable for the physician’s negligence.⁵⁰ Liability may occur, for example, if the health care facility was aware that the physician was engaged in careless practice or was otherwise a risk to patients but the facility did not take steps to avoid those risks.⁵¹ The basis for liability is that the health care organization owes a duty to patients to take reasonable care to ensure that its facilities are not used to injure patients negligently.⁵² Just as it must take care that unqualified physicians are not granted privileges to practice, it also must take reasonable steps to protect patients when it is aware (through nurses or other agents) of a physician’s negligent practice.

In one case, for example, the court found liability where a staff member had “severe” burnout in a physician’s office and failed to read fetal monitoring strips. The physician was found negligent for relying on the staff member who was obviously making errors in interpretation of fetal distress.⁵³

Continue to: Legal obligations of health care organizations to physicians and others...

In addition to obligations to patients, health care organizations may have obligations to employees (and others) at risk for injury. For example, assume a patient is diagnosed with a highly contagious disease. The health care organization would be obligated to warn, and take reasonable steps to protect, the staff (employees and independent contractors) from being harmed from exposure to the disease. This principle may apply to coworkers of employees with significant burnout, thereby presenting a danger in the workplace. The liability issue is more difficult for employees experiencing job-related burnout themselves. Organizations generally compensate injured employees through no-fault workers’ compensation (an insurance-like system); for independent contractors, the liability is usually through a tort claim (negligence).⁵⁴

In modern times, a focus has been on preventing those injuries, not just providing compensation after injuries have occurred. Notably, federal and state occupational health and safety laws (particularly the Occupational Safety and Health Administration [OSHA]) require most organizations (including those employing health care providers) to take steps to mitigate various kinds of worker injuries.⁵⁵

Although these worker protections have commonly been applied to hospitals and other health care providers, burnout has not traditionally been a significant concern in federal or state OSHA enforcement. For example, no formal federal OSHA regulations govern work-related burnout. Regulators, including OSHA, are increasingly interested in burnout that may affect many employees. OSHA has several recommendations for reducing health care work burnout.⁵⁶ The Surgeon General has expressed similar concerns.⁵⁷ The federal government recently allocated $103 million from the American Rescue Plan to address burnout among health care workers.⁵⁸ Also, OSHA appears to be increasing its oversight of healthcare-institution-worker injuries.⁵⁵

Is burnout a “disability”?

The federal Americans with Disabilities Act (ADA) and similar state laws prohibit discrimination based on disability.⁵⁹ A disability is defined as a “physical or mental impairment that substantially limits one or more major life activities” or “perceived as having such an impairment.”⁶⁰ The initial issue is whether burnout is a “mental impairment.” As noted earlier, it is not officially a “medical condition.”⁶¹ To date, the United Nations has classified it as an “occupational phenomenon.”⁶² It may, therefore, not qualify under the ADA, even if it “interferes with a major life activity.” There is, however, some movement toward defining burnout as a mental condition. Even if defined as a disability, there would still be legal issues of how severe it must be to qualify as a disability and the proper accommodation. Apart from the legal definition of an ADA disability, as a practical matter it likely is in the best interest of health care facilities to provide accommodations that reduce burnout. A number of strategies to decrease the incidence of burnout include the role of health care systems (FIGURE 2).

In conclusion we look at several things that can be done to “treat” or reduce burnout. That effort requires the cooperation of physicians and other providers, health care facilities, training programs, licensing authorities, and professional organizations. See suggestions below.

Conclusion

There are many excellent suggestions for reducing burnout and improving patient care and practitioner satisfaction.^63-65 We conclude with a summary of some of these suggestions for individual practitioners, health care organizations, the profession, and licensing. It is worth remembering, however, that it will require the efforts of each area to reduce burnout substantially.

For practitioners:

• Engage in quality coaching/therapy on mindfulness and stress management.
• Practice self-care, including exercise and relaxation techniques.
• Make work-life balance a priority.
• Take opportunities for collegial social and professional discussions.
• Prioritize (and periodically assess) your own professional satisfaction and burnout risk.
• Smile—enjoy a sense of humor (endorphins and cortisol).

