Alopecia areata (AA) is an autoimmune disorder characterized by transient hair loss with preservation of the hair follicle (HF). The lifetime incidence risk of AA is approximately 2%,¹ with a mean age of onset of 25 to 36 years and with no clinically relevant significant differences between sex or ethnicity.² Most commonly, it presents as round, well-demarcated patches of alopecia on the scalp and spontaneously resolves in nearly 30% of patients. However, severe disease is associated with younger age of presentation and can progress to a total loss of scalp or body hair—referred to as alopecia totalis and alopecia universalis, respectively—thus severely impacting quality of life.^3,4

First-line treatment options for AA include potent topical steroids^5,6 and intralesional (IL) steroids, most commonly IL triamcinolone acetonide (ILTA). Intralesional steroids have been found to be more effective than topicals in stimulating hair growth at the injection site.^7,8 A recent systemic therapy—the Janus kinase inhibitor baricitinib—was approved by the US Food and Drug Administration for AA.⁹ Other systemic therapies such as oral corticosteroids have been studied in small trials with promising results.¹⁰ However, the risks of systemic therapies may outweigh the benefits.^9,10

Another less common topical therapy is contact immunotherapy, which involves topical application of an unlicensed non–pharmaceutical-grade agent to areas affected with AA. It is reported to have a wide range of response rates (29%–87%).¹¹

We report 2 cases of extensive AA that were treated with a novel combination regimen— 2.5 mg/mL of ILTA diluted with lidocaine 1% and epinephrine 1:100,000 in place of normal saline (NS)— which is a modification to an already widely used first-line treatment.

Case Reports

Patient 1—An 11-year-old girl presented with nonscarring alopecia of the vertex and occipital scalp. Three years prior she was treated with topical and IL corticosteroids by a different provider. Physical examination revealed almost complete alopecia involving the bottom two-thirds of the occipital scalp as well as the medial eyebrows (Figures 1A and 1B). Over the span of 1 year she was treated with betamethasone dipropionate cream 0.05% and several rounds of ILTA 2.5 mg/mL buffered with NS, with minimal improvement. A year after the initial presentation, the decision was made to initiate monthly injections of ILTA 2.5 mg/mL buffered with 1% lidocaine and epinephrine 1:100,000. Some hair regrowth of the occipital scalp was noted by 3 months, with near-complete regrowth of the scalp hair and eyebrows by 7 months and 5 months, respectively (Figures 1C and 1D). During this period, the patient continued to develop new areas of alopecia of the scalp and eyebrows, which also were injected with this combination. In total, the patient received 8 rounds of IL injections 4 to 6 weeks apart in the scalp and 6 rounds in the eyebrows. The treated areas showed resolution over a follow-up period of 14 months, though there was recurrence at the right medial eyebrow at 5 months. No localized skin atrophy or other adverse effects were noted.

Patient 2—A 34-year-old woman who was otherwise healthy presented with previously untreated AA involving the scalp of 2 months’ duration. Physical examination revealed the following areas of nonscarring alopecia: a 10×10-cm area of the right occipital scalp with some regrowth; a 10×14-cm area of the left parieto-occipital scalp; and a 1-cm area posterior to the vertex (Figure 2A). Given the extensive involvement, the decision was made to initiate ILTA 2.5 mg/mL buffered with 1% lidocaine and epinephrine 1:100,000 once monthly. Appreciable hair regrowth was noted within 1 month, mostly on the parietal scalp. Substantial improvement was noted after 3 months in all affected areas of the hair-bearing scalp, with near-complete regrowth on the left occipital scalp and greater than 50% regrowth on the right occipital scalp (Figure 2B). No adverse effects were noted. She currently has no alopecia.

Comment

Alopecia Pathogenesis—The most widely adopted theory of AA etiology implicates an aberrant immune response. The HF, which is a dynamic “mini-organ” with its own immune and hormonal microenvironment, is considered an “immune-privileged site”—meaning it is less exposed to immune responses than most other body areas. It is hypothesized that AA results from a breakdown in this immune privilege, with the subsequent attack on the peribulbar part of the follicle by CD8⁺ T lymphocytes. This lymphocytic infiltrate induces apoptosis in the HF keratinocytes, resulting in inhibition of hair shaft production.¹² Other theories suggest a link to the sympathetic-adrenal-medullary system and hypothalamic-pituitary-adrenal axis.¹³

Therapies for Alopecia—Topical and IL corticosteroids are the first-line therapies for localized AA in patients with less than 50% scalp involvement. Triamcinolone acetonide generally is the IL steroid of choice because it is widely available and less atrophogenic than other steroids. Unlike topicals, ILTA bypasses the epidermis when injected, achieving direct access to the HF.¹⁴

High-quality controlled studies regarding the use of ILTA in AA are scarce. A meta-analysis concluded that 5 mg/mL and 10 mg/mL of ILTA diluted in NS were equally effective (80.9% [P<.05] vs 76.4% [P<.005], respectively). Concentrations of less than 5 mg/mL of ILTA resulted in lower rates of hair regrowth (62.3%; P=.04).¹⁵ The role of diluents other than NS has not been studied.

Benefits of Epinephrine in ILTA Therapy—The role of epinephrine 1:100,000 is to decrease the rate of clearance of triamcinolone acetonide from the HF, allowing for a better therapeutic effect. Laser Doppler blood flowmeter studies have shown that epinephrine 1:100,000 injected in the scalp causes vasoconstriction, thereby decreasing the blood flow rate of clearance of other substances in the same solution.¹⁶ Also, a more gradual systemic absorption is achieved, decreasing systemic side effects such as osteoporosis.¹⁷

Another potential benefit of epinephrine has been suggested in animal studies that demonstrate the important role of the sympathetic nervous system in HF growth. In a mouse study, chemical sympathectomy led to diminished norepinephrine levels in the skin, accompanied by a decreased keratinocyte proliferation and hair growth. Conversely, norepinephrine was found to promote HF growth in an organotypic skin culture model.¹⁸ Topically applied isoproterenol, a panadrenergic receptor agonist, accelerated HF growth in an organotypic skin culture. It also has been shown that external light and temperature changes stimulate hair growth via the sympathetic nervous system, promoting anagen HF growth in cultured skin explants, further linking HF activity with sympathetic nerve activity.¹⁹

In our experience, cases of AA that at first failed ILTA 5 mg/mL in NS have been successfully treated with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000. One such case was alopecia totalis, though we do not have high-quality photographs to present for this report. The 2 cases presented here are the ones with the best photographs to demonstrate our outcomes. Both were treated with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000 administered using a 0.5-in long 30-gauge needle, with 0.05 to 0.1 mL per injection approximately 0.51-cm apart. The treatment intervals were 4 weeks, with a maximal dose of 20 mg per session. In addition to the 2 cases reported here, the Table includes 2 other patients in our practice who were successfully treated with this novel regimen.

Prior to adopting this combination regimen, our standard therapy for AA was 5 mg/mL ILTA buffered with NS. Instead of NS, we now use the widely available 1% lidocaine with epinephrine 1:100,000 and dilute the ILTA to 2.5 mg/mL. We postulate that epinephrine 1:100,000 enhances therapeutic efficacy via local vasoconstriction, thus keeping the ILTA in situ longer than NS. This effect allows for a lower concentration of ILTA (2.5 mg/mL) to be effective. Furthermore, epinephrine 1:100,000 may have an independent effect, as suggested in mouse studies.¹⁸

Our first case demonstrated the ophiasis subtype of AA (symmetric bandlike hair loss), which has a poorer prognosis and is less responsive to therapy.²⁰ In this patient, prior treatment with topical corticosteroids and ILTA in NS failed to induce a response. After a series of injections with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000, she entered remission. Our second case is one of alopecia subtotalis, which responded quickly, and the patient entered remission after just 3 months of treatment. These 2 cases are illustrative of the results that we regularly get and have come to expect with this treatment.

Conclusion

Our novel modified regimen of 2.5 mg/mL ILTA diluted with 1% lidocaine and epinephrine 1:100,000 has yielded a series of excellent outcomes in many of our most challenging AA cases without any untoward effects. Two cases are presented here. Higher-powered studies are needed to validate this new yet simple approach. A split-scalp or split-lesion study comparing ILTA with and without epinephrine 1:100,000 would be warranted for further investigation.

Alopecia areata (AA) is an autoimmune disorder characterized by transient hair loss with preservation of the hair follicle (HF). The lifetime incidence risk of AA is approximately 2%,¹ with a mean age of onset of 25 to 36 years and with no clinically relevant significant differences between sex or ethnicity.² Most commonly, it presents as round, well-demarcated patches of alopecia on the scalp and spontaneously resolves in nearly 30% of patients. However, severe disease is associated with younger age of presentation and can progress to a total loss of scalp or body hair—referred to as alopecia totalis and alopecia universalis, respectively—thus severely impacting quality of life.^3,4

First-line treatment options for AA include potent topical steroids^5,6 and intralesional (IL) steroids, most commonly IL triamcinolone acetonide (ILTA). Intralesional steroids have been found to be more effective than topicals in stimulating hair growth at the injection site.^7,8 A recent systemic therapy—the Janus kinase inhibitor baricitinib—was approved by the US Food and Drug Administration for AA.⁹ Other systemic therapies such as oral corticosteroids have been studied in small trials with promising results.¹⁰ However, the risks of systemic therapies may outweigh the benefits.^9,10

Another less common topical therapy is contact immunotherapy, which involves topical application of an unlicensed non–pharmaceutical-grade agent to areas affected with AA. It is reported to have a wide range of response rates (29%–87%).¹¹

We report 2 cases of extensive AA that were treated with a novel combination regimen— 2.5 mg/mL of ILTA diluted with lidocaine 1% and epinephrine 1:100,000 in place of normal saline (NS)— which is a modification to an already widely used first-line treatment.

Case Reports

Patient 1—An 11-year-old girl presented with nonscarring alopecia of the vertex and occipital scalp. Three years prior she was treated with topical and IL corticosteroids by a different provider. Physical examination revealed almost complete alopecia involving the bottom two-thirds of the occipital scalp as well as the medial eyebrows (Figures 1A and 1B). Over the span of 1 year she was treated with betamethasone dipropionate cream 0.05% and several rounds of ILTA 2.5 mg/mL buffered with NS, with minimal improvement. A year after the initial presentation, the decision was made to initiate monthly injections of ILTA 2.5 mg/mL buffered with 1% lidocaine and epinephrine 1:100,000. Some hair regrowth of the occipital scalp was noted by 3 months, with near-complete regrowth of the scalp hair and eyebrows by 7 months and 5 months, respectively (Figures 1C and 1D). During this period, the patient continued to develop new areas of alopecia of the scalp and eyebrows, which also were injected with this combination. In total, the patient received 8 rounds of IL injections 4 to 6 weeks apart in the scalp and 6 rounds in the eyebrows. The treated areas showed resolution over a follow-up period of 14 months, though there was recurrence at the right medial eyebrow at 5 months. No localized skin atrophy or other adverse effects were noted.

Patient 2—A 34-year-old woman who was otherwise healthy presented with previously untreated AA involving the scalp of 2 months’ duration. Physical examination revealed the following areas of nonscarring alopecia: a 10×10-cm area of the right occipital scalp with some regrowth; a 10×14-cm area of the left parieto-occipital scalp; and a 1-cm area posterior to the vertex (Figure 2A). Given the extensive involvement, the decision was made to initiate ILTA 2.5 mg/mL buffered with 1% lidocaine and epinephrine 1:100,000 once monthly. Appreciable hair regrowth was noted within 1 month, mostly on the parietal scalp. Substantial improvement was noted after 3 months in all affected areas of the hair-bearing scalp, with near-complete regrowth on the left occipital scalp and greater than 50% regrowth on the right occipital scalp (Figure 2B). No adverse effects were noted. She currently has no alopecia.

Comment

Alopecia Pathogenesis—The most widely adopted theory of AA etiology implicates an aberrant immune response. The HF, which is a dynamic “mini-organ” with its own immune and hormonal microenvironment, is considered an “immune-privileged site”—meaning it is less exposed to immune responses than most other body areas. It is hypothesized that AA results from a breakdown in this immune privilege, with the subsequent attack on the peribulbar part of the follicle by CD8⁺ T lymphocytes. This lymphocytic infiltrate induces apoptosis in the HF keratinocytes, resulting in inhibition of hair shaft production.¹² Other theories suggest a link to the sympathetic-adrenal-medullary system and hypothalamic-pituitary-adrenal axis.¹³

Therapies for Alopecia—Topical and IL corticosteroids are the first-line therapies for localized AA in patients with less than 50% scalp involvement. Triamcinolone acetonide generally is the IL steroid of choice because it is widely available and less atrophogenic than other steroids. Unlike topicals, ILTA bypasses the epidermis when injected, achieving direct access to the HF.¹⁴

High-quality controlled studies regarding the use of ILTA in AA are scarce. A meta-analysis concluded that 5 mg/mL and 10 mg/mL of ILTA diluted in NS were equally effective (80.9% [P<.05] vs 76.4% [P<.005], respectively). Concentrations of less than 5 mg/mL of ILTA resulted in lower rates of hair regrowth (62.3%; P=.04).¹⁵ The role of diluents other than NS has not been studied.

Benefits of Epinephrine in ILTA Therapy—The role of epinephrine 1:100,000 is to decrease the rate of clearance of triamcinolone acetonide from the HF, allowing for a better therapeutic effect. Laser Doppler blood flowmeter studies have shown that epinephrine 1:100,000 injected in the scalp causes vasoconstriction, thereby decreasing the blood flow rate of clearance of other substances in the same solution.¹⁶ Also, a more gradual systemic absorption is achieved, decreasing systemic side effects such as osteoporosis.¹⁷

Another potential benefit of epinephrine has been suggested in animal studies that demonstrate the important role of the sympathetic nervous system in HF growth. In a mouse study, chemical sympathectomy led to diminished norepinephrine levels in the skin, accompanied by a decreased keratinocyte proliferation and hair growth. Conversely, norepinephrine was found to promote HF growth in an organotypic skin culture model.¹⁸ Topically applied isoproterenol, a panadrenergic receptor agonist, accelerated HF growth in an organotypic skin culture. It also has been shown that external light and temperature changes stimulate hair growth via the sympathetic nervous system, promoting anagen HF growth in cultured skin explants, further linking HF activity with sympathetic nerve activity.¹⁹

In our experience, cases of AA that at first failed ILTA 5 mg/mL in NS have been successfully treated with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000. One such case was alopecia totalis, though we do not have high-quality photographs to present for this report. The 2 cases presented here are the ones with the best photographs to demonstrate our outcomes. Both were treated with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000 administered using a 0.5-in long 30-gauge needle, with 0.05 to 0.1 mL per injection approximately 0.51-cm apart. The treatment intervals were 4 weeks, with a maximal dose of 20 mg per session. In addition to the 2 cases reported here, the Table includes 2 other patients in our practice who were successfully treated with this novel regimen.

Prior to adopting this combination regimen, our standard therapy for AA was 5 mg/mL ILTA buffered with NS. Instead of NS, we now use the widely available 1% lidocaine with epinephrine 1:100,000 and dilute the ILTA to 2.5 mg/mL. We postulate that epinephrine 1:100,000 enhances therapeutic efficacy via local vasoconstriction, thus keeping the ILTA in situ longer than NS. This effect allows for a lower concentration of ILTA (2.5 mg/mL) to be effective. Furthermore, epinephrine 1:100,000 may have an independent effect, as suggested in mouse studies.¹⁸

Our first case demonstrated the ophiasis subtype of AA (symmetric bandlike hair loss), which has a poorer prognosis and is less responsive to therapy.²⁰ In this patient, prior treatment with topical corticosteroids and ILTA in NS failed to induce a response. After a series of injections with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000, she entered remission. Our second case is one of alopecia subtotalis, which responded quickly, and the patient entered remission after just 3 months of treatment. These 2 cases are illustrative of the results that we regularly get and have come to expect with this treatment.

Conclusion

Our novel modified regimen of 2.5 mg/mL ILTA diluted with 1% lidocaine and epinephrine 1:100,000 has yielded a series of excellent outcomes in many of our most challenging AA cases without any untoward effects. Two cases are presented here. Higher-powered studies are needed to validate this new yet simple approach. A split-scalp or split-lesion study comparing ILTA with and without epinephrine 1:100,000 would be warranted for further investigation.

Alopecia areata (AA) is an autoimmune disorder characterized by transient hair loss with preservation of the hair follicle (HF). The lifetime incidence risk of AA is approximately 2%,¹ with a mean age of onset of 25 to 36 years and with no clinically relevant significant differences between sex or ethnicity.² Most commonly, it presents as round, well-demarcated patches of alopecia on the scalp and spontaneously resolves in nearly 30% of patients. However, severe disease is associated with younger age of presentation and can progress to a total loss of scalp or body hair—referred to as alopecia totalis and alopecia universalis, respectively—thus severely impacting quality of life.^3,4

First-line treatment options for AA include potent topical steroids^5,6 and intralesional (IL) steroids, most commonly IL triamcinolone acetonide (ILTA). Intralesional steroids have been found to be more effective than topicals in stimulating hair growth at the injection site.^7,8 A recent systemic therapy—the Janus kinase inhibitor baricitinib—was approved by the US Food and Drug Administration for AA.⁹ Other systemic therapies such as oral corticosteroids have been studied in small trials with promising results.¹⁰ However, the risks of systemic therapies may outweigh the benefits.^9,10

Another less common topical therapy is contact immunotherapy, which involves topical application of an unlicensed non–pharmaceutical-grade agent to areas affected with AA. It is reported to have a wide range of response rates (29%–87%).¹¹

We report 2 cases of extensive AA that were treated with a novel combination regimen— 2.5 mg/mL of ILTA diluted with lidocaine 1% and epinephrine 1:100,000 in place of normal saline (NS)— which is a modification to an already widely used first-line treatment.

Case Reports

Patient 1—An 11-year-old girl presented with nonscarring alopecia of the vertex and occipital scalp. Three years prior she was treated with topical and IL corticosteroids by a different provider. Physical examination revealed almost complete alopecia involving the bottom two-thirds of the occipital scalp as well as the medial eyebrows (Figures 1A and 1B). Over the span of 1 year she was treated with betamethasone dipropionate cream 0.05% and several rounds of ILTA 2.5 mg/mL buffered with NS, with minimal improvement. A year after the initial presentation, the decision was made to initiate monthly injections of ILTA 2.5 mg/mL buffered with 1% lidocaine and epinephrine 1:100,000. Some hair regrowth of the occipital scalp was noted by 3 months, with near-complete regrowth of the scalp hair and eyebrows by 7 months and 5 months, respectively (Figures 1C and 1D). During this period, the patient continued to develop new areas of alopecia of the scalp and eyebrows, which also were injected with this combination. In total, the patient received 8 rounds of IL injections 4 to 6 weeks apart in the scalp and 6 rounds in the eyebrows. The treated areas showed resolution over a follow-up period of 14 months, though there was recurrence at the right medial eyebrow at 5 months. No localized skin atrophy or other adverse effects were noted.

Patient 2—A 34-year-old woman who was otherwise healthy presented with previously untreated AA involving the scalp of 2 months’ duration. Physical examination revealed the following areas of nonscarring alopecia: a 10×10-cm area of the right occipital scalp with some regrowth; a 10×14-cm area of the left parieto-occipital scalp; and a 1-cm area posterior to the vertex (Figure 2A). Given the extensive involvement, the decision was made to initiate ILTA 2.5 mg/mL buffered with 1% lidocaine and epinephrine 1:100,000 once monthly. Appreciable hair regrowth was noted within 1 month, mostly on the parietal scalp. Substantial improvement was noted after 3 months in all affected areas of the hair-bearing scalp, with near-complete regrowth on the left occipital scalp and greater than 50% regrowth on the right occipital scalp (Figure 2B). No adverse effects were noted. She currently has no alopecia.