For health care organizations:

• Urgently work with vendors and regulators to revise electronic health records to reduce their substantial impact on burnout.
• Reduce physicians’ time on clerical and administrative tasks (eg, by enhancing the use of quality AI, scribes, and automated notes from appointments. (This may increase the time they spend with patients.) Eliminate “pajama-time” charting.
• Provide various kinds of confidential professional counseling, therapy, and support related to burnout prevention and treatment, and avoid any penalty or stigma related to their use.
• Provide reasonable flexibility in scheduling.
• Routinely provide employees with information about burnout prevention and services.
• Appoint a wellness officer with authority to ensure the organization maximizes its prevention and treatment services.
• Constantly seek input from practitioners on how to improve the atmosphere for practice to maximize patient care and practitioner satisfaction.
• Provide ample professional and social opportunities for discussing and learning about work-life balance, resilience, intellectual stimulation, and career development.

For regulators, licensors, and professional organizations:

• Work with health care organizations and EHR vendors to substantially reduce the complexity, physician effort, and stress associated with those record systems. Streamlining should, in the future, be part of formally certifying EHR systems.
• Reduce the administrative burden on physicians by modifying complex regulations and using AI and other technology to the extent possible to obtain necessary reimbursement information.
• Eliminate unnecessary data gathering that requires practitioner time or attention.
• Licensing, educational, and certifying bodies should eliminate any questions regarding the diagnosis or treatment of mental health and focus on current (or very recent) impairments.
• Seek funding for research on burnout prevention and treatment.

Quenby S, Booth K, Hiller L, et al; ALIFE2 Block Writing Committee and ALIFE2 Investigators. Heparin for women with recurrent miscarriage and inherited thrombophilia (ALIFE2): an international open-label, randomised controlled trial. Lancet. 2023;402:54-61. doi:10.1016/S0140-6736(23)00693-1.

EXPERT COMMENTARY

“Follow the evidence to where it leads, even if the conclusion is uncomfortable.”

—Steven James, author

Women with RPL have endured overzealous evaluations and management despite a lack of proven efficacy. From alloimmune testing that results in paternal leukocyte immunization¹ and the long-entrusted metroplasty for a septate uterus recently put under fire² to the “hammer and nail” approach of preimplantation genetic testing for embryo aneuploid screening,³ patients have been subjected to unsubstantiated treatments.

While the evaluation of RPL has evolved, guidelines from the American Society for Reproductive Medicine (ASRM), American College of Obstetricians and Gynecologists (ACOG), and Royal College of Obstetricians and Gynaecologists (RCOG) do not recommend testing for inherited thrombophilias outside of a history for venous thromboembolism.^4-6 These 3 societies support treating acquired thrombophilias that represent the antiphospholipid antibody syndrome.

Citing insufficient evidence for reducing adverse pregnancy outcomes, ACOG recommends the use of prophylactic- or intermediate-dose LMWH or unfractionated heparin (UFH) for patients with “high-risk” thrombophilias only to prevent venous thromboembolism during pregnancy and continuing postpartum.⁴ (High-risk thrombophilias are defined as factor V Leiden homozygosity, prothrombin gene G20210A mutation homozygosity, heterozygosity for both factor V Leiden homozygosity and prothrombin gene G20210A mutation, or an antithrombin deficiency.⁴)

To determine the impact of LMWH treatment versus no treatment on live birth rate, Quenby and colleagues conducted a prospective randomized controlled trial of women with RPL and inherited thrombophilias (the ALIFE2 trial). This was a follow-up to their 2010 randomized controlled trial that demonstrated no effect of LMWH with low-dose aspirin versus low-dose aspirin alone compared with placebo in women with unexplained RPL.⁷

PHOTO: BETAVERSO/SHUTTERSTOCK

Continue to: Details of the study...

The ALIFE2 study took place over 8 years and involved 5 countries, including the United States, with the 2 main centers in the Netherlands and the United Kingdom. Women eligible for the study were aged 18 to 42 years, had an inherited thrombophilia (confirmed by 2 tests), experienced recurrent miscarriages (2 or more consecutive miscarriages, nonconsecutive miscarriages, or intrauterine fetal deaths, irrespective of gestational age), and were less than 7 weeks’ estimated gestational age. Study patients were randomly allocated with a positive pregnancy test to either surveillance or LMWH treatment, which was continued throughout pregnancy.

The primary outcome was live birth rate, and secondary outcomes were a history of miscarriage, ectopic pregnancy, and obstetric complications. A total of 164 women were allocated to LMWH plus standard care, and 162 women to standard care alone. LMWH was shown to be safe without major/minor bleeding or maternal heparin-induced thrombocytopenia.

The statistical calculation was by “intention to treat,” which considers all enrolled participants, including those who dropped out of the study, as opposed to a “per protocol” analysis in which only patients who completed the study were analyzed.

Results. Primary outcome data were available for 320 participants. Of the 162 women in the LMWH-treated group, 116 (72%) had live birth rates, as did 112 (71%) of 158 in the standard care group. There was no significant difference between groups (OR, 1.04; 95% CI, 0.64–1.68).

Study strengths and limitations

The outcome of the ALIFE2 study is consistent with that of a Cochrane review that found insufficient evidence for improved live birth rate in patients with RPL and inherited thrombophilias treated with LMWH versus low-dose aspirin. Of their review of the studies at low risk of bias, only 1 was placebo controlled.⁸

This study by Quenby and colleagues was well designed and ensured a sufficient number of enrolled participants to comply with their power analysis. However, by beginning LMWH at 7 weeks’ gestation, patients may not have received a therapeutic benefit as opposed to initiation of treatment with a positive pregnancy test. The authors did not describe when testing for thrombophilias occurred or explain the protocol and reason for repeat testing.

Study limitations included a deviation from protocol in the standard care group, which was the initiation of LMWH after 7 weeks’ gestation. In the standard care group, 30 participants received LMWH, 18 of whom started heparin treatment before 12 weeks of gestation. The other 12 participants received LMWH after 12 weeks’ gestation, and 6 of those 12 started after 28 weeks’ gestation, since they were determined to need LMWH for thromboprophylaxis according to RCOG guidelines. While this had the potential to influence outcomes, only 18 of 162 (11%) patients were involved.

The authors did not define RPL based on a clinical versus a biochemical pregnancy loss as the latter is more common and is without agreed upon criteria for testing. Additionally, a lack of patient masking to medication could play an undetermined role in affecting the outcome. ●

Quenby S, Booth K, Hiller L, et al; ALIFE2 Block Writing Committee and ALIFE2 Investigators. Heparin for women with recurrent miscarriage and inherited thrombophilia (ALIFE2): an international open-label, randomised controlled trial. Lancet. 2023;402:54-61. doi:10.1016/S0140-6736(23)00693-1.

EXPERT COMMENTARY

“Follow the evidence to where it leads, even if the conclusion is uncomfortable.”

—Steven James, author

Women with RPL have endured overzealous evaluations and management despite a lack of proven efficacy. From alloimmune testing that results in paternal leukocyte immunization¹ and the long-entrusted metroplasty for a septate uterus recently put under fire² to the “hammer and nail” approach of preimplantation genetic testing for embryo aneuploid screening,³ patients have been subjected to unsubstantiated treatments.

While the evaluation of RPL has evolved, guidelines from the American Society for Reproductive Medicine (ASRM), American College of Obstetricians and Gynecologists (ACOG), and Royal College of Obstetricians and Gynaecologists (RCOG) do not recommend testing for inherited thrombophilias outside of a history for venous thromboembolism.^4-6 These 3 societies support treating acquired thrombophilias that represent the antiphospholipid antibody syndrome.