Comment

Alopecia Pathogenesis—The most widely adopted theory of AA etiology implicates an aberrant immune response. The HF, which is a dynamic “mini-organ” with its own immune and hormonal microenvironment, is considered an “immune-privileged site”—meaning it is less exposed to immune responses than most other body areas. It is hypothesized that AA results from a breakdown in this immune privilege, with the subsequent attack on the peribulbar part of the follicle by CD8⁺ T lymphocytes. This lymphocytic infiltrate induces apoptosis in the HF keratinocytes, resulting in inhibition of hair shaft production.¹² Other theories suggest a link to the sympathetic-adrenal-medullary system and hypothalamic-pituitary-adrenal axis.¹³

Therapies for Alopecia—Topical and IL corticosteroids are the first-line therapies for localized AA in patients with less than 50% scalp involvement. Triamcinolone acetonide generally is the IL steroid of choice because it is widely available and less atrophogenic than other steroids. Unlike topicals, ILTA bypasses the epidermis when injected, achieving direct access to the HF.¹⁴

High-quality controlled studies regarding the use of ILTA in AA are scarce. A meta-analysis concluded that 5 mg/mL and 10 mg/mL of ILTA diluted in NS were equally effective (80.9% [P<.05] vs 76.4% [P<.005], respectively). Concentrations of less than 5 mg/mL of ILTA resulted in lower rates of hair regrowth (62.3%; P=.04).¹⁵ The role of diluents other than NS has not been studied.

Benefits of Epinephrine in ILTA Therapy—The role of epinephrine 1:100,000 is to decrease the rate of clearance of triamcinolone acetonide from the HF, allowing for a better therapeutic effect. Laser Doppler blood flowmeter studies have shown that epinephrine 1:100,000 injected in the scalp causes vasoconstriction, thereby decreasing the blood flow rate of clearance of other substances in the same solution.¹⁶ Also, a more gradual systemic absorption is achieved, decreasing systemic side effects such as osteoporosis.¹⁷

Another potential benefit of epinephrine has been suggested in animal studies that demonstrate the important role of the sympathetic nervous system in HF growth. In a mouse study, chemical sympathectomy led to diminished norepinephrine levels in the skin, accompanied by a decreased keratinocyte proliferation and hair growth. Conversely, norepinephrine was found to promote HF growth in an organotypic skin culture model.¹⁸ Topically applied isoproterenol, a panadrenergic receptor agonist, accelerated HF growth in an organotypic skin culture. It also has been shown that external light and temperature changes stimulate hair growth via the sympathetic nervous system, promoting anagen HF growth in cultured skin explants, further linking HF activity with sympathetic nerve activity.¹⁹

In our experience, cases of AA that at first failed ILTA 5 mg/mL in NS have been successfully treated with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000. One such case was alopecia totalis, though we do not have high-quality photographs to present for this report. The 2 cases presented here are the ones with the best photographs to demonstrate our outcomes. Both were treated with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000 administered using a 0.5-in long 30-gauge needle, with 0.05 to 0.1 mL per injection approximately 0.51-cm apart. The treatment intervals were 4 weeks, with a maximal dose of 20 mg per session. In addition to the 2 cases reported here, the Table includes 2 other patients in our practice who were successfully treated with this novel regimen.

Prior to adopting this combination regimen, our standard therapy for AA was 5 mg/mL ILTA buffered with NS. Instead of NS, we now use the widely available 1% lidocaine with epinephrine 1:100,000 and dilute the ILTA to 2.5 mg/mL. We postulate that epinephrine 1:100,000 enhances therapeutic efficacy via local vasoconstriction, thus keeping the ILTA in situ longer than NS. This effect allows for a lower concentration of ILTA (2.5 mg/mL) to be effective. Furthermore, epinephrine 1:100,000 may have an independent effect, as suggested in mouse studies.¹⁸

Our first case demonstrated the ophiasis subtype of AA (symmetric bandlike hair loss), which has a poorer prognosis and is less responsive to therapy.²⁰ In this patient, prior treatment with topical corticosteroids and ILTA in NS failed to induce a response. After a series of injections with 2.5 mg/mL ILTA in 1% lidocaine and epinephrine 1:100,000, she entered remission. Our second case is one of alopecia subtotalis, which responded quickly, and the patient entered remission after just 3 months of treatment. These 2 cases are illustrative of the results that we regularly get and have come to expect with this treatment.

Conclusion

Our novel modified regimen of 2.5 mg/mL ILTA diluted with 1% lidocaine and epinephrine 1:100,000 has yielded a series of excellent outcomes in many of our most challenging AA cases without any untoward effects. Two cases are presented here. Higher-powered studies are needed to validate this new yet simple approach. A split-scalp or split-lesion study comparing ILTA with and without epinephrine 1:100,000 would be warranted for further investigation.

A risk-tailored early-detection strategy for pancreatic cancer that targets patients with new-onset diabetes could be cost effective, according to a recent study.

Screening for pancreatic ductal adenocarcinoma in asymptomatic adults is not recommended, but patients with new-onset diabetes have a risk that’s eight times higher than expected. Screening these patients could improve diagnosis and survival rates if the cancer can be identified at earlier stages, researchers led by Louise Wang, MD, a gastroenterology fellow at the University of Pennsylvania, Philadelphia, wrote in Clinical Gastroenterology and Hepatology.

“As we continue to improve therapies for early-stage pancreatic cancers, especially among the local/resectable stage, the case for the targeted early-detection strategy will be stronger,” they wrote. “Policy makers should take into consideration these novel findings when formulating [pancreatic ductal adenocarcinoma] screening policy and making coverage determinations.”

The research team compared early detection strategies for pancreatic ductal adenocarcinoma that target new-onset diabetes patients at age 50 years and older with standard of care, defined as no early detection strategy. They looked at various minimal predicted cancer risk thresholds versus current standard of care in a Markov state-transition decision model. The analysis assumed a health care sector perspective and a lifetime horizon, with two willingness-to-pay thresholds ($100,000 and $150,000) per quality-adjusted life-year gained.

The researchers used data from one of their previously published studies, which included 89,881 patients with new-onset diabetes diagnosed at age 50 or older. The cumulative incidence of pancreatic cancer was 0.42% during the 3 years after diagnosis.

In the early detection strategy, all patients 50 years and older who were newly diagnosed with diabetes mellitus were placed into low-risk and high-risk cohorts based on their predicted 3-year risk of pancreatic ductal adenocarcinoma under a range of assumed minimum-risk thresholds – 0.5%, 1%, 2%, 3%, 4%, and 5%; these thresholds were based on a previously established prediction model.

The research team found that the early detection strategy that targeted patients with a minimum predicted 3-year pancreatic ductal adenocarcinoma risk of 1% was cost effective, based on a willingness-to-pay threshold of $150,000 per quality-adjusted life-year. The incremental cost-effectiveness ratio was $116,911 per quality-adjusted life-year.

At a willingness-to-pay threshold of $100,000 per quality-adjusted life-year, the early detection strategy at the 2% risk threshold was cost effective. The incremental cost-effectiveness ratio was $63,045 per quality-adjusted life-year.

The most influential factors included the proportion of pancreatic ductal adenocarcinomas detected at the local stage, costs of treatment for metastatic cancer, utilities of local and regional cancers, and sensitivity of screening.

A probabilistic sensitivity analysis confirmed that, at a willingness-to-pay threshold of $150,000, early detection at the 1% risk threshold was favored at 30.6%, followed by the 0.5% risk threshold at 20.4%, compared with the standard of care at 1.7%. In addition, at a willingness-to-pay threshold of $100,000, early detection at the 1% risk threshold was favored at 27.3%, followed by the 2% risk threshold at 22.8%, as compared with the standard of care at 2%.

The two early detection strategies were cost effective, capturing 26%-45% of the pancreatic ductal adenocarcinoma cases in patients with new-onset diabetes.

The study authors noted several limitations, including the inability to incorporate out-of-pocket costs for patients, as well as focusing the analysis on the health care perspective.

“We acknowledge that, by incorporating the full consequences of decisions for all stakeholders, a societal perspective would have offered a more complete view on which to base public policy,” they wrote.

At the same time, “given the substantial prevalence of [new-onset diabetes] among [pancreatic ductal adenocarcinoma] cases, this strategy could improve the survival of a substantial proportion of sporadic PDAC cases in the general population,” they concluded.

The study authors reported various disclosures, including grants and research support from Takeda Pharmaceuticals USA, Janssen Pharmaceuticals, the National Institutes of Health, the Crohn’s and Colitis Foundation, Lilly Oncology, GSK, and Clovis Oncology.

A risk-tailored early-detection strategy for pancreatic cancer that targets patients with new-onset diabetes could be cost effective, according to a recent study.

Screening for pancreatic ductal adenocarcinoma in asymptomatic adults is not recommended, but patients with new-onset diabetes have a risk that’s eight times higher than expected. Screening these patients could improve diagnosis and survival rates if the cancer can be identified at earlier stages, researchers led by Louise Wang, MD, a gastroenterology fellow at the University of Pennsylvania, Philadelphia, wrote in Clinical Gastroenterology and Hepatology.

“As we continue to improve therapies for early-stage pancreatic cancers, especially among the local/resectable stage, the case for the targeted early-detection strategy will be stronger,” they wrote. “Policy makers should take into consideration these novel findings when formulating [pancreatic ductal adenocarcinoma] screening policy and making coverage determinations.”

The research team compared early detection strategies for pancreatic ductal adenocarcinoma that target new-onset diabetes patients at age 50 years and older with standard of care, defined as no early detection strategy. They looked at various minimal predicted cancer risk thresholds versus current standard of care in a Markov state-transition decision model. The analysis assumed a health care sector perspective and a lifetime horizon, with two willingness-to-pay thresholds ($100,000 and $150,000) per quality-adjusted life-year gained.

The researchers used data from one of their previously published studies, which included 89,881 patients with new-onset diabetes diagnosed at age 50 or older. The cumulative incidence of pancreatic cancer was 0.42% during the 3 years after diagnosis.

In the early detection strategy, all patients 50 years and older who were newly diagnosed with diabetes mellitus were placed into low-risk and high-risk cohorts based on their predicted 3-year risk of pancreatic ductal adenocarcinoma under a range of assumed minimum-risk thresholds – 0.5%, 1%, 2%, 3%, 4%, and 5%; these thresholds were based on a previously established prediction model.

The research team found that the early detection strategy that targeted patients with a minimum predicted 3-year pancreatic ductal adenocarcinoma risk of 1% was cost effective, based on a willingness-to-pay threshold of $150,000 per quality-adjusted life-year. The incremental cost-effectiveness ratio was $116,911 per quality-adjusted life-year.

At a willingness-to-pay threshold of $100,000 per quality-adjusted life-year, the early detection strategy at the 2% risk threshold was cost effective. The incremental cost-effectiveness ratio was $63,045 per quality-adjusted life-year.

The most influential factors included the proportion of pancreatic ductal adenocarcinomas detected at the local stage, costs of treatment for metastatic cancer, utilities of local and regional cancers, and sensitivity of screening.

A probabilistic sensitivity analysis confirmed that, at a willingness-to-pay threshold of $150,000, early detection at the 1% risk threshold was favored at 30.6%, followed by the 0.5% risk threshold at 20.4%, compared with the standard of care at 1.7%. In addition, at a willingness-to-pay threshold of $100,000, early detection at the 1% risk threshold was favored at 27.3%, followed by the 2% risk threshold at 22.8%, as compared with the standard of care at 2%.

The two early detection strategies were cost effective, capturing 26%-45% of the pancreatic ductal adenocarcinoma cases in patients with new-onset diabetes.

The study authors noted several limitations, including the inability to incorporate out-of-pocket costs for patients, as well as focusing the analysis on the health care perspective.

“We acknowledge that, by incorporating the full consequences of decisions for all stakeholders, a societal perspective would have offered a more complete view on which to base public policy,” they wrote.

At the same time, “given the substantial prevalence of [new-onset diabetes] among [pancreatic ductal adenocarcinoma] cases, this strategy could improve the survival of a substantial proportion of sporadic PDAC cases in the general population,” they concluded.

The study authors reported various disclosures, including grants and research support from Takeda Pharmaceuticals USA, Janssen Pharmaceuticals, the National Institutes of Health, the Crohn’s and Colitis Foundation, Lilly Oncology, GSK, and Clovis Oncology.

A risk-tailored early-detection strategy for pancreatic cancer that targets patients with new-onset diabetes could be cost effective, according to a recent study.

Screening for pancreatic ductal adenocarcinoma in asymptomatic adults is not recommended, but patients with new-onset diabetes have a risk that’s eight times higher than expected. Screening these patients could improve diagnosis and survival rates if the cancer can be identified at earlier stages, researchers led by Louise Wang, MD, a gastroenterology fellow at the University of Pennsylvania, Philadelphia, wrote in Clinical Gastroenterology and Hepatology.

“As we continue to improve therapies for early-stage pancreatic cancers, especially among the local/resectable stage, the case for the targeted early-detection strategy will be stronger,” they wrote. “Policy makers should take into consideration these novel findings when formulating [pancreatic ductal adenocarcinoma] screening policy and making coverage determinations.”

The research team compared early detection strategies for pancreatic ductal adenocarcinoma that target new-onset diabetes patients at age 50 years and older with standard of care, defined as no early detection strategy. They looked at various minimal predicted cancer risk thresholds versus current standard of care in a Markov state-transition decision model. The analysis assumed a health care sector perspective and a lifetime horizon, with two willingness-to-pay thresholds ($100,000 and $150,000) per quality-adjusted life-year gained.

The researchers used data from one of their previously published studies, which included 89,881 patients with new-onset diabetes diagnosed at age 50 or older. The cumulative incidence of pancreatic cancer was 0.42% during the 3 years after diagnosis.

In the early detection strategy, all patients 50 years and older who were newly diagnosed with diabetes mellitus were placed into low-risk and high-risk cohorts based on their predicted 3-year risk of pancreatic ductal adenocarcinoma under a range of assumed minimum-risk thresholds – 0.5%, 1%, 2%, 3%, 4%, and 5%; these thresholds were based on a previously established prediction model.

The research team found that the early detection strategy that targeted patients with a minimum predicted 3-year pancreatic ductal adenocarcinoma risk of 1% was cost effective, based on a willingness-to-pay threshold of $150,000 per quality-adjusted life-year. The incremental cost-effectiveness ratio was $116,911 per quality-adjusted life-year.

At a willingness-to-pay threshold of $100,000 per quality-adjusted life-year, the early detection strategy at the 2% risk threshold was cost effective. The incremental cost-effectiveness ratio was $63,045 per quality-adjusted life-year.

The most influential factors included the proportion of pancreatic ductal adenocarcinomas detected at the local stage, costs of treatment for metastatic cancer, utilities of local and regional cancers, and sensitivity of screening.

A probabilistic sensitivity analysis confirmed that, at a willingness-to-pay threshold of $150,000, early detection at the 1% risk threshold was favored at 30.6%, followed by the 0.5% risk threshold at 20.4%, compared with the standard of care at 1.7%. In addition, at a willingness-to-pay threshold of $100,000, early detection at the 1% risk threshold was favored at 27.3%, followed by the 2% risk threshold at 22.8%, as compared with the standard of care at 2%.

The two early detection strategies were cost effective, capturing 26%-45% of the pancreatic ductal adenocarcinoma cases in patients with new-onset diabetes.

The study authors noted several limitations, including the inability to incorporate out-of-pocket costs for patients, as well as focusing the analysis on the health care perspective.

“We acknowledge that, by incorporating the full consequences of decisions for all stakeholders, a societal perspective would have offered a more complete view on which to base public policy,” they wrote.

At the same time, “given the substantial prevalence of [new-onset diabetes] among [pancreatic ductal adenocarcinoma] cases, this strategy could improve the survival of a substantial proportion of sporadic PDAC cases in the general population,” they concluded.

The study authors reported various disclosures, including grants and research support from Takeda Pharmaceuticals USA, Janssen Pharmaceuticals, the National Institutes of Health, the Crohn’s and Colitis Foundation, Lilly Oncology, GSK, and Clovis Oncology.

In 2021, in U.S. states far removed from one another, numerous cases of melioidosis (Whitmore’s disease) sprang up, some with a fatal outcome. What is the common factor linking all of those affected? So begins the search for evidence.

No relations or common journeys

Between March and July 2021, cases of the bacterial infectious disease sprang up in Georgia, Kansas, Minnesota, and Texas, with the disease being fatal for two of those affected. Usually, cases of melioidosis occur in the United States after traveling to regions where the pathogen is prevalent. However, none of the patients had undertaken any previous international travel.

When the genomes of the bacterial strains (Burkholderia pseudomallei) were sequenced, they showed a high level of concordance, suggesting a common source of infection. The bacterial strain is similar to those that are found in Southeast Asia above all. An imported product from there was taken into consideration as the trigger.

The Centers for Disease Control and Prevention examined blood samples from the patients, as well as samples from the soil, water, food, and household items around their homes.
 

Aroma spray as a trigger

In October, the cause of the melioidosis was finally identified in the house of the patient from Georgia: an aromatherapy spray. The genetic fingerprint of the bacterial strain matched with that from the other patients. The common trigger was thus discovered.

The contaminated spray, with a lavender-chamomile scent for room fragrancing, was sold between February and October in some branches of Walmart, as well as in their online store. The product was therefore recalled and it was checked whether the ingredients were also being used in other products.

The CDC requested physicians to also take melioidosis into account if they were presented with acute bacterial infections that did not respond to normal antibiotics and to inquire whether the affected room spray had been used.
 

More information about melioidosis

Melioidosis is an infectious disease affecting humans and animals. The trigger is the bacteria B pseudomallei. The disease appears predominantly in tropical regions, especially in Southeast Asia and northern Australia.

Transmission

The bacteria can be found in contaminated water and soil. It is disseminated between humans and animals through direct contact with the infectious source, such as through inhaling dust particles or water droplets, or through consuming contaminated water or food. Human-to-human transmission is extremely rare. Recently however, tropical saltwater fish were identified as potential carriers.

Symptoms

Melioidosis has a wide range of symptoms, which can lead to its being confused with other diseases such as tuberculosis or other forms of pneumonia. There are different forms of the disease, each with different symptoms.

• Localized infection: localized pain and swelling, fever, ulceration, and abscess.
• Pulmonary infection: cough, chest pain, high fever, headaches, and loss of appetite
• Bacteremia: fever, headaches, breathing problems, stomach discomfort, joint pain, and disorientation.
• Disseminated infection: fever, weight loss, stomach or chest pain, muscle or joint pain, headaches, central nervous system infections, and epileptic seizures.

The incubation time is not clearly defined and can be from 1 day to several years; however, the symptoms mostly emerge 2-4 weeks after exposure. The risk factors include diabetes, high alcohol consumption, chronic pulmonary or kidney disease, and immunodeficiencies.

Diagnosis based on the symptoms is often difficult since the clinical picture is similar to other, more common conditions.
 

Therapy

If the melioidosis is identified as such, it can be treated with only mildly effective antibiotics, since it has a natural resistance to many commonly used antibiotics. The type of infection and the course of treatment also affects the long-term outcome. Without treatment, 90% of the infections have a fatal outcome. With appropriate treatment, the mortality rate still lies at 40%.

Therapy generally begins with intravenous antibiotic therapy for at least 2-8 weeks (ceftazidime or meropenem). Oral antibiotic therapy then follows for 3-6 months (trimethoprim-sulfamethoxazole or amoxicillin/clavulanic acid). If the patient is allergic to penicillin, alternative antibiotics can be used.
 