Citing insufficient evidence for reducing adverse pregnancy outcomes, ACOG recommends the use of prophylactic- or intermediate-dose LMWH or unfractionated heparin (UFH) for patients with “high-risk” thrombophilias only to prevent venous thromboembolism during pregnancy and continuing postpartum.⁴ (High-risk thrombophilias are defined as factor V Leiden homozygosity, prothrombin gene G20210A mutation homozygosity, heterozygosity for both factor V Leiden homozygosity and prothrombin gene G20210A mutation, or an antithrombin deficiency.⁴)

To determine the impact of LMWH treatment versus no treatment on live birth rate, Quenby and colleagues conducted a prospective randomized controlled trial of women with RPL and inherited thrombophilias (the ALIFE2 trial). This was a follow-up to their 2010 randomized controlled trial that demonstrated no effect of LMWH with low-dose aspirin versus low-dose aspirin alone compared with placebo in women with unexplained RPL.⁷

PHOTO: BETAVERSO/SHUTTERSTOCK

Continue to: Details of the study...

The ALIFE2 study took place over 8 years and involved 5 countries, including the United States, with the 2 main centers in the Netherlands and the United Kingdom. Women eligible for the study were aged 18 to 42 years, had an inherited thrombophilia (confirmed by 2 tests), experienced recurrent miscarriages (2 or more consecutive miscarriages, nonconsecutive miscarriages, or intrauterine fetal deaths, irrespective of gestational age), and were less than 7 weeks’ estimated gestational age. Study patients were randomly allocated with a positive pregnancy test to either surveillance or LMWH treatment, which was continued throughout pregnancy.

The primary outcome was live birth rate, and secondary outcomes were a history of miscarriage, ectopic pregnancy, and obstetric complications. A total of 164 women were allocated to LMWH plus standard care, and 162 women to standard care alone. LMWH was shown to be safe without major/minor bleeding or maternal heparin-induced thrombocytopenia.

The statistical calculation was by “intention to treat,” which considers all enrolled participants, including those who dropped out of the study, as opposed to a “per protocol” analysis in which only patients who completed the study were analyzed.

Results. Primary outcome data were available for 320 participants. Of the 162 women in the LMWH-treated group, 116 (72%) had live birth rates, as did 112 (71%) of 158 in the standard care group. There was no significant difference between groups (OR, 1.04; 95% CI, 0.64–1.68).

Study strengths and limitations

The outcome of the ALIFE2 study is consistent with that of a Cochrane review that found insufficient evidence for improved live birth rate in patients with RPL and inherited thrombophilias treated with LMWH versus low-dose aspirin. Of their review of the studies at low risk of bias, only 1 was placebo controlled.⁸

This study by Quenby and colleagues was well designed and ensured a sufficient number of enrolled participants to comply with their power analysis. However, by beginning LMWH at 7 weeks’ gestation, patients may not have received a therapeutic benefit as opposed to initiation of treatment with a positive pregnancy test. The authors did not describe when testing for thrombophilias occurred or explain the protocol and reason for repeat testing.

Study limitations included a deviation from protocol in the standard care group, which was the initiation of LMWH after 7 weeks’ gestation. In the standard care group, 30 participants received LMWH, 18 of whom started heparin treatment before 12 weeks of gestation. The other 12 participants received LMWH after 12 weeks’ gestation, and 6 of those 12 started after 28 weeks’ gestation, since they were determined to need LMWH for thromboprophylaxis according to RCOG guidelines. While this had the potential to influence outcomes, only 18 of 162 (11%) patients were involved.

The authors did not define RPL based on a clinical versus a biochemical pregnancy loss as the latter is more common and is without agreed upon criteria for testing. Additionally, a lack of patient masking to medication could play an undetermined role in affecting the outcome. ●

Quenby S, Booth K, Hiller L, et al; ALIFE2 Block Writing Committee and ALIFE2 Investigators. Heparin for women with recurrent miscarriage and inherited thrombophilia (ALIFE2): an international open-label, randomised controlled trial. Lancet. 2023;402:54-61. doi:10.1016/S0140-6736(23)00693-1.

EXPERT COMMENTARY

“Follow the evidence to where it leads, even if the conclusion is uncomfortable.”

—Steven James, author

Women with RPL have endured overzealous evaluations and management despite a lack of proven efficacy. From alloimmune testing that results in paternal leukocyte immunization¹ and the long-entrusted metroplasty for a septate uterus recently put under fire² to the “hammer and nail” approach of preimplantation genetic testing for embryo aneuploid screening,³ patients have been subjected to unsubstantiated treatments.

While the evaluation of RPL has evolved, guidelines from the American Society for Reproductive Medicine (ASRM), American College of Obstetricians and Gynecologists (ACOG), and Royal College of Obstetricians and Gynaecologists (RCOG) do not recommend testing for inherited thrombophilias outside of a history for venous thromboembolism.^4-6 These 3 societies support treating acquired thrombophilias that represent the antiphospholipid antibody syndrome.

Citing insufficient evidence for reducing adverse pregnancy outcomes, ACOG recommends the use of prophylactic- or intermediate-dose LMWH or unfractionated heparin (UFH) for patients with “high-risk” thrombophilias only to prevent venous thromboembolism during pregnancy and continuing postpartum.⁴ (High-risk thrombophilias are defined as factor V Leiden homozygosity, prothrombin gene G20210A mutation homozygosity, heterozygosity for both factor V Leiden homozygosity and prothrombin gene G20210A mutation, or an antithrombin deficiency.⁴)

To determine the impact of LMWH treatment versus no treatment on live birth rate, Quenby and colleagues conducted a prospective randomized controlled trial of women with RPL and inherited thrombophilias (the ALIFE2 trial). This was a follow-up to their 2010 randomized controlled trial that demonstrated no effect of LMWH with low-dose aspirin versus low-dose aspirin alone compared with placebo in women with unexplained RPL.⁷

PHOTO: BETAVERSO/SHUTTERSTOCK

Continue to: Details of the study...

The ALIFE2 study took place over 8 years and involved 5 countries, including the United States, with the 2 main centers in the Netherlands and the United Kingdom. Women eligible for the study were aged 18 to 42 years, had an inherited thrombophilia (confirmed by 2 tests), experienced recurrent miscarriages (2 or more consecutive miscarriages, nonconsecutive miscarriages, or intrauterine fetal deaths, irrespective of gestational age), and were less than 7 weeks’ estimated gestational age. Study patients were randomly allocated with a positive pregnancy test to either surveillance or LMWH treatment, which was continued throughout pregnancy.

The primary outcome was live birth rate, and secondary outcomes were a history of miscarriage, ectopic pregnancy, and obstetric complications. A total of 164 women were allocated to LMWH plus standard care, and 162 women to standard care alone. LMWH was shown to be safe without major/minor bleeding or maternal heparin-induced thrombocytopenia.

The statistical calculation was by “intention to treat,” which considers all enrolled participants, including those who dropped out of the study, as opposed to a “per protocol” analysis in which only patients who completed the study were analyzed.

Results. Primary outcome data were available for 320 participants. Of the 162 women in the LMWH-treated group, 116 (72%) had live birth rates, as did 112 (71%) of 158 in the standard care group. There was no significant difference between groups (OR, 1.04; 95% CI, 0.64–1.68).

Study strengths and limitations

The outcome of the ALIFE2 study is consistent with that of a Cochrane review that found insufficient evidence for improved live birth rate in patients with RPL and inherited thrombophilias treated with LMWH versus low-dose aspirin. Of their review of the studies at low risk of bias, only 1 was placebo controlled.⁸

This study by Quenby and colleagues was well designed and ensured a sufficient number of enrolled participants to comply with their power analysis. However, by beginning LMWH at 7 weeks’ gestation, patients may not have received a therapeutic benefit as opposed to initiation of treatment with a positive pregnancy test. The authors did not describe when testing for thrombophilias occurred or explain the protocol and reason for repeat testing.

Study limitations included a deviation from protocol in the standard care group, which was the initiation of LMWH after 7 weeks’ gestation. In the standard care group, 30 participants received LMWH, 18 of whom started heparin treatment before 12 weeks of gestation. The other 12 participants received LMWH after 12 weeks’ gestation, and 6 of those 12 started after 28 weeks’ gestation, since they were determined to need LMWH for thromboprophylaxis according to RCOG guidelines. While this had the potential to influence outcomes, only 18 of 162 (11%) patients were involved.

The authors did not define RPL based on a clinical versus a biochemical pregnancy loss as the latter is more common and is without agreed upon criteria for testing. Additionally, a lack of patient masking to medication could play an undetermined role in affecting the outcome. ●