Use as a bioweapon

The CDC classifies B. pseudomallei as a potential pathogen for biological attack (class-B candidate). The agency lists the potential reasons for use as a bioweapon as:

• The pathogen can be found naturally in certain regions.
• The triggered disease can take a serious course and ultimately be fatal without appropriate therapy.
• In the past, the United States has used similar pathogens in wars as bioweapons.

In a potential attack, the pathogen could be spread through air, water, or food, and by doing so, many people would be exposed. Any contact with the bacteria can result in melioidosis. As the bacteria cannot be seen, smelled, or tasted, the biological attack would not be recognized for some time. A certain amount of time can also pass until the pathogen is identified, once fever and respiratory diseases have developed.

In such an emergency, the CDC would collaborate with other federal and local authorities to supply specialized testing laboratories and provide the public with information.

This content was translated from Coliquio. A version appeared on Medscape.com.

In 2021, in U.S. states far removed from one another, numerous cases of melioidosis (Whitmore’s disease) sprang up, some with a fatal outcome. What is the common factor linking all of those affected? So begins the search for evidence.

No relations or common journeys

Between March and July 2021, cases of the bacterial infectious disease sprang up in Georgia, Kansas, Minnesota, and Texas, with the disease being fatal for two of those affected. Usually, cases of melioidosis occur in the United States after traveling to regions where the pathogen is prevalent. However, none of the patients had undertaken any previous international travel.

When the genomes of the bacterial strains (Burkholderia pseudomallei) were sequenced, they showed a high level of concordance, suggesting a common source of infection. The bacterial strain is similar to those that are found in Southeast Asia above all. An imported product from there was taken into consideration as the trigger.

The Centers for Disease Control and Prevention examined blood samples from the patients, as well as samples from the soil, water, food, and household items around their homes.
 

Aroma spray as a trigger

In October, the cause of the melioidosis was finally identified in the house of the patient from Georgia: an aromatherapy spray. The genetic fingerprint of the bacterial strain matched with that from the other patients. The common trigger was thus discovered.

The contaminated spray, with a lavender-chamomile scent for room fragrancing, was sold between February and October in some branches of Walmart, as well as in their online store. The product was therefore recalled and it was checked whether the ingredients were also being used in other products.

The CDC requested physicians to also take melioidosis into account if they were presented with acute bacterial infections that did not respond to normal antibiotics and to inquire whether the affected room spray had been used.
 

More information about melioidosis

Melioidosis is an infectious disease affecting humans and animals. The trigger is the bacteria B pseudomallei. The disease appears predominantly in tropical regions, especially in Southeast Asia and northern Australia.

Transmission

The bacteria can be found in contaminated water and soil. It is disseminated between humans and animals through direct contact with the infectious source, such as through inhaling dust particles or water droplets, or through consuming contaminated water or food. Human-to-human transmission is extremely rare. Recently however, tropical saltwater fish were identified as potential carriers.

Symptoms

Melioidosis has a wide range of symptoms, which can lead to its being confused with other diseases such as tuberculosis or other forms of pneumonia. There are different forms of the disease, each with different symptoms.

• Localized infection: localized pain and swelling, fever, ulceration, and abscess.
• Pulmonary infection: cough, chest pain, high fever, headaches, and loss of appetite
• Bacteremia: fever, headaches, breathing problems, stomach discomfort, joint pain, and disorientation.
• Disseminated infection: fever, weight loss, stomach or chest pain, muscle or joint pain, headaches, central nervous system infections, and epileptic seizures.

The incubation time is not clearly defined and can be from 1 day to several years; however, the symptoms mostly emerge 2-4 weeks after exposure. The risk factors include diabetes, high alcohol consumption, chronic pulmonary or kidney disease, and immunodeficiencies.

Diagnosis based on the symptoms is often difficult since the clinical picture is similar to other, more common conditions.
 

Therapy

If the melioidosis is identified as such, it can be treated with only mildly effective antibiotics, since it has a natural resistance to many commonly used antibiotics. The type of infection and the course of treatment also affects the long-term outcome. Without treatment, 90% of the infections have a fatal outcome. With appropriate treatment, the mortality rate still lies at 40%.

Therapy generally begins with intravenous antibiotic therapy for at least 2-8 weeks (ceftazidime or meropenem). Oral antibiotic therapy then follows for 3-6 months (trimethoprim-sulfamethoxazole or amoxicillin/clavulanic acid). If the patient is allergic to penicillin, alternative antibiotics can be used.
 

Use as a bioweapon

The CDC classifies B. pseudomallei as a potential pathogen for biological attack (class-B candidate). The agency lists the potential reasons for use as a bioweapon as:

• The pathogen can be found naturally in certain regions.
• The triggered disease can take a serious course and ultimately be fatal without appropriate therapy.
• In the past, the United States has used similar pathogens in wars as bioweapons.

In a potential attack, the pathogen could be spread through air, water, or food, and by doing so, many people would be exposed. Any contact with the bacteria can result in melioidosis. As the bacteria cannot be seen, smelled, or tasted, the biological attack would not be recognized for some time. A certain amount of time can also pass until the pathogen is identified, once fever and respiratory diseases have developed.

In such an emergency, the CDC would collaborate with other federal and local authorities to supply specialized testing laboratories and provide the public with information.

This content was translated from Coliquio. A version appeared on Medscape.com.

In 2021, in U.S. states far removed from one another, numerous cases of melioidosis (Whitmore’s disease) sprang up, some with a fatal outcome. What is the common factor linking all of those affected? So begins the search for evidence.

No relations or common journeys

Between March and July 2021, cases of the bacterial infectious disease sprang up in Georgia, Kansas, Minnesota, and Texas, with the disease being fatal for two of those affected. Usually, cases of melioidosis occur in the United States after traveling to regions where the pathogen is prevalent. However, none of the patients had undertaken any previous international travel.

When the genomes of the bacterial strains (Burkholderia pseudomallei) were sequenced, they showed a high level of concordance, suggesting a common source of infection. The bacterial strain is similar to those that are found in Southeast Asia above all. An imported product from there was taken into consideration as the trigger.

The Centers for Disease Control and Prevention examined blood samples from the patients, as well as samples from the soil, water, food, and household items around their homes.
 

Aroma spray as a trigger

In October, the cause of the melioidosis was finally identified in the house of the patient from Georgia: an aromatherapy spray. The genetic fingerprint of the bacterial strain matched with that from the other patients. The common trigger was thus discovered.

The contaminated spray, with a lavender-chamomile scent for room fragrancing, was sold between February and October in some branches of Walmart, as well as in their online store. The product was therefore recalled and it was checked whether the ingredients were also being used in other products.

The CDC requested physicians to also take melioidosis into account if they were presented with acute bacterial infections that did not respond to normal antibiotics and to inquire whether the affected room spray had been used.
 

More information about melioidosis

Melioidosis is an infectious disease affecting humans and animals. The trigger is the bacteria B pseudomallei. The disease appears predominantly in tropical regions, especially in Southeast Asia and northern Australia.

Transmission

The bacteria can be found in contaminated water and soil. It is disseminated between humans and animals through direct contact with the infectious source, such as through inhaling dust particles or water droplets, or through consuming contaminated water or food. Human-to-human transmission is extremely rare. Recently however, tropical saltwater fish were identified as potential carriers.

Symptoms

Melioidosis has a wide range of symptoms, which can lead to its being confused with other diseases such as tuberculosis or other forms of pneumonia. There are different forms of the disease, each with different symptoms.

• Localized infection: localized pain and swelling, fever, ulceration, and abscess.
• Pulmonary infection: cough, chest pain, high fever, headaches, and loss of appetite
• Bacteremia: fever, headaches, breathing problems, stomach discomfort, joint pain, and disorientation.
• Disseminated infection: fever, weight loss, stomach or chest pain, muscle or joint pain, headaches, central nervous system infections, and epileptic seizures.

The incubation time is not clearly defined and can be from 1 day to several years; however, the symptoms mostly emerge 2-4 weeks after exposure. The risk factors include diabetes, high alcohol consumption, chronic pulmonary or kidney disease, and immunodeficiencies.

Diagnosis based on the symptoms is often difficult since the clinical picture is similar to other, more common conditions.
 

Therapy

If the melioidosis is identified as such, it can be treated with only mildly effective antibiotics, since it has a natural resistance to many commonly used antibiotics. The type of infection and the course of treatment also affects the long-term outcome. Without treatment, 90% of the infections have a fatal outcome. With appropriate treatment, the mortality rate still lies at 40%.

Therapy generally begins with intravenous antibiotic therapy for at least 2-8 weeks (ceftazidime or meropenem). Oral antibiotic therapy then follows for 3-6 months (trimethoprim-sulfamethoxazole or amoxicillin/clavulanic acid). If the patient is allergic to penicillin, alternative antibiotics can be used.
 

Use as a bioweapon

The CDC classifies B. pseudomallei as a potential pathogen for biological attack (class-B candidate). The agency lists the potential reasons for use as a bioweapon as:

• The pathogen can be found naturally in certain regions.
• The triggered disease can take a serious course and ultimately be fatal without appropriate therapy.
• In the past, the United States has used similar pathogens in wars as bioweapons.

In a potential attack, the pathogen could be spread through air, water, or food, and by doing so, many people would be exposed. Any contact with the bacteria can result in melioidosis. As the bacteria cannot be seen, smelled, or tasted, the biological attack would not be recognized for some time. A certain amount of time can also pass until the pathogen is identified, once fever and respiratory diseases have developed.

In such an emergency, the CDC would collaborate with other federal and local authorities to supply specialized testing laboratories and provide the public with information.

This content was translated from Coliquio. A version appeared on Medscape.com.

Although cardiovascular disease (CVD) is known to often strike the mortal blow in patients with cancer, a national analysis puts in stark relief the burden of CV-related hospitalizations in this vulnerable population.

Results show that between 2004 and 2017, CV admissions increased 23.2% among patients with a cancer diagnosis, whereas admissions fell 10.9% among those without cancer.

Admissions increased steadily across all cancer types, except prostate cancer, with heart failure being the most common reason for admission.

“Hospital admissions is really important because we know that the size of this group is increasing, given that they live longer and many of the treatments that we offer cause cardiovascular disease or increase the risk of having cardiovascular events. So, from a health care planning perspective, I think it’s really important to see what the burden is likely to be in the next few years,” senior author Mamas Mamas, MD, Keele University, England, told this news organization.

For physicians and the wider population, he said, the findings underscore the need to shift the conversation from saying that patients with cancer are at increased CVD risk to asking how to mitigate this risk. “Because I would say that this increase in cardiovascular admissions, that’s a failure from a preventative perspective.”

The study was published in the European Heart Journal: Quality of Care & Clinical Outcomes.

Individual cancer types

The researchers, led by Ofer Kobo, MD, also with Keele University, used the National Inpatient Sample to identify 42.5 million weighted cases of CV admissions for acute myocardial infarction (AMI), pulmonary embolism, ischemic stroke, heart failure, atrial fibrillation (AFib) or atrial flutter, and intracranial hemorrhage from January 2004 to December 2017. Of these, 1.9 million had a record of cancer.

Patients with cancer were older; had a higher prevalence of valvular disease, anemia, and coagulopathy; and had a lower prevalence of hypertension, diabetes mellitus, and obesity than did patients without cancer.

The most common cancer type was hematologic cancers (26.1%), followed by lung (18.7%), gastrointestinal (12.4%), prostate (11.6%), breast (6.7%), and other in 24.4%.

The admission rate increased across all six admission causes – between 7% for AMI and ischemic stroke and 46% for AFib.

Heart failure was the chief reason for admission among all patients. Annual rates per 100,000 U.S. population increased in patients with cancer (from 13.6 to 16.6; P for trend = .02) and declined in those without (from 352.2 to 349.8; P for trend < .001).

“In the past, patients would be started on medications, and perhaps the importance of monitoring [left ventricular] LV function wasn’t as widely known, whereas now we’re much more aggressive in looking at it and much more aggressive at trying to prevent it,” Dr. Mamas said. “But even with this greater identification and attempting to modify regimens, we’re still getting quite substantial increases in heart failure admissions in this population. And what really surprised me is that it wasn’t just in the breast cancer population, but it was nearly across the board.”

He noted that patients are at highest risk from CV events within the first 2 years of cancer diagnosis. “So that’s really the time where you’ve got to be really aggressive in looking and working up their cardiovascular profile.”

Patients with hematologic cancers (9.7-13.5), lung (7.4-8.9), and gastrointestinal cancer (4.6-6.3) had the highest crude admission rates of CV hospitalizations per 100,000 U.S. population.

The CV admission rate went up from 2.5 to 3.7 per 100,000 U.S. population for breast cancer, and in prostate cancer, the rate dropped from 5.8 to 4.8 per 100,000 U.S. population.

Of note, patients with hematologic cancers also had the highest rate of heart failure hospitalization across all cancer types, which, coupled with their increasing admission rates, likely reflects their exposure to a “constellation of cardiotoxic therapies” as well as pathologic processes related to the cancers themselves, the authors suggest.

In-hospital mortality rates were higher among patients with cancer than those without, ranging from 5% for patients with breast cancer to 9.6% for patients with lung cancer versus 4.2% for those without cancer.

Among patients with cancer, the odds ratio for mortality was highest in those admitted with AFib (4.43), followed by pulmonary embolism (2.36), AMI (2.31), ischemic stroke (2.29), and heart failure (2.24).

In line with prior work and general population trends, in-hospital deaths in primary CV admissions trended lower among patients with cancer over the study period.

Mitigating risk

Commenting on the study, Joerg Herrmann, MD, director of the cardio-oncology clinic at Mayo Clinic, Rochester, Minn., said that the data are “extremely important” because they reflect admissions during a new era of cancer therapy. “Targeted therapies all came out about the turn of the millennium, so we’re not really looking at cancer patients treated with only old and ancient strategies.”

This may be one reason for the increased admissions, but because the study lacked information on specific cancer treatments and the date of cancer diagnosis, it’s not possible to tease out whether the uptick is related to cardiotoxicity or because the oncology outcomes have improved so much that this is a growing population, he said.

One clear implication, however, is that whoever is working on the hospital service will see more patients with a cancer diagnosis, Dr. Herrmann observed.

“Though some may have tried to maybe not get involved with this topic as much, it really calls for some broader scope to get familiar with this very entity,” he said. “And that plays out, in particular, in those patients with a diagnosis of active cancer.”

Dr. Herrmann and colleagues previously reported that patients with active leukemia or lymphoma who were hospitalized with acute coronary syndrome were less likely to receive guideline-directed therapies, even at the Mayo Clinic.

Similarly, a 2020 report by Dr. Mamas and colleagues found that patients with a variety of active cancers derived similar benefit from primary percutaneous coronary intervention for ST-segment–elevation MI as those without cancer but received the treatment less commonly.

Although there’s a greater appreciation that patients with cancer benefit equally from aggressive treatment, much more can be done to mitigate CV risk, Dr. Mamas noted. Valuable coronary information captured by MRI and CT done as part of the cancer investigation is often overlooked. For example, “we know that breast calcification and vascular calcification in the breast are very strong predictors of cardiovascular outcomes and yet people aren’t using this information.”

There are numerous shared risk factors in the development of cancer and coronary artery disease, and patients with cancer often have much worse CV risk profiles but aren’t routinely risk stratified from a CV perspective, he said.

Dr. Mamas said that his team is also studying whether CVD risk prediction tools like the Framingham Risk Score, which were derived from noncancer populations, work as well in patients with cancer. “Often, when you look at the performance of these tools in populations that weren’t covered, they’re much worse.”

“A lot of cancer survivors worry about the recurrence of their cancer and will religiously go and have repeated scans, religiously check themselves, and have all these investigations but don’t think about the actual risk that is greater for them, which is cardiovascular risk,” he said.

The authors report no study funding or relevant financial relationships.

A version of this article first appeared on Medscape.com.

Although cardiovascular disease (CVD) is known to often strike the mortal blow in patients with cancer, a national analysis puts in stark relief the burden of CV-related hospitalizations in this vulnerable population.

Results show that between 2004 and 2017, CV admissions increased 23.2% among patients with a cancer diagnosis, whereas admissions fell 10.9% among those without cancer.

Admissions increased steadily across all cancer types, except prostate cancer, with heart failure being the most common reason for admission.

“Hospital admissions is really important because we know that the size of this group is increasing, given that they live longer and many of the treatments that we offer cause cardiovascular disease or increase the risk of having cardiovascular events. So, from a health care planning perspective, I think it’s really important to see what the burden is likely to be in the next few years,” senior author Mamas Mamas, MD, Keele University, England, told this news organization.

For physicians and the wider population, he said, the findings underscore the need to shift the conversation from saying that patients with cancer are at increased CVD risk to asking how to mitigate this risk. “Because I would say that this increase in cardiovascular admissions, that’s a failure from a preventative perspective.”

The study was published in the European Heart Journal: Quality of Care & Clinical Outcomes.

Individual cancer types

The researchers, led by Ofer Kobo, MD, also with Keele University, used the National Inpatient Sample to identify 42.5 million weighted cases of CV admissions for acute myocardial infarction (AMI), pulmonary embolism, ischemic stroke, heart failure, atrial fibrillation (AFib) or atrial flutter, and intracranial hemorrhage from January 2004 to December 2017. Of these, 1.9 million had a record of cancer.

Patients with cancer were older; had a higher prevalence of valvular disease, anemia, and coagulopathy; and had a lower prevalence of hypertension, diabetes mellitus, and obesity than did patients without cancer.

The most common cancer type was hematologic cancers (26.1%), followed by lung (18.7%), gastrointestinal (12.4%), prostate (11.6%), breast (6.7%), and other in 24.4%.

The admission rate increased across all six admission causes – between 7% for AMI and ischemic stroke and 46% for AFib.

Heart failure was the chief reason for admission among all patients. Annual rates per 100,000 U.S. population increased in patients with cancer (from 13.6 to 16.6; P for trend = .02) and declined in those without (from 352.2 to 349.8; P for trend < .001).

“In the past, patients would be started on medications, and perhaps the importance of monitoring [left ventricular] LV function wasn’t as widely known, whereas now we’re much more aggressive in looking at it and much more aggressive at trying to prevent it,” Dr. Mamas said. “But even with this greater identification and attempting to modify regimens, we’re still getting quite substantial increases in heart failure admissions in this population. And what really surprised me is that it wasn’t just in the breast cancer population, but it was nearly across the board.”

He noted that patients are at highest risk from CV events within the first 2 years of cancer diagnosis. “So that’s really the time where you’ve got to be really aggressive in looking and working up their cardiovascular profile.”

Patients with hematologic cancers (9.7-13.5), lung (7.4-8.9), and gastrointestinal cancer (4.6-6.3) had the highest crude admission rates of CV hospitalizations per 100,000 U.S. population.

The CV admission rate went up from 2.5 to 3.7 per 100,000 U.S. population for breast cancer, and in prostate cancer, the rate dropped from 5.8 to 4.8 per 100,000 U.S. population.

Of note, patients with hematologic cancers also had the highest rate of heart failure hospitalization across all cancer types, which, coupled with their increasing admission rates, likely reflects their exposure to a “constellation of cardiotoxic therapies” as well as pathologic processes related to the cancers themselves, the authors suggest.

In-hospital mortality rates were higher among patients with cancer than those without, ranging from 5% for patients with breast cancer to 9.6% for patients with lung cancer versus 4.2% for those without cancer.

Among patients with cancer, the odds ratio for mortality was highest in those admitted with AFib (4.43), followed by pulmonary embolism (2.36), AMI (2.31), ischemic stroke (2.29), and heart failure (2.24).

In line with prior work and general population trends, in-hospital deaths in primary CV admissions trended lower among patients with cancer over the study period.

Mitigating risk

Commenting on the study, Joerg Herrmann, MD, director of the cardio-oncology clinic at Mayo Clinic, Rochester, Minn., said that the data are “extremely important” because they reflect admissions during a new era of cancer therapy. “Targeted therapies all came out about the turn of the millennium, so we’re not really looking at cancer patients treated with only old and ancient strategies.”

This may be one reason for the increased admissions, but because the study lacked information on specific cancer treatments and the date of cancer diagnosis, it’s not possible to tease out whether the uptick is related to cardiotoxicity or because the oncology outcomes have improved so much that this is a growing population, he said.

One clear implication, however, is that whoever is working on the hospital service will see more patients with a cancer diagnosis, Dr. Herrmann observed.

“Though some may have tried to maybe not get involved with this topic as much, it really calls for some broader scope to get familiar with this very entity,” he said. “And that plays out, in particular, in those patients with a diagnosis of active cancer.”

Dr. Herrmann and colleagues previously reported that patients with active leukemia or lymphoma who were hospitalized with acute coronary syndrome were less likely to receive guideline-directed therapies, even at the Mayo Clinic.

Similarly, a 2020 report by Dr. Mamas and colleagues found that patients with a variety of active cancers derived similar benefit from primary percutaneous coronary intervention for ST-segment–elevation MI as those without cancer but received the treatment less commonly.

Although there’s a greater appreciation that patients with cancer benefit equally from aggressive treatment, much more can be done to mitigate CV risk, Dr. Mamas noted. Valuable coronary information captured by MRI and CT done as part of the cancer investigation is often overlooked. For example, “we know that breast calcification and vascular calcification in the breast are very strong predictors of cardiovascular outcomes and yet people aren’t using this information.”

There are numerous shared risk factors in the development of cancer and coronary artery disease, and patients with cancer often have much worse CV risk profiles but aren’t routinely risk stratified from a CV perspective, he said.

Dr. Mamas said that his team is also studying whether CVD risk prediction tools like the Framingham Risk Score, which were derived from noncancer populations, work as well in patients with cancer. “Often, when you look at the performance of these tools in populations that weren’t covered, they’re much worse.”

“A lot of cancer survivors worry about the recurrence of their cancer and will religiously go and have repeated scans, religiously check themselves, and have all these investigations but don’t think about the actual risk that is greater for them, which is cardiovascular risk,” he said.

The authors report no study funding or relevant financial relationships.

A version of this article first appeared on Medscape.com.

Although cardiovascular disease (CVD) is known to often strike the mortal blow in patients with cancer, a national analysis puts in stark relief the burden of CV-related hospitalizations in this vulnerable population.

Results show that between 2004 and 2017, CV admissions increased 23.2% among patients with a cancer diagnosis, whereas admissions fell 10.9% among those without cancer.

Admissions increased steadily across all cancer types, except prostate cancer, with heart failure being the most common reason for admission.

“Hospital admissions is really important because we know that the size of this group is increasing, given that they live longer and many of the treatments that we offer cause cardiovascular disease or increase the risk of having cardiovascular events. So, from a health care planning perspective, I think it’s really important to see what the burden is likely to be in the next few years,” senior author Mamas Mamas, MD, Keele University, England, told this news organization.

For physicians and the wider population, he said, the findings underscore the need to shift the conversation from saying that patients with cancer are at increased CVD risk to asking how to mitigate this risk. “Because I would say that this increase in cardiovascular admissions, that’s a failure from a preventative perspective.”

The study was published in the European Heart Journal: Quality of Care & Clinical Outcomes.

Individual cancer types

The researchers, led by Ofer Kobo, MD, also with Keele University, used the National Inpatient Sample to identify 42.5 million weighted cases of CV admissions for acute myocardial infarction (AMI), pulmonary embolism, ischemic stroke, heart failure, atrial fibrillation (AFib) or atrial flutter, and intracranial hemorrhage from January 2004 to December 2017. Of these, 1.9 million had a record of cancer.

Patients with cancer were older; had a higher prevalence of valvular disease, anemia, and coagulopathy; and had a lower prevalence of hypertension, diabetes mellitus, and obesity than did patients without cancer.

The most common cancer type was hematologic cancers (26.1%), followed by lung (18.7%), gastrointestinal (12.4%), prostate (11.6%), breast (6.7%), and other in 24.4%.

The admission rate increased across all six admission causes – between 7% for AMI and ischemic stroke and 46% for AFib.

Heart failure was the chief reason for admission among all patients. Annual rates per 100,000 U.S. population increased in patients with cancer (from 13.6 to 16.6; P for trend = .02) and declined in those without (from 352.2 to 349.8; P for trend < .001).

“In the past, patients would be started on medications, and perhaps the importance of monitoring [left ventricular] LV function wasn’t as widely known, whereas now we’re much more aggressive in looking at it and much more aggressive at trying to prevent it,” Dr. Mamas said. “But even with this greater identification and attempting to modify regimens, we’re still getting quite substantial increases in heart failure admissions in this population. And what really surprised me is that it wasn’t just in the breast cancer population, but it was nearly across the board.”

He noted that patients are at highest risk from CV events within the first 2 years of cancer diagnosis. “So that’s really the time where you’ve got to be really aggressive in looking and working up their cardiovascular profile.”

Patients with hematologic cancers (9.7-13.5), lung (7.4-8.9), and gastrointestinal cancer (4.6-6.3) had the highest crude admission rates of CV hospitalizations per 100,000 U.S. population.

The CV admission rate went up from 2.5 to 3.7 per 100,000 U.S. population for breast cancer, and in prostate cancer, the rate dropped from 5.8 to 4.8 per 100,000 U.S. population.

Of note, patients with hematologic cancers also had the highest rate of heart failure hospitalization across all cancer types, which, coupled with their increasing admission rates, likely reflects their exposure to a “constellation of cardiotoxic therapies” as well as pathologic processes related to the cancers themselves, the authors suggest.

In-hospital mortality rates were higher among patients with cancer than those without, ranging from 5% for patients with breast cancer to 9.6% for patients with lung cancer versus 4.2% for those without cancer.

Among patients with cancer, the odds ratio for mortality was highest in those admitted with AFib (4.43), followed by pulmonary embolism (2.36), AMI (2.31), ischemic stroke (2.29), and heart failure (2.24).

In line with prior work and general population trends, in-hospital deaths in primary CV admissions trended lower among patients with cancer over the study period.

Mitigating risk

Commenting on the study, Joerg Herrmann, MD, director of the cardio-oncology clinic at Mayo Clinic, Rochester, Minn., said that the data are “extremely important” because they reflect admissions during a new era of cancer therapy. “Targeted therapies all came out about the turn of the millennium, so we’re not really looking at cancer patients treated with only old and ancient strategies.”

This may be one reason for the increased admissions, but because the study lacked information on specific cancer treatments and the date of cancer diagnosis, it’s not possible to tease out whether the uptick is related to cardiotoxicity or because the oncology outcomes have improved so much that this is a growing population, he said.

One clear implication, however, is that whoever is working on the hospital service will see more patients with a cancer diagnosis, Dr. Herrmann observed.

“Though some may have tried to maybe not get involved with this topic as much, it really calls for some broader scope to get familiar with this very entity,” he said. “And that plays out, in particular, in those patients with a diagnosis of active cancer.”

Dr. Herrmann and colleagues previously reported that patients with active leukemia or lymphoma who were hospitalized with acute coronary syndrome were less likely to receive guideline-directed therapies, even at the Mayo Clinic.

Similarly, a 2020 report by Dr. Mamas and colleagues found that patients with a variety of active cancers derived similar benefit from primary percutaneous coronary intervention for ST-segment–elevation MI as those without cancer but received the treatment less commonly.

Although there’s a greater appreciation that patients with cancer benefit equally from aggressive treatment, much more can be done to mitigate CV risk, Dr. Mamas noted. Valuable coronary information captured by MRI and CT done as part of the cancer investigation is often overlooked. For example, “we know that breast calcification and vascular calcification in the breast are very strong predictors of cardiovascular outcomes and yet people aren’t using this information.”

There are numerous shared risk factors in the development of cancer and coronary artery disease, and patients with cancer often have much worse CV risk profiles but aren’t routinely risk stratified from a CV perspective, he said.

Dr. Mamas said that his team is also studying whether CVD risk prediction tools like the Framingham Risk Score, which were derived from noncancer populations, work as well in patients with cancer. “Often, when you look at the performance of these tools in populations that weren’t covered, they’re much worse.”

“A lot of cancer survivors worry about the recurrence of their cancer and will religiously go and have repeated scans, religiously check themselves, and have all these investigations but don’t think about the actual risk that is greater for them, which is cardiovascular risk,” he said.

The authors report no study funding or relevant financial relationships.

A version of this article first appeared on Medscape.com.

New York City veterinarian Erin Kulick used to be a weekend warrior. Only 2½ years ago, the 38-year-old new mother played ultimate Frisbee and flag football with friends. She went for regular 30-minute runs to burn off stress.

Now, Dr. Kulick is usually so exhausted, she can’t walk nonstop for 15 minutes. She recently tried to take her 4-year-old son, Cooper, to the American Museum of Natural History for his first visit, but ended up on a bench outside the museum, sobbing in the rain, because she couldn’t even get through the first hurdle of standing in line. “I just wanted to be there with my kid,” she said.

Dr. Kulick got sick with COVID-19 at the start of the pandemic in March 2020, 9 months before the first vaccine would be approved. Now she is among the estimated one in five infected Americans, or 19%, whose symptoms developed into long COVID.

Dr. Kulick also is now vaccinated and boosted. Had a vaccine been available sooner, could it have protected her from long COVID?

Evidence is starting to show it’s likely.

“The best way not to have long COVID is not to have COVID at all,” said Leora Horwitz, MD, a professor of population health and medicine at New York University. “To the extent that vaccination can prevent you from getting COVID at all, then it helps to reduce long COVID.”

And just as vaccines reduce the risk of severe disease, hospitalization, and death, they also seem to reduce the risk of long COVID if people do get breakthrough infections. People with more serious initial illness appear more likely to have prolonged symptoms, but those with milder disease can certainly get it, too.

“You’re more likely to have long COVID with more severe disease, and we have ample evidence that vaccination reduces the severity of disease,” Dr. Horwitz said. “We also now have quite a lot of evidence that vaccination does reduce your risk of long COVID – probably because it reduces your risk of severe disease.”

There is little consensus about how much vaccines can lower the risk of long-term COVID symptoms, but several studies suggest that number lies anywhere from 15% to more than 80%.

That might seem like a big variation, but infectious disease experts argue that trying to interpret the gap isn’t as important as noticing what’s consistent across all these studies: “Vaccines do offer some protection, but it’s incomplete,” said Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System. Dr. Al-Aly, who has led several large studies on long COVID, said focusing on the fact that vaccines do offer some protection is a much better public health message than looking at the different levels of risk.

“Vaccines do a miraculous job for what they were designed to do,” said Dr. Al-Aly. “Vaccines were designed to reduce the risk of hospitalization ... and for that, vaccines are still holding up, even with all the changes in the virus.”

Still, Elena Azzolini, MD, PhD, head of the Humanitas Research Hospital’s vaccination center in Milan, thinks some studies may have underestimated the level of long COVID protection from vaccines because of limits in the study methods, such as not including enough women, who are more affected by long COVID. Her recent study, which looked at 2,560 health care professionals working in nine Italian centers from March 2020 to April 2022, focused on the risk for healthy women and men in their 20s to their 70s.

In the paper, Dr. Azzolini and associates reported that two or three doses of vaccine reduced the risk of hospitalization from COVID-19 from 42% among those who are unvaccinated to 16%-17%. In other words, they found unvaccinated people in the study were nearly three times as likely to have serious symptoms for longer than 4 weeks.

But Dr. Azzolini and Dr. Al-Aly still say that, even for the vaccinated, as long as COVID is around, masks are necessary. That’s because current vaccines don’t do enough to reduce transmission, said Dr. Al-Aly. “The only way that can really help [stop] transmission is covering our nose and mouth with a mask.”
 

How vaccinations affect people who already have long COVID

Some long COVID patients have said they got better after they get boosted, while some say they’re getting worse, said Dr. Horwitz, who is also a lead investigator at the National Institutes of Health’s flagship RECOVER program, a 4-year research project to study long COVID across the United States. (The NIH is still recruiting volunteers for these studies, which are also open to people who have never had COVID.)

One study published in the British Medical Journal analyzed survey data of more than 28,000 people infected with COVID in the United Kingdom and found a 13% reduction in long-term symptoms after a first dose of the vaccine, although it was unclear from the data if the improvement was sustained.

A second dose was associated with another 8% improvement over a 2-month period. “It’s reassuring that we see an average modest improvement in symptoms, not an average worsening in symptoms,” said Daniel Ayoubkhani, principal statistician at the U.K. Office for National Statistics and lead author of the study. Of course, the experience will differ among different people.

“It doesn’t appear that vaccination is the silver bullet that’s going to eradicate long COVID,” he said, but evidence from multiple studies suggests vaccines may help people with long-term symptoms.

Akiko Iwasaki, PhD, an immunobiologist at Yale University, New Haven, Conn., told a White House summit in July that one of the best ways to prevent long COVID is to develop the next generation of vaccines that also prevent milder cases by blocking transmission in the first place.

Back in New York, Dr. Kulick is now triple vaccinated. She’s due for a fourth dose soon but admits she’s “terrified every time” that she’s going to get sicker.

In her Facebook support group for long COVID, she reads that most people with prolonged symptoms handle it well. She has also noticed some of her symptoms eased after her first two doses of vaccine.

Since being diagnosed, Dr. Kulick learned she has a genetic condition, Ehlers-Danlos syndrome, which affects connective tissues that support skin, joints, organs, and blood vessels, and which her doctors say may have made her more prone to long COVID. She’s also being screened for autoimmune diseases, but for now, the only relief she has found has come from long COVID physical therapy, changes to her diet, and integrative medicine.

Dr. Kulick is still trying to figure out how she can get better while keeping her long hours at her veterinary job – and her health benefits. She is thankful her husband is a devoted caregiver to their son and a professional jazz musician with a schedule that allows for some flexibility.

“But it’s really hard when every week feels like I’ve run a marathon,” she said. “I can barely make it through.”

A version of this article first appeared on WebMD.com.

New York City veterinarian Erin Kulick used to be a weekend warrior. Only 2½ years ago, the 38-year-old new mother played ultimate Frisbee and flag football with friends. She went for regular 30-minute runs to burn off stress.

Now, Dr. Kulick is usually so exhausted, she can’t walk nonstop for 15 minutes. She recently tried to take her 4-year-old son, Cooper, to the American Museum of Natural History for his first visit, but ended up on a bench outside the museum, sobbing in the rain, because she couldn’t even get through the first hurdle of standing in line. “I just wanted to be there with my kid,” she said.

Dr. Kulick got sick with COVID-19 at the start of the pandemic in March 2020, 9 months before the first vaccine would be approved. Now she is among the estimated one in five infected Americans, or 19%, whose symptoms developed into long COVID.

Dr. Kulick also is now vaccinated and boosted. Had a vaccine been available sooner, could it have protected her from long COVID?

Evidence is starting to show it’s likely.

“The best way not to have long COVID is not to have COVID at all,” said Leora Horwitz, MD, a professor of population health and medicine at New York University. “To the extent that vaccination can prevent you from getting COVID at all, then it helps to reduce long COVID.”

And just as vaccines reduce the risk of severe disease, hospitalization, and death, they also seem to reduce the risk of long COVID if people do get breakthrough infections. People with more serious initial illness appear more likely to have prolonged symptoms, but those with milder disease can certainly get it, too.

“You’re more likely to have long COVID with more severe disease, and we have ample evidence that vaccination reduces the severity of disease,” Dr. Horwitz said. “We also now have quite a lot of evidence that vaccination does reduce your risk of long COVID – probably because it reduces your risk of severe disease.”

There is little consensus about how much vaccines can lower the risk of long-term COVID symptoms, but several studies suggest that number lies anywhere from 15% to more than 80%.

That might seem like a big variation, but infectious disease experts argue that trying to interpret the gap isn’t as important as noticing what’s consistent across all these studies: “Vaccines do offer some protection, but it’s incomplete,” said Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System. Dr. Al-Aly, who has led several large studies on long COVID, said focusing on the fact that vaccines do offer some protection is a much better public health message than looking at the different levels of risk.

“Vaccines do a miraculous job for what they were designed to do,” said Dr. Al-Aly. “Vaccines were designed to reduce the risk of hospitalization ... and for that, vaccines are still holding up, even with all the changes in the virus.”

Still, Elena Azzolini, MD, PhD, head of the Humanitas Research Hospital’s vaccination center in Milan, thinks some studies may have underestimated the level of long COVID protection from vaccines because of limits in the study methods, such as not including enough women, who are more affected by long COVID. Her recent study, which looked at 2,560 health care professionals working in nine Italian centers from March 2020 to April 2022, focused on the risk for healthy women and men in their 20s to their 70s.

In the paper, Dr. Azzolini and associates reported that two or three doses of vaccine reduced the risk of hospitalization from COVID-19 from 42% among those who are unvaccinated to 16%-17%. In other words, they found unvaccinated people in the study were nearly three times as likely to have serious symptoms for longer than 4 weeks.

But Dr. Azzolini and Dr. Al-Aly still say that, even for the vaccinated, as long as COVID is around, masks are necessary. That’s because current vaccines don’t do enough to reduce transmission, said Dr. Al-Aly. “The only way that can really help [stop] transmission is covering our nose and mouth with a mask.”
 

How vaccinations affect people who already have long COVID

Some long COVID patients have said they got better after they get boosted, while some say they’re getting worse, said Dr. Horwitz, who is also a lead investigator at the National Institutes of Health’s flagship RECOVER program, a 4-year research project to study long COVID across the United States. (The NIH is still recruiting volunteers for these studies, which are also open to people who have never had COVID.)

One study published in the British Medical Journal analyzed survey data of more than 28,000 people infected with COVID in the United Kingdom and found a 13% reduction in long-term symptoms after a first dose of the vaccine, although it was unclear from the data if the improvement was sustained.

A second dose was associated with another 8% improvement over a 2-month period. “It’s reassuring that we see an average modest improvement in symptoms, not an average worsening in symptoms,” said Daniel Ayoubkhani, principal statistician at the U.K. Office for National Statistics and lead author of the study. Of course, the experience will differ among different people.

“It doesn’t appear that vaccination is the silver bullet that’s going to eradicate long COVID,” he said, but evidence from multiple studies suggests vaccines may help people with long-term symptoms.

Akiko Iwasaki, PhD, an immunobiologist at Yale University, New Haven, Conn., told a White House summit in July that one of the best ways to prevent long COVID is to develop the next generation of vaccines that also prevent milder cases by blocking transmission in the first place.

Back in New York, Dr. Kulick is now triple vaccinated. She’s due for a fourth dose soon but admits she’s “terrified every time” that she’s going to get sicker.

In her Facebook support group for long COVID, she reads that most people with prolonged symptoms handle it well. She has also noticed some of her symptoms eased after her first two doses of vaccine.

Since being diagnosed, Dr. Kulick learned she has a genetic condition, Ehlers-Danlos syndrome, which affects connective tissues that support skin, joints, organs, and blood vessels, and which her doctors say may have made her more prone to long COVID. She’s also being screened for autoimmune diseases, but for now, the only relief she has found has come from long COVID physical therapy, changes to her diet, and integrative medicine.

Dr. Kulick is still trying to figure out how she can get better while keeping her long hours at her veterinary job – and her health benefits. She is thankful her husband is a devoted caregiver to their son and a professional jazz musician with a schedule that allows for some flexibility.

“But it’s really hard when every week feels like I’ve run a marathon,” she said. “I can barely make it through.”

A version of this article first appeared on WebMD.com.

New York City veterinarian Erin Kulick used to be a weekend warrior. Only 2½ years ago, the 38-year-old new mother played ultimate Frisbee and flag football with friends. She went for regular 30-minute runs to burn off stress.

Now, Dr. Kulick is usually so exhausted, she can’t walk nonstop for 15 minutes. She recently tried to take her 4-year-old son, Cooper, to the American Museum of Natural History for his first visit, but ended up on a bench outside the museum, sobbing in the rain, because she couldn’t even get through the first hurdle of standing in line. “I just wanted to be there with my kid,” she said.

Dr. Kulick got sick with COVID-19 at the start of the pandemic in March 2020, 9 months before the first vaccine would be approved. Now she is among the estimated one in five infected Americans, or 19%, whose symptoms developed into long COVID.

Dr. Kulick also is now vaccinated and boosted. Had a vaccine been available sooner, could it have protected her from long COVID?

Evidence is starting to show it’s likely.

“The best way not to have long COVID is not to have COVID at all,” said Leora Horwitz, MD, a professor of population health and medicine at New York University. “To the extent that vaccination can prevent you from getting COVID at all, then it helps to reduce long COVID.”

And just as vaccines reduce the risk of severe disease, hospitalization, and death, they also seem to reduce the risk of long COVID if people do get breakthrough infections. People with more serious initial illness appear more likely to have prolonged symptoms, but those with milder disease can certainly get it, too.

“You’re more likely to have long COVID with more severe disease, and we have ample evidence that vaccination reduces the severity of disease,” Dr. Horwitz said. “We also now have quite a lot of evidence that vaccination does reduce your risk of long COVID – probably because it reduces your risk of severe disease.”

There is little consensus about how much vaccines can lower the risk of long-term COVID symptoms, but several studies suggest that number lies anywhere from 15% to more than 80%.

That might seem like a big variation, but infectious disease experts argue that trying to interpret the gap isn’t as important as noticing what’s consistent across all these studies: “Vaccines do offer some protection, but it’s incomplete,” said Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System. Dr. Al-Aly, who has led several large studies on long COVID, said focusing on the fact that vaccines do offer some protection is a much better public health message than looking at the different levels of risk.

“Vaccines do a miraculous job for what they were designed to do,” said Dr. Al-Aly. “Vaccines were designed to reduce the risk of hospitalization ... and for that, vaccines are still holding up, even with all the changes in the virus.”

Still, Elena Azzolini, MD, PhD, head of the Humanitas Research Hospital’s vaccination center in Milan, thinks some studies may have underestimated the level of long COVID protection from vaccines because of limits in the study methods, such as not including enough women, who are more affected by long COVID. Her recent study, which looked at 2,560 health care professionals working in nine Italian centers from March 2020 to April 2022, focused on the risk for healthy women and men in their 20s to their 70s.

In the paper, Dr. Azzolini and associates reported that two or three doses of vaccine reduced the risk of hospitalization from COVID-19 from 42% among those who are unvaccinated to 16%-17%. In other words, they found unvaccinated people in the study were nearly three times as likely to have serious symptoms for longer than 4 weeks.

But Dr. Azzolini and Dr. Al-Aly still say that, even for the vaccinated, as long as COVID is around, masks are necessary. That’s because current vaccines don’t do enough to reduce transmission, said Dr. Al-Aly. “The only way that can really help [stop] transmission is covering our nose and mouth with a mask.”
 

How vaccinations affect people who already have long COVID

Some long COVID patients have said they got better after they get boosted, while some say they’re getting worse, said Dr. Horwitz, who is also a lead investigator at the National Institutes of Health’s flagship RECOVER program, a 4-year research project to study long COVID across the United States. (The NIH is still recruiting volunteers for these studies, which are also open to people who have never had COVID.)

One study published in the British Medical Journal analyzed survey data of more than 28,000 people infected with COVID in the United Kingdom and found a 13% reduction in long-term symptoms after a first dose of the vaccine, although it was unclear from the data if the improvement was sustained.

A second dose was associated with another 8% improvement over a 2-month period. “It’s reassuring that we see an average modest improvement in symptoms, not an average worsening in symptoms,” said Daniel Ayoubkhani, principal statistician at the U.K. Office for National Statistics and lead author of the study. Of course, the experience will differ among different people.

“It doesn’t appear that vaccination is the silver bullet that’s going to eradicate long COVID,” he said, but evidence from multiple studies suggests vaccines may help people with long-term symptoms.

Akiko Iwasaki, PhD, an immunobiologist at Yale University, New Haven, Conn., told a White House summit in July that one of the best ways to prevent long COVID is to develop the next generation of vaccines that also prevent milder cases by blocking transmission in the first place.

Back in New York, Dr. Kulick is now triple vaccinated. She’s due for a fourth dose soon but admits she’s “terrified every time” that she’s going to get sicker.

In her Facebook support group for long COVID, she reads that most people with prolonged symptoms handle it well. She has also noticed some of her symptoms eased after her first two doses of vaccine.

Since being diagnosed, Dr. Kulick learned she has a genetic condition, Ehlers-Danlos syndrome, which affects connective tissues that support skin, joints, organs, and blood vessels, and which her doctors say may have made her more prone to long COVID. She’s also being screened for autoimmune diseases, but for now, the only relief she has found has come from long COVID physical therapy, changes to her diet, and integrative medicine.

Dr. Kulick is still trying to figure out how she can get better while keeping her long hours at her veterinary job – and her health benefits. She is thankful her husband is a devoted caregiver to their son and a professional jazz musician with a schedule that allows for some flexibility.

“But it’s really hard when every week feels like I’ve run a marathon,” she said. “I can barely make it through.”

A version of this article first appeared on WebMD.com.

Many authors have commented on the lack of research into female sexual dysfunction, especially when compared with the hundreds of research publications related to male sexual health and dysfunction. Not surprisingly, very little has been published in the past year on the subject of female sexual health.

Recently, the International Society for the Study of Women’s Sexual Health (ISSWSH) published 2 important papers: a guideline on the use of testosterone for hypoactive sexual desire disorder (HSDD) in women and a consensus document on the management of persistent genital arousal disorder (PGAD). The lack of funding and support for female sexual health leaves women’s health professionals with little education or guidance on how to identify and treat conditions that are likely as common in women as erectile dysfunction is in men. While we would like to rely on randomized trials to inform our clinical care, the very limited literature on female sexual health makes this difficult. Bringing together experienced clinicians who focus their practices on sexual health, ISSWSH has provided some much-needed recommendations for the management of difficult conditions.

ISSWSH provides clinical guidance on testosterone therapy for women with HSDD

Parish S, Simon J, Davis S, et al. International Society for the Study of Women’s Sexual Health clinical practice guideline for the use of systemic testosterone for hypoactive sexual desire disorder in women. J Sex Med. 2021;18:849-867.

For development of the ISSWSH clinical practice guideline on testosterone therapy for women with HSDD, 16 international researchers and clinicians were convened. A modified Delphi method was used to establish consensus at the meeting on the recommended indications for testosterone treatment, formulations, and when measurement of testosterone levels is appropriate.

An extensive evidence-based literature review was performed, which included original research, meta-analyses, reviews, and clinical practice guidelines, to address the use of testosterone in women for management of HSDD. Notably, in 2019, representatives of  10 medical societies published a Global Consensus Position Statement on the Use of Testosterone Therapy for Women that reviewed the existing literature on testosterone’s effects on sexual dysfunction, mood, cognition, musculoskeletal, cardiovascular, and breast health as well as androgenic side effects and adverse events.¹ Based on their review, the only evidence-based indication for testosterone use is for the treatment of HSDD.

Testosterone formulations, HSDD diagnosis, and sex steroid physiology

More than 10 years ago, the US Food and Drug Administration (FDA) reviewed an application for the use of a transdermal testosterone patch (Intrinsa) in women for the treatment of HSDD. Efficacy of treatment was clearly demonstrated, and no safety signals were found in the placebo-controlled trial. Based, however, on the opinions of regulators who were “concerned” about the potential for cardiovascular adverse outcomes and worry that the peripheral conversion of testosterone to estradiol might lead to an increase in breast cancer—worry generated from the findings of the Women’s Health Initiative (which did not demonstrate an increase in breast cancer risk with estrogen alone but only when estrogen was combined with medroxyprogesterone acetate)—the FDA declined to approve the testosterone patch for women.

The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) defined HSDD as “persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity with marked distress or interpersonal difficulty.” The guideline authors noted that although the DSM-5 edition merged female arousal disorder with desire disorder into a single diagnosis, they used the DSM-IV definition as it had been the basis for the studies and literature reviewed. HSDD is a prevalent condition worldwide that affects between 12% and  53% of peri- and postmenopausal women.

The consensus guideline authors extensively reviewed the physiology and mechanism of action of sex steroids in women, particularly their impact on sexual function and the biologic alterations that occur during peri- and postmenopause.

Continue to: Consensus position  and recommendations...

Consensus position  and recommendations

The ISSWSH consensus guideline concluded that there is a moderate therapeutic benefit in adding testosterone therapy to achieve up to premenopausal levels in postmenopausal women with self-reported reduction in sexual desire that is causing distress as determined by a validated instrument.

The authors advise baseline hormone testing to rule out androgen excess and baseline renal, lipid, liver, and metabolic testing, even though transdermal testosterone therapy was not shown to alter these parameters in randomized trials of more than 3,000 women. Laboratory assays for both total and free testosterone are “highly unreliable” in the female range as they have been calibrated for male levels of hormone.

FDA-approved testosterone treatments for men with hypogonadism include transdermal gels, patches, intramuscular injection, and an oral formulation. Dosing for women is approximately one-tenth the dosage for treatment of men. Patients should be informed that this treatment is off-label and that long-term studies to establish safety are not available. The authors advised against the use of compounded formulations based on the National Academies of Science, Engineering, and Medicine guidelines, but they went on to say that if compounded products are used, the pharmacy should adhere to Good Manufacturing Practice and Active Pharmaceutical Ingredients standards.

Rare, complex sexual function disorder requires integrated biopsychosocial approach, says ISSWSH

Goldstein I, Komisaruk BR, Pukall CF, et al. International Society for the Study of Women’s Sexual Health (ISSWSH) review of epidemiology and pathophysiology, and a consensus nomenclature and process of care for the management of persistent genital arousal disorder/genito-pelvic dyesthesia (PGAD/GPD). J Sex Med. 2021;18:665-697.

Persistent genital arousal disorder is a poorly understood and relatively rare sexual dysfunction in women. The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin on Female Sexual Dysfunction does not mention this condition, leaving women’s health practitioners with little guidance as to diagnosis or management.² Prevalence for the condition is estimated at 1% to 3%. The symptoms may be intermittent or continuous.

In a recent ISSWSH review, a consensus panel defined 5 criteria for this disorder: the perception of genital arousal that is involuntary, unrelated to sexual desire, without any identified cause, not relieved with orgasm, and distressing to the patient. The panel made a clear distinction between PGAD/ genito-pelvic dysesthesia (GPD) and Compulsive Sexual Behavior Disorder (defined by the International Classification of Diseases revision 11 as “a persistent pattern of failure to control intense, repetitive sexual impulses or urges). Because there is considerable overlap with syndromes of genital dysesthesia—itching, burning, tingling, or pain— the consensus panel elected to expand the nomenclature to describe both persistent genital arousal and genito-pelvic dysesthesia as a single syndrome, namely, PGAD/GPD.

Continue to: Negative impact of PGAD/GPD...

Negative impact of PGAD/GPD

The consensus panel identified several contributors to the overall morbidity of this complex disorder, including end organ pathology, peripheral nerve, spinal cord and central sensory processing malfunction, and significant psychological issues. PGAD/GPD also may be associated with spinal cysts, cauda equina pathology, and withdrawal from selective serotonin reuptake inhibitors (SSRIs). Functional magnetic resonance imaging has identified specific brain regions (for example, the paracentral lobule) that are active during clitoral stimulation and that also activate during patients’ experience of persistent genital arousal.

PGAD/GPD negatively impacts sexual function, mental health, and ability to function in daily life. Of major importance is that a large proportion of people with this disorder have significant mental health disorders; in a survey, 54% of patients with PGAD reported suicidal ideation, compared with 25% of participants in a control group.

Evaluation and management recommendations

Diagnosis and management of PGAD/GPD are directed at the 5 areas of evaluation:

• end organ
• pelvis and perineum (assess for pelvic floor tension myalgia, pudendal neuropathy, pelvic congestion syndrome, or pelvic arteriovenous malformation)
• cauda equina (evaluate for neurologic deficits related to cysts compressing S2-S3 nerve roots)
• spinal cord (serotonin and norepinephrine pathways modulate nociceptive sensory activity; either SSRI/serotonin and norepinephrine reuptake inhibitor (SNRI) withdrawal or treatment could impact PGAD/ GPD based on their actions in the spinal cord)
• brain.

The consensus panel recommends an integrated biopsychosocial model for evaluation and treatment of PGAD/GPD. Comorbid mental health conditions, such as depression and anxiety, are common. Small studies suggest that a history of sexual trauma may contribute to catastrophizing and the experience of distressing persistent genital sensations, either arousal or dyesthesia, with 46.7% to 52.6% of patients reporting childhood sexual abuse.³

Future possibilities and current  actualities for patient care

Research dollars and investment in female sexual dysfunction remain inadequate to address the considerable gaps that exist in evidence-based clinical guidelines. ISSWSH is working to help clinicians approach these evidence gaps with guidelines and consensus statements to help women’s health professionals identify and manage our patients with sexual concerns and symptoms. An expert consensus guideline on the assessment and management of female orgasmic disorder is currently under development (personal communication, Dr. Sheryl Kingsberg). In addition, a phase 2b trial is underway to assess the impact of topical sildenafil cream for the treatment of female arousal disorder. Stay tuned for the results of these studies.

For now, women’s health professionals have 2 FDA-approved treatment options for premenopausal women with arousal disorder, flibanserin (a daily oral medication that requires abstinence from alcohol) and bremelanotide (an injectable medication that can be used just prior to a sexual encounter). For postmenopausal women, there are no FDA-approved therapies; however, based on the ISSWSH guideline summarized above, transdermal testosterone may be offered to postmenopausal women with distressing loss of sexual desire in doses approximately one-tenth those used to treat men with androgen deficiency. These small doses are challenging to achieve consistently with the delivery systems available for FDA-approved products sold for men.

The National Academies of Science, Engineering, and Medicine advise against the use of compounded hormonal products due to the potential for inconsistency and lack of FDA oversight in the manufacturing/compounding process. I have found and used some compounding pharmacies that are dedicated to safety, quality control, and compliance; test their products; and provide consistent, reliable compounded drugs for my patients. Consideration of compounded testosterone should be discussed with patients, and they should be informed of the current professional association guidelines. Testosterone creams may be compounded to a 1% product—20 mg/mL. Researchers in Australia have demonstrated that 5 mg of transdermal testosterone cream (one-quarter of a mL) results in typical premenopausal testosterone levels.⁴ When prescribing testosterone for postmenopausal women, check in with them after 6 weeks of treatment to assess impact and check blood levels to ensure that levels are not too high.

Testosterone pellets and intramuscular testosterone are not recommended and in fact should be actively avoided. These methods of administration are associated with extreme variation in hormone levels over time. There are typically supraphysiologic and quite high levels immediately after implantation or injection, followed by fairly significant drop-offs and rapid return of symptoms over time. This may lead to more and more frequent dosing and markedly elevated serum levels.

Management of PGAD/GPD is difficult, but knowing it exists as a valid syndrome will help clinicians validate patients’ symptoms and begin to approach appropriate evaluation and workup targeted to the 5 domains suggested by the ISSWSH expert panel. It is useful to understand the possible relationship to initiation or withdrawal from SSRIs or SNRIs and how aberrant norepinephrine signaling along the sensory pathways may contribute to genital dysesthesia or chronic sensations of arousal. Nonpharmacologic therapies, such as cognitive-behavioral therapy and others, are essential components of the multifaceted approach to treatment. Finally, many complex problems, such as chronic pelvic pain, vestibulodynia, vulvodynia, and chronic fatigue syndrome, are associated with childhood adverse experiences and sexual trauma. Approaching these patients with trauma-informed care is important to create the trust and therapeutic environment they need for successful multidisciplinary care. ●

Many authors have commented on the lack of research into female sexual dysfunction, especially when compared with the hundreds of research publications related to male sexual health and dysfunction. Not surprisingly, very little has been published in the past year on the subject of female sexual health.

Recently, the International Society for the Study of Women’s Sexual Health (ISSWSH) published 2 important papers: a guideline on the use of testosterone for hypoactive sexual desire disorder (HSDD) in women and a consensus document on the management of persistent genital arousal disorder (PGAD). The lack of funding and support for female sexual health leaves women’s health professionals with little education or guidance on how to identify and treat conditions that are likely as common in women as erectile dysfunction is in men. While we would like to rely on randomized trials to inform our clinical care, the very limited literature on female sexual health makes this difficult. Bringing together experienced clinicians who focus their practices on sexual health, ISSWSH has provided some much-needed recommendations for the management of difficult conditions.

ISSWSH provides clinical guidance on testosterone therapy for women with HSDD

Parish S, Simon J, Davis S, et al. International Society for the Study of Women’s Sexual Health clinical practice guideline for the use of systemic testosterone for hypoactive sexual desire disorder in women. J Sex Med. 2021;18:849-867.

For development of the ISSWSH clinical practice guideline on testosterone therapy for women with HSDD, 16 international researchers and clinicians were convened. A modified Delphi method was used to establish consensus at the meeting on the recommended indications for testosterone treatment, formulations, and when measurement of testosterone levels is appropriate.

An extensive evidence-based literature review was performed, which included original research, meta-analyses, reviews, and clinical practice guidelines, to address the use of testosterone in women for management of HSDD. Notably, in 2019, representatives of  10 medical societies published a Global Consensus Position Statement on the Use of Testosterone Therapy for Women that reviewed the existing literature on testosterone’s effects on sexual dysfunction, mood, cognition, musculoskeletal, cardiovascular, and breast health as well as androgenic side effects and adverse events.¹ Based on their review, the only evidence-based indication for testosterone use is for the treatment of HSDD.

Testosterone formulations, HSDD diagnosis, and sex steroid physiology

More than 10 years ago, the US Food and Drug Administration (FDA) reviewed an application for the use of a transdermal testosterone patch (Intrinsa) in women for the treatment of HSDD. Efficacy of treatment was clearly demonstrated, and no safety signals were found in the placebo-controlled trial. Based, however, on the opinions of regulators who were “concerned” about the potential for cardiovascular adverse outcomes and worry that the peripheral conversion of testosterone to estradiol might lead to an increase in breast cancer—worry generated from the findings of the Women’s Health Initiative (which did not demonstrate an increase in breast cancer risk with estrogen alone but only when estrogen was combined with medroxyprogesterone acetate)—the FDA declined to approve the testosterone patch for women.

The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) defined HSDD as “persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity with marked distress or interpersonal difficulty.” The guideline authors noted that although the DSM-5 edition merged female arousal disorder with desire disorder into a single diagnosis, they used the DSM-IV definition as it had been the basis for the studies and literature reviewed. HSDD is a prevalent condition worldwide that affects between 12% and  53% of peri- and postmenopausal women.

The consensus guideline authors extensively reviewed the physiology and mechanism of action of sex steroids in women, particularly their impact on sexual function and the biologic alterations that occur during peri- and postmenopause.

Continue to: Consensus position  and recommendations...

Consensus position  and recommendations

The ISSWSH consensus guideline concluded that there is a moderate therapeutic benefit in adding testosterone therapy to achieve up to premenopausal levels in postmenopausal women with self-reported reduction in sexual desire that is causing distress as determined by a validated instrument.

The authors advise baseline hormone testing to rule out androgen excess and baseline renal, lipid, liver, and metabolic testing, even though transdermal testosterone therapy was not shown to alter these parameters in randomized trials of more than 3,000 women. Laboratory assays for both total and free testosterone are “highly unreliable” in the female range as they have been calibrated for male levels of hormone.

FDA-approved testosterone treatments for men with hypogonadism include transdermal gels, patches, intramuscular injection, and an oral formulation. Dosing for women is approximately one-tenth the dosage for treatment of men. Patients should be informed that this treatment is off-label and that long-term studies to establish safety are not available. The authors advised against the use of compounded formulations based on the National Academies of Science, Engineering, and Medicine guidelines, but they went on to say that if compounded products are used, the pharmacy should adhere to Good Manufacturing Practice and Active Pharmaceutical Ingredients standards.

Rare, complex sexual function disorder requires integrated biopsychosocial approach, says ISSWSH

Goldstein I, Komisaruk BR, Pukall CF, et al. International Society for the Study of Women’s Sexual Health (ISSWSH) review of epidemiology and pathophysiology, and a consensus nomenclature and process of care for the management of persistent genital arousal disorder/genito-pelvic dyesthesia (PGAD/GPD). J Sex Med. 2021;18:665-697.

Persistent genital arousal disorder is a poorly understood and relatively rare sexual dysfunction in women. The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin on Female Sexual Dysfunction does not mention this condition, leaving women’s health practitioners with little guidance as to diagnosis or management.² Prevalence for the condition is estimated at 1% to 3%. The symptoms may be intermittent or continuous.

In a recent ISSWSH review, a consensus panel defined 5 criteria for this disorder: the perception of genital arousal that is involuntary, unrelated to sexual desire, without any identified cause, not relieved with orgasm, and distressing to the patient. The panel made a clear distinction between PGAD/ genito-pelvic dysesthesia (GPD) and Compulsive Sexual Behavior Disorder (defined by the International Classification of Diseases revision 11 as “a persistent pattern of failure to control intense, repetitive sexual impulses or urges). Because there is considerable overlap with syndromes of genital dysesthesia—itching, burning, tingling, or pain— the consensus panel elected to expand the nomenclature to describe both persistent genital arousal and genito-pelvic dysesthesia as a single syndrome, namely, PGAD/GPD.

Continue to: Negative impact of PGAD/GPD...

Negative impact of PGAD/GPD

The consensus panel identified several contributors to the overall morbidity of this complex disorder, including end organ pathology, peripheral nerve, spinal cord and central sensory processing malfunction, and significant psychological issues. PGAD/GPD also may be associated with spinal cysts, cauda equina pathology, and withdrawal from selective serotonin reuptake inhibitors (SSRIs). Functional magnetic resonance imaging has identified specific brain regions (for example, the paracentral lobule) that are active during clitoral stimulation and that also activate during patients’ experience of persistent genital arousal.

PGAD/GPD negatively impacts sexual function, mental health, and ability to function in daily life. Of major importance is that a large proportion of people with this disorder have significant mental health disorders; in a survey, 54% of patients with PGAD reported suicidal ideation, compared with 25% of participants in a control group.

Evaluation and management recommendations

Diagnosis and management of PGAD/GPD are directed at the 5 areas of evaluation:

• end organ
• pelvis and perineum (assess for pelvic floor tension myalgia, pudendal neuropathy, pelvic congestion syndrome, or pelvic arteriovenous malformation)
• cauda equina (evaluate for neurologic deficits related to cysts compressing S2-S3 nerve roots)
• spinal cord (serotonin and norepinephrine pathways modulate nociceptive sensory activity; either SSRI/serotonin and norepinephrine reuptake inhibitor (SNRI) withdrawal or treatment could impact PGAD/ GPD based on their actions in the spinal cord)
• brain.

The consensus panel recommends an integrated biopsychosocial model for evaluation and treatment of PGAD/GPD. Comorbid mental health conditions, such as depression and anxiety, are common. Small studies suggest that a history of sexual trauma may contribute to catastrophizing and the experience of distressing persistent genital sensations, either arousal or dyesthesia, with 46.7% to 52.6% of patients reporting childhood sexual abuse.³

Future possibilities and current  actualities for patient care

Research dollars and investment in female sexual dysfunction remain inadequate to address the considerable gaps that exist in evidence-based clinical guidelines. ISSWSH is working to help clinicians approach these evidence gaps with guidelines and consensus statements to help women’s health professionals identify and manage our patients with sexual concerns and symptoms. An expert consensus guideline on the assessment and management of female orgasmic disorder is currently under development (personal communication, Dr. Sheryl Kingsberg). In addition, a phase 2b trial is underway to assess the impact of topical sildenafil cream for the treatment of female arousal disorder. Stay tuned for the results of these studies.

For now, women’s health professionals have 2 FDA-approved treatment options for premenopausal women with arousal disorder, flibanserin (a daily oral medication that requires abstinence from alcohol) and bremelanotide (an injectable medication that can be used just prior to a sexual encounter). For postmenopausal women, there are no FDA-approved therapies; however, based on the ISSWSH guideline summarized above, transdermal testosterone may be offered to postmenopausal women with distressing loss of sexual desire in doses approximately one-tenth those used to treat men with androgen deficiency. These small doses are challenging to achieve consistently with the delivery systems available for FDA-approved products sold for men.

The National Academies of Science, Engineering, and Medicine advise against the use of compounded hormonal products due to the potential for inconsistency and lack of FDA oversight in the manufacturing/compounding process. I have found and used some compounding pharmacies that are dedicated to safety, quality control, and compliance; test their products; and provide consistent, reliable compounded drugs for my patients. Consideration of compounded testosterone should be discussed with patients, and they should be informed of the current professional association guidelines. Testosterone creams may be compounded to a 1% product—20 mg/mL. Researchers in Australia have demonstrated that 5 mg of transdermal testosterone cream (one-quarter of a mL) results in typical premenopausal testosterone levels.⁴ When prescribing testosterone for postmenopausal women, check in with them after 6 weeks of treatment to assess impact and check blood levels to ensure that levels are not too high.

Testosterone pellets and intramuscular testosterone are not recommended and in fact should be actively avoided. These methods of administration are associated with extreme variation in hormone levels over time. There are typically supraphysiologic and quite high levels immediately after implantation or injection, followed by fairly significant drop-offs and rapid return of symptoms over time. This may lead to more and more frequent dosing and markedly elevated serum levels.

Management of PGAD/GPD is difficult, but knowing it exists as a valid syndrome will help clinicians validate patients’ symptoms and begin to approach appropriate evaluation and workup targeted to the 5 domains suggested by the ISSWSH expert panel. It is useful to understand the possible relationship to initiation or withdrawal from SSRIs or SNRIs and how aberrant norepinephrine signaling along the sensory pathways may contribute to genital dysesthesia or chronic sensations of arousal. Nonpharmacologic therapies, such as cognitive-behavioral therapy and others, are essential components of the multifaceted approach to treatment. Finally, many complex problems, such as chronic pelvic pain, vestibulodynia, vulvodynia, and chronic fatigue syndrome, are associated with childhood adverse experiences and sexual trauma. Approaching these patients with trauma-informed care is important to create the trust and therapeutic environment they need for successful multidisciplinary care. ●

Many authors have commented on the lack of research into female sexual dysfunction, especially when compared with the hundreds of research publications related to male sexual health and dysfunction. Not surprisingly, very little has been published in the past year on the subject of female sexual health.

Recently, the International Society for the Study of Women’s Sexual Health (ISSWSH) published 2 important papers: a guideline on the use of testosterone for hypoactive sexual desire disorder (HSDD) in women and a consensus document on the management of persistent genital arousal disorder (PGAD). The lack of funding and support for female sexual health leaves women’s health professionals with little education or guidance on how to identify and treat conditions that are likely as common in women as erectile dysfunction is in men. While we would like to rely on randomized trials to inform our clinical care, the very limited literature on female sexual health makes this difficult. Bringing together experienced clinicians who focus their practices on sexual health, ISSWSH has provided some much-needed recommendations for the management of difficult conditions.

ISSWSH provides clinical guidance on testosterone therapy for women with HSDD

Parish S, Simon J, Davis S, et al. International Society for the Study of Women’s Sexual Health clinical practice guideline for the use of systemic testosterone for hypoactive sexual desire disorder in women. J Sex Med. 2021;18:849-867.

For development of the ISSWSH clinical practice guideline on testosterone therapy for women with HSDD, 16 international researchers and clinicians were convened. A modified Delphi method was used to establish consensus at the meeting on the recommended indications for testosterone treatment, formulations, and when measurement of testosterone levels is appropriate.

An extensive evidence-based literature review was performed, which included original research, meta-analyses, reviews, and clinical practice guidelines, to address the use of testosterone in women for management of HSDD. Notably, in 2019, representatives of  10 medical societies published a Global Consensus Position Statement on the Use of Testosterone Therapy for Women that reviewed the existing literature on testosterone’s effects on sexual dysfunction, mood, cognition, musculoskeletal, cardiovascular, and breast health as well as androgenic side effects and adverse events.¹ Based on their review, the only evidence-based indication for testosterone use is for the treatment of HSDD.

Testosterone formulations, HSDD diagnosis, and sex steroid physiology

More than 10 years ago, the US Food and Drug Administration (FDA) reviewed an application for the use of a transdermal testosterone patch (Intrinsa) in women for the treatment of HSDD. Efficacy of treatment was clearly demonstrated, and no safety signals were found in the placebo-controlled trial. Based, however, on the opinions of regulators who were “concerned” about the potential for cardiovascular adverse outcomes and worry that the peripheral conversion of testosterone to estradiol might lead to an increase in breast cancer—worry generated from the findings of the Women’s Health Initiative (which did not demonstrate an increase in breast cancer risk with estrogen alone but only when estrogen was combined with medroxyprogesterone acetate)—the FDA declined to approve the testosterone patch for women.

The Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) defined HSDD as “persistent or recurrent deficiency or absence of sexual fantasies and desire for sexual activity with marked distress or interpersonal difficulty.” The guideline authors noted that although the DSM-5 edition merged female arousal disorder with desire disorder into a single diagnosis, they used the DSM-IV definition as it had been the basis for the studies and literature reviewed. HSDD is a prevalent condition worldwide that affects between 12% and  53% of peri- and postmenopausal women.

The consensus guideline authors extensively reviewed the physiology and mechanism of action of sex steroids in women, particularly their impact on sexual function and the biologic alterations that occur during peri- and postmenopause.

Continue to: Consensus position  and recommendations...

Consensus position  and recommendations

The ISSWSH consensus guideline concluded that there is a moderate therapeutic benefit in adding testosterone therapy to achieve up to premenopausal levels in postmenopausal women with self-reported reduction in sexual desire that is causing distress as determined by a validated instrument.

The authors advise baseline hormone testing to rule out androgen excess and baseline renal, lipid, liver, and metabolic testing, even though transdermal testosterone therapy was not shown to alter these parameters in randomized trials of more than 3,000 women. Laboratory assays for both total and free testosterone are “highly unreliable” in the female range as they have been calibrated for male levels of hormone.

FDA-approved testosterone treatments for men with hypogonadism include transdermal gels, patches, intramuscular injection, and an oral formulation. Dosing for women is approximately one-tenth the dosage for treatment of men. Patients should be informed that this treatment is off-label and that long-term studies to establish safety are not available. The authors advised against the use of compounded formulations based on the National Academies of Science, Engineering, and Medicine guidelines, but they went on to say that if compounded products are used, the pharmacy should adhere to Good Manufacturing Practice and Active Pharmaceutical Ingredients standards.

Rare, complex sexual function disorder requires integrated biopsychosocial approach, says ISSWSH

Goldstein I, Komisaruk BR, Pukall CF, et al. International Society for the Study of Women’s Sexual Health (ISSWSH) review of epidemiology and pathophysiology, and a consensus nomenclature and process of care for the management of persistent genital arousal disorder/genito-pelvic dyesthesia (PGAD/GPD). J Sex Med. 2021;18:665-697.

Persistent genital arousal disorder is a poorly understood and relatively rare sexual dysfunction in women. The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin on Female Sexual Dysfunction does not mention this condition, leaving women’s health practitioners with little guidance as to diagnosis or management.² Prevalence for the condition is estimated at 1% to 3%. The symptoms may be intermittent or continuous.

In a recent ISSWSH review, a consensus panel defined 5 criteria for this disorder: the perception of genital arousal that is involuntary, unrelated to sexual desire, without any identified cause, not relieved with orgasm, and distressing to the patient. The panel made a clear distinction between PGAD/ genito-pelvic dysesthesia (GPD) and Compulsive Sexual Behavior Disorder (defined by the International Classification of Diseases revision 11 as “a persistent pattern of failure to control intense, repetitive sexual impulses or urges). Because there is considerable overlap with syndromes of genital dysesthesia—itching, burning, tingling, or pain— the consensus panel elected to expand the nomenclature to describe both persistent genital arousal and genito-pelvic dysesthesia as a single syndrome, namely, PGAD/GPD.

Continue to: Negative impact of PGAD/GPD...

Negative impact of PGAD/GPD

The consensus panel identified several contributors to the overall morbidity of this complex disorder, including end organ pathology, peripheral nerve, spinal cord and central sensory processing malfunction, and significant psychological issues. PGAD/GPD also may be associated with spinal cysts, cauda equina pathology, and withdrawal from selective serotonin reuptake inhibitors (SSRIs). Functional magnetic resonance imaging has identified specific brain regions (for example, the paracentral lobule) that are active during clitoral stimulation and that also activate during patients’ experience of persistent genital arousal.

PGAD/GPD negatively impacts sexual function, mental health, and ability to function in daily life. Of major importance is that a large proportion of people with this disorder have significant mental health disorders; in a survey, 54% of patients with PGAD reported suicidal ideation, compared with 25% of participants in a control group.

Evaluation and management recommendations

Diagnosis and management of PGAD/GPD are directed at the 5 areas of evaluation:

• end organ
• pelvis and perineum (assess for pelvic floor tension myalgia, pudendal neuropathy, pelvic congestion syndrome, or pelvic arteriovenous malformation)
• cauda equina (evaluate for neurologic deficits related to cysts compressing S2-S3 nerve roots)
• spinal cord (serotonin and norepinephrine pathways modulate nociceptive sensory activity; either SSRI/serotonin and norepinephrine reuptake inhibitor (SNRI) withdrawal or treatment could impact PGAD/ GPD based on their actions in the spinal cord)
• brain.

The consensus panel recommends an integrated biopsychosocial model for evaluation and treatment of PGAD/GPD. Comorbid mental health conditions, such as depression and anxiety, are common. Small studies suggest that a history of sexual trauma may contribute to catastrophizing and the experience of distressing persistent genital sensations, either arousal or dyesthesia, with 46.7% to 52.6% of patients reporting childhood sexual abuse.³

Future possibilities and current  actualities for patient care

Research dollars and investment in female sexual dysfunction remain inadequate to address the considerable gaps that exist in evidence-based clinical guidelines. ISSWSH is working to help clinicians approach these evidence gaps with guidelines and consensus statements to help women’s health professionals identify and manage our patients with sexual concerns and symptoms. An expert consensus guideline on the assessment and management of female orgasmic disorder is currently under development (personal communication, Dr. Sheryl Kingsberg). In addition, a phase 2b trial is underway to assess the impact of topical sildenafil cream for the treatment of female arousal disorder. Stay tuned for the results of these studies.

For now, women’s health professionals have 2 FDA-approved treatment options for premenopausal women with arousal disorder, flibanserin (a daily oral medication that requires abstinence from alcohol) and bremelanotide (an injectable medication that can be used just prior to a sexual encounter). For postmenopausal women, there are no FDA-approved therapies; however, based on the ISSWSH guideline summarized above, transdermal testosterone may be offered to postmenopausal women with distressing loss of sexual desire in doses approximately one-tenth those used to treat men with androgen deficiency. These small doses are challenging to achieve consistently with the delivery systems available for FDA-approved products sold for men.

The National Academies of Science, Engineering, and Medicine advise against the use of compounded hormonal products due to the potential for inconsistency and lack of FDA oversight in the manufacturing/compounding process. I have found and used some compounding pharmacies that are dedicated to safety, quality control, and compliance; test their products; and provide consistent, reliable compounded drugs for my patients. Consideration of compounded testosterone should be discussed with patients, and they should be informed of the current professional association guidelines. Testosterone creams may be compounded to a 1% product—20 mg/mL. Researchers in Australia have demonstrated that 5 mg of transdermal testosterone cream (one-quarter of a mL) results in typical premenopausal testosterone levels.⁴ When prescribing testosterone for postmenopausal women, check in with them after 6 weeks of treatment to assess impact and check blood levels to ensure that levels are not too high.

Testosterone pellets and intramuscular testosterone are not recommended and in fact should be actively avoided. These methods of administration are associated with extreme variation in hormone levels over time. There are typically supraphysiologic and quite high levels immediately after implantation or injection, followed by fairly significant drop-offs and rapid return of symptoms over time. This may lead to more and more frequent dosing and markedly elevated serum levels.

Management of PGAD/GPD is difficult, but knowing it exists as a valid syndrome will help clinicians validate patients’ symptoms and begin to approach appropriate evaluation and workup targeted to the 5 domains suggested by the ISSWSH expert panel. It is useful to understand the possible relationship to initiation or withdrawal from SSRIs or SNRIs and how aberrant norepinephrine signaling along the sensory pathways may contribute to genital dysesthesia or chronic sensations of arousal. Nonpharmacologic therapies, such as cognitive-behavioral therapy and others, are essential components of the multifaceted approach to treatment. Finally, many complex problems, such as chronic pelvic pain, vestibulodynia, vulvodynia, and chronic fatigue syndrome, are associated with childhood adverse experiences and sexual trauma. Approaching these patients with trauma-informed care is important to create the trust and therapeutic environment they need for successful multidisciplinary care. ●

It is time to reconsider the recommendation for practicing fetal kick counts. A meta-analysis demonstrated no decrease in the outcome of stillbirth, but instead an increased risk of iatrogenic delivery.¹

CASE 1 8 vs 10 fetal movements in 2 hours

Ms. M is 38 weeks pregnant with an uncomplicated pregnancy. She calls your practice with concerns about fetal kick counts. During her prenatal care, she was counseled to ensure that the baby moved 10 times over a period of 2 hours. This morning, however, she only perceived 8 movements in 2 hours. She is scheduled for evaluation with a nonstress test (NST) on the labor and delivery unit. The NST reveals a reassuring, reactive tracing. Ultrasonography evaluation demonstrates a normal amniotic fluid index and normal fetal growth. The patient is reassured, returns home, and goes on to deliver a healthy baby at 39 weeks and 5 days.

Perception of decreased movement triggers evaluation and monitoring

Maternal perception of normal fetal movement has conceivably been used throughout history as a means of reassurance of fetal well-being; it is highly predictive of fetal viability.^2,3 When fetal movement is lacking or decreased, it can be an alarm sign and may result in concerns by the mother that her baby is unwell. Maternal perception of decreased fetal movements affects 5% to 15% of all pregnancies.^2,4 While decreased fetal movement can be associated with poor perinatal outcomes such as fetal growth restriction, oligohydramnios, and neuro-developmental disability, it also can be reflective of more benign issues such as anterior placenta, maternal activity, maternal caffeine or sugar consumption, or maternal position.^4,5

However, the definition of decreased fetal movement is subject to significant variation, from a total absence of movement over an entire day or what has commonly become accepted as the definition of fetal kick counts with Pearson’s Cardiff chart (which was defined in the 1970s as 10 movements within 12 hours).^6,7 Today, women in the United States are commonly recommended to monitor their baby over a 2-hour period and to look for 10 movements during that time.⁸ Anything less is considered reduced fetal movement and results in recommendations to undergo assessment of previously known high-risk conditions or any possible underlying conditions, such as hypertension, gestational diabetes, or fetal growth restriction. Further evaluation with more objective measures such as electronic fetal monitoring or ultrasonography with biophysical profile are often recommended concurrently.⁹

It is estimated that up to 15% of women present reporting decreased fetal movement in the third trimester and, as such, require additional monitoring and evaluation. This is not without cost of time and money to the health care system and pregnant patients.

It is uncertain that fetal kick counting prevents stillbirth

Intrauterine fetal demise is neither an uncommon nor completely preventable outcome, despite advances in antenatal care. Many cases occur without evidence of fetal abnormality or other risk factors, and 30% to 55% of women who experience intrauterine fetal demise experience decreased fetal movement in the preceding week.¹⁰ It makes physiologic sense that a fetus’ adaptive response to decreased oxygenation is reduced fetal movement, resulting from the prioritization of blood to the fetal brain and other organs over skeletal muscle.^4,9,11 Results of a 1976 small study of 61 low-risk pregnancies seemed to confirm that a decrease in fetal movement preceded intrauterine death by 3 to 4 days. Conversely, they found that a normal fetal movement count was generally associated with a good neonatal outcome.⁶ Thus, experts have long extrapolated that decreased fetal movement can be an indicator for utero-placental insufficiency and, in turn, chronic or acute hypoxia.

However, in larger studies, the ability of fetal movement counting to predict fetal death and fetal compromise appears limited.^8,10,11 A meta-analysis of studies, including 5 randomized controlled trials and 468,000 fetuses, compared the incidence of stillbirth in women receiving instructions for fetal movement counting versus women who did not. Rates of stillbirth were the same for each group, demonstrating no advantage to fetal kick counts to prevent a poor perinatal outcome, including stillbirth.¹

CASE 2 Reported reduced fetal movement over 4 weeks

Ms. E is a 20-year-old nullipara at 36 weeks’ and 6 days gestation who has come in to triage weekly for the last 4 weeks with concerns about decreased fetal movement. She states that she goes for several hours each day without feeling 10 movements in 2 hours. Recent fetal growth recorded 3 weeks ago was in the 45th percentile, and the amniotic fluid index has been above 10 cm on each weekly ultrasound. Her weekly NSTs have been reactive, and she has been normotensive. However, because she has had several weeks of persistent decreased fetal movement, the labor and delivery team opts to keep her for induction as she is “close to term.”

Decreased kick count frequency may increase unnecessary interventions

Women with fewer kick counts are more likely to present with concerns about the well-being of their baby. In a survey of obstetricians and midwives, a large proportion of providers were more apt to recommend delivery or admission to the hospital for women presenting with decreased fetal movements.² It stands to reason that recommendations for delivery or admission can lead to outcomes like preterm delivery or recommendations for cesarean delivery (CD). However, using fetal kick counts to portend stillbirth or other poor fetal and neonatal outcomes has been shown to be limited in its value with the AFFIRM trial.¹⁰ The results of this large study, which included more than 400,000 pregnancies from 37 hospitals, show the challenges of any study to address the use of management strategies for recent change in the frequency of fetal movements in the reduction of and cause of stillbirth. Additionally, the relatively low risk of stillbirth overall (4.06 stillbirths per 1,000 livebirths during the intervention period and 4.40 per 1,000 livebirths during the control period) but higher incidence of other outcomes, such as prolonged (>48 hours) antepartum admission (6.7% in the intervention period and 6.2% in the control period), induction of labor (40.7% in the intervention period and 35.9% in the control period), and CD (28.4% and 25.5%, respectively) may result in increased harm for many women rather than the intended benefit of preventing stillbirth.^10,12

Mindfetalness may be a viable and valuable alternative to kick counts

Alternatives have been proposed as a measure of fetal movement without using kick counts specifically. Mindfetalness has been a method studied in Sweden; its purpose is to strengthen the mother’s awareness of her baby through developing an understanding of the fetal-movement pattern. It is practiced starting at 28 weeks’ gestation for 15 minutes a day, with the woman instructed to lie on her left side and discern the intensity and character of the movements, as well as frequency, without overtly counting the movements.¹² In one small study, women felt more connected to their babies and felt less worried.¹² In a much larger study of 13,000 women, the authors found no evidence of harm from generalized awareness of fetal movements in a population of pregnant women at or beyond 32 weeks; in fact, they did see significant reductions in iatrogenic outcomes such as CDs and labor inductions.¹³

The case for movement awareness over kick counts

Stillbirth risk does not appear to be modified by the use of methods to detect fetal movement.^10,12 However, a perceived decrease in fetal kick counts has been shown to result in increased interventions and preterm deliveries. A more prudent approach appears to be educating mothers about general fetal movement, which appears to reduce potentially unnecessary visits and interventions without sacrificing the ability to reassure mothers about the well-being of their babies in utero. ●

It is time to reconsider the recommendation for practicing fetal kick counts. A meta-analysis demonstrated no decrease in the outcome of stillbirth, but instead an increased risk of iatrogenic delivery.¹

CASE 1 8 vs 10 fetal movements in 2 hours

Ms. M is 38 weeks pregnant with an uncomplicated pregnancy. She calls your practice with concerns about fetal kick counts. During her prenatal care, she was counseled to ensure that the baby moved 10 times over a period of 2 hours. This morning, however, she only perceived 8 movements in 2 hours. She is scheduled for evaluation with a nonstress test (NST) on the labor and delivery unit. The NST reveals a reassuring, reactive tracing. Ultrasonography evaluation demonstrates a normal amniotic fluid index and normal fetal growth. The patient is reassured, returns home, and goes on to deliver a healthy baby at 39 weeks and 5 days.

Perception of decreased movement triggers evaluation and monitoring

Maternal perception of normal fetal movement has conceivably been used throughout history as a means of reassurance of fetal well-being; it is highly predictive of fetal viability.^2,3 When fetal movement is lacking or decreased, it can be an alarm sign and may result in concerns by the mother that her baby is unwell. Maternal perception of decreased fetal movements affects 5% to 15% of all pregnancies.^2,4 While decreased fetal movement can be associated with poor perinatal outcomes such as fetal growth restriction, oligohydramnios, and neuro-developmental disability, it also can be reflective of more benign issues such as anterior placenta, maternal activity, maternal caffeine or sugar consumption, or maternal position.^4,5

However, the definition of decreased fetal movement is subject to significant variation, from a total absence of movement over an entire day or what has commonly become accepted as the definition of fetal kick counts with Pearson’s Cardiff chart (which was defined in the 1970s as 10 movements within 12 hours).^6,7 Today, women in the United States are commonly recommended to monitor their baby over a 2-hour period and to look for 10 movements during that time.⁸ Anything less is considered reduced fetal movement and results in recommendations to undergo assessment of previously known high-risk conditions or any possible underlying conditions, such as hypertension, gestational diabetes, or fetal growth restriction. Further evaluation with more objective measures such as electronic fetal monitoring or ultrasonography with biophysical profile are often recommended concurrently.⁹

It is estimated that up to 15% of women present reporting decreased fetal movement in the third trimester and, as such, require additional monitoring and evaluation. This is not without cost of time and money to the health care system and pregnant patients.

It is uncertain that fetal kick counting prevents stillbirth

Intrauterine fetal demise is neither an uncommon nor completely preventable outcome, despite advances in antenatal care. Many cases occur without evidence of fetal abnormality or other risk factors, and 30% to 55% of women who experience intrauterine fetal demise experience decreased fetal movement in the preceding week.¹⁰ It makes physiologic sense that a fetus’ adaptive response to decreased oxygenation is reduced fetal movement, resulting from the prioritization of blood to the fetal brain and other organs over skeletal muscle.^4,9,11 Results of a 1976 small study of 61 low-risk pregnancies seemed to confirm that a decrease in fetal movement preceded intrauterine death by 3 to 4 days. Conversely, they found that a normal fetal movement count was generally associated with a good neonatal outcome.⁶ Thus, experts have long extrapolated that decreased fetal movement can be an indicator for utero-placental insufficiency and, in turn, chronic or acute hypoxia.

However, in larger studies, the ability of fetal movement counting to predict fetal death and fetal compromise appears limited.^8,10,11 A meta-analysis of studies, including 5 randomized controlled trials and 468,000 fetuses, compared the incidence of stillbirth in women receiving instructions for fetal movement counting versus women who did not. Rates of stillbirth were the same for each group, demonstrating no advantage to fetal kick counts to prevent a poor perinatal outcome, including stillbirth.¹

CASE 2 Reported reduced fetal movement over 4 weeks

Ms. E is a 20-year-old nullipara at 36 weeks’ and 6 days gestation who has come in to triage weekly for the last 4 weeks with concerns about decreased fetal movement. She states that she goes for several hours each day without feeling 10 movements in 2 hours. Recent fetal growth recorded 3 weeks ago was in the 45th percentile, and the amniotic fluid index has been above 10 cm on each weekly ultrasound. Her weekly NSTs have been reactive, and she has been normotensive. However, because she has had several weeks of persistent decreased fetal movement, the labor and delivery team opts to keep her for induction as she is “close to term.”

Decreased kick count frequency may increase unnecessary interventions

Women with fewer kick counts are more likely to present with concerns about the well-being of their baby. In a survey of obstetricians and midwives, a large proportion of providers were more apt to recommend delivery or admission to the hospital for women presenting with decreased fetal movements.² It stands to reason that recommendations for delivery or admission can lead to outcomes like preterm delivery or recommendations for cesarean delivery (CD). However, using fetal kick counts to portend stillbirth or other poor fetal and neonatal outcomes has been shown to be limited in its value with the AFFIRM trial.¹⁰ The results of this large study, which included more than 400,000 pregnancies from 37 hospitals, show the challenges of any study to address the use of management strategies for recent change in the frequency of fetal movements in the reduction of and cause of stillbirth. Additionally, the relatively low risk of stillbirth overall (4.06 stillbirths per 1,000 livebirths during the intervention period and 4.40 per 1,000 livebirths during the control period) but higher incidence of other outcomes, such as prolonged (>48 hours) antepartum admission (6.7% in the intervention period and 6.2% in the control period), induction of labor (40.7% in the intervention period and 35.9% in the control period), and CD (28.4% and 25.5%, respectively) may result in increased harm for many women rather than the intended benefit of preventing stillbirth.^10,12

Mindfetalness may be a viable and valuable alternative to kick counts

Alternatives have been proposed as a measure of fetal movement without using kick counts specifically. Mindfetalness has been a method studied in Sweden; its purpose is to strengthen the mother’s awareness of her baby through developing an understanding of the fetal-movement pattern. It is practiced starting at 28 weeks’ gestation for 15 minutes a day, with the woman instructed to lie on her left side and discern the intensity and character of the movements, as well as frequency, without overtly counting the movements.¹² In one small study, women felt more connected to their babies and felt less worried.¹² In a much larger study of 13,000 women, the authors found no evidence of harm from generalized awareness of fetal movements in a population of pregnant women at or beyond 32 weeks; in fact, they did see significant reductions in iatrogenic outcomes such as CDs and labor inductions.¹³

The case for movement awareness over kick counts

Stillbirth risk does not appear to be modified by the use of methods to detect fetal movement.^10,12 However, a perceived decrease in fetal kick counts has been shown to result in increased interventions and preterm deliveries. A more prudent approach appears to be educating mothers about general fetal movement, which appears to reduce potentially unnecessary visits and interventions without sacrificing the ability to reassure mothers about the well-being of their babies in utero. ●

It is time to reconsider the recommendation for practicing fetal kick counts. A meta-analysis demonstrated no decrease in the outcome of stillbirth, but instead an increased risk of iatrogenic delivery.¹

CASE 1 8 vs 10 fetal movements in 2 hours

Ms. M is 38 weeks pregnant with an uncomplicated pregnancy. She calls your practice with concerns about fetal kick counts. During her prenatal care, she was counseled to ensure that the baby moved 10 times over a period of 2 hours. This morning, however, she only perceived 8 movements in 2 hours. She is scheduled for evaluation with a nonstress test (NST) on the labor and delivery unit. The NST reveals a reassuring, reactive tracing. Ultrasonography evaluation demonstrates a normal amniotic fluid index and normal fetal growth. The patient is reassured, returns home, and goes on to deliver a healthy baby at 39 weeks and 5 days.

Perception of decreased movement triggers evaluation and monitoring

Maternal perception of normal fetal movement has conceivably been used throughout history as a means of reassurance of fetal well-being; it is highly predictive of fetal viability.^2,3 When fetal movement is lacking or decreased, it can be an alarm sign and may result in concerns by the mother that her baby is unwell. Maternal perception of decreased fetal movements affects 5% to 15% of all pregnancies.^2,4 While decreased fetal movement can be associated with poor perinatal outcomes such as fetal growth restriction, oligohydramnios, and neuro-developmental disability, it also can be reflective of more benign issues such as anterior placenta, maternal activity, maternal caffeine or sugar consumption, or maternal position.^4,5

However, the definition of decreased fetal movement is subject to significant variation, from a total absence of movement over an entire day or what has commonly become accepted as the definition of fetal kick counts with Pearson’s Cardiff chart (which was defined in the 1970s as 10 movements within 12 hours).^6,7 Today, women in the United States are commonly recommended to monitor their baby over a 2-hour period and to look for 10 movements during that time.⁸ Anything less is considered reduced fetal movement and results in recommendations to undergo assessment of previously known high-risk conditions or any possible underlying conditions, such as hypertension, gestational diabetes, or fetal growth restriction. Further evaluation with more objective measures such as electronic fetal monitoring or ultrasonography with biophysical profile are often recommended concurrently.⁹

It is estimated that up to 15% of women present reporting decreased fetal movement in the third trimester and, as such, require additional monitoring and evaluation. This is not without cost of time and money to the health care system and pregnant patients.

It is uncertain that fetal kick counting prevents stillbirth

Intrauterine fetal demise is neither an uncommon nor completely preventable outcome, despite advances in antenatal care. Many cases occur without evidence of fetal abnormality or other risk factors, and 30% to 55% of women who experience intrauterine fetal demise experience decreased fetal movement in the preceding week.¹⁰ It makes physiologic sense that a fetus’ adaptive response to decreased oxygenation is reduced fetal movement, resulting from the prioritization of blood to the fetal brain and other organs over skeletal muscle.^4,9,11 Results of a 1976 small study of 61 low-risk pregnancies seemed to confirm that a decrease in fetal movement preceded intrauterine death by 3 to 4 days. Conversely, they found that a normal fetal movement count was generally associated with a good neonatal outcome.⁶ Thus, experts have long extrapolated that decreased fetal movement can be an indicator for utero-placental insufficiency and, in turn, chronic or acute hypoxia.

However, in larger studies, the ability of fetal movement counting to predict fetal death and fetal compromise appears limited.^8,10,11 A meta-analysis of studies, including 5 randomized controlled trials and 468,000 fetuses, compared the incidence of stillbirth in women receiving instructions for fetal movement counting versus women who did not. Rates of stillbirth were the same for each group, demonstrating no advantage to fetal kick counts to prevent a poor perinatal outcome, including stillbirth.¹

CASE 2 Reported reduced fetal movement over 4 weeks

Ms. E is a 20-year-old nullipara at 36 weeks’ and 6 days gestation who has come in to triage weekly for the last 4 weeks with concerns about decreased fetal movement. She states that she goes for several hours each day without feeling 10 movements in 2 hours. Recent fetal growth recorded 3 weeks ago was in the 45th percentile, and the amniotic fluid index has been above 10 cm on each weekly ultrasound. Her weekly NSTs have been reactive, and she has been normotensive. However, because she has had several weeks of persistent decreased fetal movement, the labor and delivery team opts to keep her for induction as she is “close to term.”

Decreased kick count frequency may increase unnecessary interventions

Women with fewer kick counts are more likely to present with concerns about the well-being of their baby. In a survey of obstetricians and midwives, a large proportion of providers were more apt to recommend delivery or admission to the hospital for women presenting with decreased fetal movements.² It stands to reason that recommendations for delivery or admission can lead to outcomes like preterm delivery or recommendations for cesarean delivery (CD). However, using fetal kick counts to portend stillbirth or other poor fetal and neonatal outcomes has been shown to be limited in its value with the AFFIRM trial.¹⁰ The results of this large study, which included more than 400,000 pregnancies from 37 hospitals, show the challenges of any study to address the use of management strategies for recent change in the frequency of fetal movements in the reduction of and cause of stillbirth. Additionally, the relatively low risk of stillbirth overall (4.06 stillbirths per 1,000 livebirths during the intervention period and 4.40 per 1,000 livebirths during the control period) but higher incidence of other outcomes, such as prolonged (>48 hours) antepartum admission (6.7% in the intervention period and 6.2% in the control period), induction of labor (40.7% in the intervention period and 35.9% in the control period), and CD (28.4% and 25.5%, respectively) may result in increased harm for many women rather than the intended benefit of preventing stillbirth.^10,12

Mindfetalness may be a viable and valuable alternative to kick counts

Alternatives have been proposed as a measure of fetal movement without using kick counts specifically. Mindfetalness has been a method studied in Sweden; its purpose is to strengthen the mother’s awareness of her baby through developing an understanding of the fetal-movement pattern. It is practiced starting at 28 weeks’ gestation for 15 minutes a day, with the woman instructed to lie on her left side and discern the intensity and character of the movements, as well as frequency, without overtly counting the movements.¹² In one small study, women felt more connected to their babies and felt less worried.¹² In a much larger study of 13,000 women, the authors found no evidence of harm from generalized awareness of fetal movements in a population of pregnant women at or beyond 32 weeks; in fact, they did see significant reductions in iatrogenic outcomes such as CDs and labor inductions.¹³

The case for movement awareness over kick counts

Stillbirth risk does not appear to be modified by the use of methods to detect fetal movement.^10,12 However, a perceived decrease in fetal kick counts has been shown to result in increased interventions and preterm deliveries. A more prudent approach appears to be educating mothers about general fetal movement, which appears to reduce potentially unnecessary visits and interventions without sacrificing the ability to reassure mothers about the well-being of their babies in utero. ●

CASE Healthy woman with hot flashes inquires about HT

A 54-year-old healthy woman with a history of hypothyroidism taking thyroid replacement medication comes in for her annual visit. Her last menstrual period was over 2 years ago and she reports severe hot flashes. They have greatly affected her quality of life and she must take frequent breaks at work. She wakes up frequently at night due to night sweats, which is impacting her sleep and, subsequently, her energy level. She has noted increased vaginal dryness so has been abstaining from sexual intercourse due to the discomfort. She has an intact uterus. Her family history is significant for heart disease, diagnosed in her mother at age 75.

On physical examination, she is normotensive and well-appearing. Her body mass index (BMI) is 21 kg/m². Labs obtained prior to her visit show normal renal and liver function. Her high-density lipid (HDL) level is 55 mg/dL, her low-density lipid (LDL) level is 80 mg/dL, and her triglyceride level is 100 mg/dL; HbA_1c is 5.5 mmol/mol.
 

She is interested in learning more about menopausal hormone therapy (HT) and whether or not she would be a candidate.

What information do you need to know to counsel and manage this patient?

Menopausal HT prescribing practices have changed over the last few decades as a better understanding of the risks and benefits of treatment have emerged. Prior to 2002, HT was commonly used for treatment of symptoms associated with menopause and was thought to have beneficial effects for chronic disease prevention.^1-4 After data from the Women’s Health Initiative (WHI) was released, concerns arose around the effect of HT on cardiovascular health and risk of breast cancer. As a result, HT prescriptions fell precipitously after around 2002.⁵ Since then, postintervention analysis and cumulative 18-year follow-up of WHI data, along with results from subsequent randomized controlled trials, including the Kronos Early Estrogen Prevention Study (KEEPS) and the Early Versus Late Intervention Trial with Estradiol (ELITE), have demonstrated a favorable safety profile for healthy women starting HT early in menopause (less than age 60, or within 10 years from their final menstrual period).^5-11

There are many types, formulations, and routes of HT, and the effects and risks differ for each (TABLE). For example, oral estrogen therapy, such as conjugated equine estrogens, portend a higher risk of adverse effects compared with transdermal formulations. Topical and transdermal estrogens bypass first-pass hepatic metabolism and thus are associated with a lower risk of venous thromboembolism (VTE) compared with oral formulations.^12-14 A progestogen such as micronized progesterone is used in postmenopausal women with a uterus to protect the endometrium from unopposed estrogen therapy (ET). While it comes in oral and transdermal forms, the oral formulation is most widely used and studied in the United States; transdermal forms do not provide adequate endometrial protection and should not be used in combination therapy.^15,16

Risks and benefits

Cardiovascular risk

Over time, the benefits and risks of HT use in menopausal patients have been further elucidated and defined, although they remain complex and dependent on patient clinical characteristics. HT remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause.^17,18 In 2002, concerns for increased cardiovascular disease (CVD) and breast cancer risk resulted in early cessation of the WHI trial. Since that time the risk of CVD in postmenopausal women taking HT has been found to be more nuanced. In fact, updates in the literature have shown that HT results in a reduction of coronary heart disease if started in healthy women younger than age 60 years within 10 years of menopause.^7,9-11 With this updated information, the North American Menopause society (NAMS), American College of Obstetricians and Gynecologists and the Endocrine Society have published guidelines supporting the initiation of HT for symptomatic healthy women: under the age of 60, within 10 years of menopause, and without contraindications. After age 60 years and further from menopause, the benefits and risks become less known.^18-20

Risk stratification allows for more comprehensive counseling in use of HT for treatment of bothersome VMS. From a cardiovascular health standpoint, calculating an atherosclerotic CVD (ASCVD) risk score helps to evaluate appropriateness of HT prescribing:

• For those with low 10-year CVD risk (<5%), either oral or transdermal HT is appropriate.
• For those with moderate 10-year CVD risk (5%-10%), transdermal HT is recommended over oral HT.
• For those with high 10-year CVD risk (>10%), HT is not recommended.^19,21

Breast cancer risk

Follow up since the initial WHI publication have shown that breast cancer risk is largely dependent on the formulation and route of HT used. Oral estrogen combined with a progestogen has been shown to increase the risk of invasive breast cancer, though very rarely.²² To put it into context, the absolute risk of breast cancer based on follow-up studies from WHI showed less than 1 additional case per 1,000 person years of use; less risk than associated with drinking 2 glasses of wine per day and similar to that of obesity and/or sedentary lifestyle.^23,24 Studies have shown estrogen treatment alone for postmenopausal women does not appear to increase the risk of breast cancer. In fact, follow-up data from WHI showed a nonsignificant reduction in breast cancer risk for those taking ET alone.²⁵

Breast cancer risk stratification is helpful when determining appropriateness of HT in postmenopausal women. Generally, if using risk stratification models for breast cancer (ie, Gail Risk model or international breast cancer intervention study [IBIS] tool), a patient who is average to moderate risk, HT can be offered with appropriate counseling. By contrast, a patient who is high risk should have a more detailed discussion about their risk (surveillance and risk-reducing treatments), and they may consider nonhormonal options for treatment of VMS. Women with a history of breast cancer should not be prescribed systemic HT.

Continue to: Additional HT benefits...

Additional HT benefits

The benefits of HT in postmenopausal women include improved bone health and reduction of fractures; reduction of risk for type 2 diabetes mellitus (T2DM); improvement of insulin sensitivity; improvement of lipid profiles with increased HDL and decreased LDL levels; and reduction of colon cancer risk.²⁵ For women aged younger than 60 years who start HT within 10 years of their last menstrual period, HT has been shown to cause a reduction in all-cause mortality. Important risks to counsel patients on when starting HT include the low risk of stroke and venous thromboembolism (VTE) when using oral formulations.²⁶

CASE Resolved

Her ASCVD risk score, based on her history, estimates her 10-year CVD risk to be low (<5%). Thus, from a cardiovascular standpoint, either oral or transdermal HT would be an appropriate option. Her IBIS 10-year score is 1.5%, placing her in a low-risk category for breast cancer based on her personal and family history. Given that she is less than 60 years of age and within 10 years of menopause, along with her low-risk stratification for CVD and breast cancer, she would be an appropriate patient to begin combined HT with an estrogen plus an oral progesterone, such as an estradiol patch 0.0375 mg twice weekly, along with oral micronized progesterone 100 mg nightly. The dose could be increased over time based on symptoms and tolerability of the treatment.

ALTERNATE CASE 1 The patient has additional risk factors

Consider the patient case with the following additions to her history: the patient has a BMI of 34 kg/m², a history of well-controlled hypertension while taking amlodipine 5 mg, and an ASCVD risk score of 7.5%. She reports severe VMS that are greatly impacting her quality of life. How would your recommendations or counseling change?

Focus on healthy lifestyle

Obesity and hypertension, both common chronic conditions, pose additional risks to be accounted for when counseling on and approaching HT prescribing. Her alternate ASCVD risk score places her at moderate risk for CVD within 10 years, based on guidelines as discussed above. It would still be appropriate to offer her combined HT after a shared decision-making discussion that includes a focus on healthy lifestyle habits.

Consider transdermal HT in obese women

Longitudinal studies have found that weight gain is more a consequence of aging, regardless of menopausal status. Fat distribution and body composition changes are a menopause-related phenomenon driven by estrogen deficiency. HT has been shown to preserve lean body mass and reduce visceral adiposity, resulting in favorable effects of body composition. Still, obesity results in increased risk of CVD, VTE, and certain hormone-sensitive cancers.²⁷ When considering HT in obese patients, a transdermal estrogen route is preferred to reduce risks.

For women with hypertension, prescribe transdermal HT

Overall, studies have found that HT has a neutral effect on blood pressure.²⁵ When considering formulation of HT, micronized progesterone, dydrogesterone, and drospirenone seem to be most neutral and possibly even beneficial on blood pressure compared with synthetic progestins.²⁶ Oral estrogen is associated with increased vasoconstriction and/or increased sodium retention with resultant worsened regulation of blood pressure in women with hypertension, so transdermal estrogen is preferred for women with hypertension.²⁶ Hypertension is a component of the ASCVD risk score; factoring this into a patient’s clinical picture is important when discussing appropriateness of HT prescribing. To minimize risks, the transdermal route of estrogen is preferred for those with hypertension.

Continue to: ALTERNATE CASE 1 Resolved...

ALTERNATE CASE 1 Resolved

She has a moderate ASCVD risk score, is obese, and has a history of hypertension. Through shared decision making, you ultimately start her on transdermal estrogen and micronized progesterone to treat her quality-of-life-impacting VMS, a formulation that is most likely to mitigate the possible risks in her clinical case. You see her back in the clinic every 3-6 months to monitor her blood pressure.

ALTERNATE CASE 2 The patient has a high risk for breast cancer

The patient reveals further her significant family history of breast cancer in her maternal grandmother and mother, both diagnosed in their 50s. You calculate her risk of breast cancer with a model that incorporates family history. Her Tyrer Cuzick-IBIS 10-year risk score is >5% and lifetime risk is >20%, putting her at high risk for breast cancer. Since she has a uterus and would need concomitant progesterone therapy, her risk for breast cancer is higher than if she was taking ET alone. Ultimately, together you and the patient decide to trial nonhormonal options for her VMS.

What are nonhormonal options for treatment of VMS?

While HT remains the most effective treatment for VMS, there are multiple nonhormonal treatments for women who are either at too high a risk for HT or who favor other options, which are outlined in the NAMS 2015 nonhormonal management position statement.²⁷ Cognitive behavioral therapy (CBT) has been shown to decrease bother related to VMS but not frequency. Clinical hypnosis has been shown to reduce hot flash frequency and improve sleep. Paroxetine salt (7.5 mg/day) remains the only FDA nonhormonal-approved medication for treatment of moderate to severe vasomotor symptoms. Off label use of other selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors have been shown in studies to reduce VMS including paroxetine at slightly higher doses (10 mg/day–20 mg/day), citalopram (10 mg/day–20 mg/day), escitalopram (10 mg/day–20 mg/day), venlafaxine (37.5 mg/day–150 mg/day), and desvenlafaxine (50 mg/day–100 mg/day). Other treatments that could be considered include off-label use of gabapentin (900 mg/day–2,400 mg/day), oxybutynin (2.5–5 mg twice daily) or clonidine (0.1 mg/day–1 mg/day divided in doses) since they all have data demonstrating they are beneficial at reducing VMS.

Nonhormonal options that may be helpful but are recommended with caution due to lack of data include weight loss, mindfulness-based stress reduction, s-equol derivatives of soy isoflavones and a stellate ganglion block. Further evidence and studies are needed for the aforementioned options.²⁷

ALTERNATE CASE 2 Resolved

She may consider any of the nonhormonal options discussed. If she meets with a medical breast specialist to discuss her elevated risk of breast cancer and considers starting risk-reducing medications, particularly tamoxifen, you will want to avoid medications that have significant CPY 2D6 inhibition, such as paroxetine and fluoxetine. Safer choices would include venlafaxine, escitalopram, or citalopram.

The bottom line

In summary, the benefits and risks of HT in the treatment of VMS remain nuanced. For healthy women younger than 60 years of age and within 10 years from their last menstrual period, the benefits of HT largely outweigh the risks. Shared decision making, along with individualized and appropriate risk stratification specific for women, can guide appropriateness of HT prescribing. For those women who cannot take HT or choose not to, there are many nonhormonal options that will help manage their bothersome VMS. ●

CASE Healthy woman with hot flashes inquires about HT

A 54-year-old healthy woman with a history of hypothyroidism taking thyroid replacement medication comes in for her annual visit. Her last menstrual period was over 2 years ago and she reports severe hot flashes. They have greatly affected her quality of life and she must take frequent breaks at work. She wakes up frequently at night due to night sweats, which is impacting her sleep and, subsequently, her energy level. She has noted increased vaginal dryness so has been abstaining from sexual intercourse due to the discomfort. She has an intact uterus. Her family history is significant for heart disease, diagnosed in her mother at age 75.

On physical examination, she is normotensive and well-appearing. Her body mass index (BMI) is 21 kg/m². Labs obtained prior to her visit show normal renal and liver function. Her high-density lipid (HDL) level is 55 mg/dL, her low-density lipid (LDL) level is 80 mg/dL, and her triglyceride level is 100 mg/dL; HbA_1c is 5.5 mmol/mol.
 

She is interested in learning more about menopausal hormone therapy (HT) and whether or not she would be a candidate.

What information do you need to know to counsel and manage this patient?

Menopausal HT prescribing practices have changed over the last few decades as a better understanding of the risks and benefits of treatment have emerged. Prior to 2002, HT was commonly used for treatment of symptoms associated with menopause and was thought to have beneficial effects for chronic disease prevention.^1-4 After data from the Women’s Health Initiative (WHI) was released, concerns arose around the effect of HT on cardiovascular health and risk of breast cancer. As a result, HT prescriptions fell precipitously after around 2002.⁵ Since then, postintervention analysis and cumulative 18-year follow-up of WHI data, along with results from subsequent randomized controlled trials, including the Kronos Early Estrogen Prevention Study (KEEPS) and the Early Versus Late Intervention Trial with Estradiol (ELITE), have demonstrated a favorable safety profile for healthy women starting HT early in menopause (less than age 60, or within 10 years from their final menstrual period).^5-11

There are many types, formulations, and routes of HT, and the effects and risks differ for each (TABLE). For example, oral estrogen therapy, such as conjugated equine estrogens, portend a higher risk of adverse effects compared with transdermal formulations. Topical and transdermal estrogens bypass first-pass hepatic metabolism and thus are associated with a lower risk of venous thromboembolism (VTE) compared with oral formulations.^12-14 A progestogen such as micronized progesterone is used in postmenopausal women with a uterus to protect the endometrium from unopposed estrogen therapy (ET). While it comes in oral and transdermal forms, the oral formulation is most widely used and studied in the United States; transdermal forms do not provide adequate endometrial protection and should not be used in combination therapy.^15,16

Risks and benefits

Cardiovascular risk

Over time, the benefits and risks of HT use in menopausal patients have been further elucidated and defined, although they remain complex and dependent on patient clinical characteristics. HT remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause.^17,18 In 2002, concerns for increased cardiovascular disease (CVD) and breast cancer risk resulted in early cessation of the WHI trial. Since that time the risk of CVD in postmenopausal women taking HT has been found to be more nuanced. In fact, updates in the literature have shown that HT results in a reduction of coronary heart disease if started in healthy women younger than age 60 years within 10 years of menopause.^7,9-11 With this updated information, the North American Menopause society (NAMS), American College of Obstetricians and Gynecologists and the Endocrine Society have published guidelines supporting the initiation of HT for symptomatic healthy women: under the age of 60, within 10 years of menopause, and without contraindications. After age 60 years and further from menopause, the benefits and risks become less known.^18-20

Risk stratification allows for more comprehensive counseling in use of HT for treatment of bothersome VMS. From a cardiovascular health standpoint, calculating an atherosclerotic CVD (ASCVD) risk score helps to evaluate appropriateness of HT prescribing:

• For those with low 10-year CVD risk (<5%), either oral or transdermal HT is appropriate.
• For those with moderate 10-year CVD risk (5%-10%), transdermal HT is recommended over oral HT.
• For those with high 10-year CVD risk (>10%), HT is not recommended.^19,21

Breast cancer risk

Follow up since the initial WHI publication have shown that breast cancer risk is largely dependent on the formulation and route of HT used. Oral estrogen combined with a progestogen has been shown to increase the risk of invasive breast cancer, though very rarely.²² To put it into context, the absolute risk of breast cancer based on follow-up studies from WHI showed less than 1 additional case per 1,000 person years of use; less risk than associated with drinking 2 glasses of wine per day and similar to that of obesity and/or sedentary lifestyle.^23,24 Studies have shown estrogen treatment alone for postmenopausal women does not appear to increase the risk of breast cancer. In fact, follow-up data from WHI showed a nonsignificant reduction in breast cancer risk for those taking ET alone.²⁵

Breast cancer risk stratification is helpful when determining appropriateness of HT in postmenopausal women. Generally, if using risk stratification models for breast cancer (ie, Gail Risk model or international breast cancer intervention study [IBIS] tool), a patient who is average to moderate risk, HT can be offered with appropriate counseling. By contrast, a patient who is high risk should have a more detailed discussion about their risk (surveillance and risk-reducing treatments), and they may consider nonhormonal options for treatment of VMS. Women with a history of breast cancer should not be prescribed systemic HT.

Continue to: Additional HT benefits...

Additional HT benefits

The benefits of HT in postmenopausal women include improved bone health and reduction of fractures; reduction of risk for type 2 diabetes mellitus (T2DM); improvement of insulin sensitivity; improvement of lipid profiles with increased HDL and decreased LDL levels; and reduction of colon cancer risk.²⁵ For women aged younger than 60 years who start HT within 10 years of their last menstrual period, HT has been shown to cause a reduction in all-cause mortality. Important risks to counsel patients on when starting HT include the low risk of stroke and venous thromboembolism (VTE) when using oral formulations.²⁶

CASE Resolved

Her ASCVD risk score, based on her history, estimates her 10-year CVD risk to be low (<5%). Thus, from a cardiovascular standpoint, either oral or transdermal HT would be an appropriate option. Her IBIS 10-year score is 1.5%, placing her in a low-risk category for breast cancer based on her personal and family history. Given that she is less than 60 years of age and within 10 years of menopause, along with her low-risk stratification for CVD and breast cancer, she would be an appropriate patient to begin combined HT with an estrogen plus an oral progesterone, such as an estradiol patch 0.0375 mg twice weekly, along with oral micronized progesterone 100 mg nightly. The dose could be increased over time based on symptoms and tolerability of the treatment.

ALTERNATE CASE 1 The patient has additional risk factors

Consider the patient case with the following additions to her history: the patient has a BMI of 34 kg/m², a history of well-controlled hypertension while taking amlodipine 5 mg, and an ASCVD risk score of 7.5%. She reports severe VMS that are greatly impacting her quality of life. How would your recommendations or counseling change?

Focus on healthy lifestyle

Obesity and hypertension, both common chronic conditions, pose additional risks to be accounted for when counseling on and approaching HT prescribing. Her alternate ASCVD risk score places her at moderate risk for CVD within 10 years, based on guidelines as discussed above. It would still be appropriate to offer her combined HT after a shared decision-making discussion that includes a focus on healthy lifestyle habits.

Consider transdermal HT in obese women

Longitudinal studies have found that weight gain is more a consequence of aging, regardless of menopausal status. Fat distribution and body composition changes are a menopause-related phenomenon driven by estrogen deficiency. HT has been shown to preserve lean body mass and reduce visceral adiposity, resulting in favorable effects of body composition. Still, obesity results in increased risk of CVD, VTE, and certain hormone-sensitive cancers.²⁷ When considering HT in obese patients, a transdermal estrogen route is preferred to reduce risks.

For women with hypertension, prescribe transdermal HT

Overall, studies have found that HT has a neutral effect on blood pressure.²⁵ When considering formulation of HT, micronized progesterone, dydrogesterone, and drospirenone seem to be most neutral and possibly even beneficial on blood pressure compared with synthetic progestins.²⁶ Oral estrogen is associated with increased vasoconstriction and/or increased sodium retention with resultant worsened regulation of blood pressure in women with hypertension, so transdermal estrogen is preferred for women with hypertension.²⁶ Hypertension is a component of the ASCVD risk score; factoring this into a patient’s clinical picture is important when discussing appropriateness of HT prescribing. To minimize risks, the transdermal route of estrogen is preferred for those with hypertension.

Continue to: ALTERNATE CASE 1 Resolved...

ALTERNATE CASE 1 Resolved

She has a moderate ASCVD risk score, is obese, and has a history of hypertension. Through shared decision making, you ultimately start her on transdermal estrogen and micronized progesterone to treat her quality-of-life-impacting VMS, a formulation that is most likely to mitigate the possible risks in her clinical case. You see her back in the clinic every 3-6 months to monitor her blood pressure.

ALTERNATE CASE 2 The patient has a high risk for breast cancer

The patient reveals further her significant family history of breast cancer in her maternal grandmother and mother, both diagnosed in their 50s. You calculate her risk of breast cancer with a model that incorporates family history. Her Tyrer Cuzick-IBIS 10-year risk score is >5% and lifetime risk is >20%, putting her at high risk for breast cancer. Since she has a uterus and would need concomitant progesterone therapy, her risk for breast cancer is higher than if she was taking ET alone. Ultimately, together you and the patient decide to trial nonhormonal options for her VMS.

What are nonhormonal options for treatment of VMS?

While HT remains the most effective treatment for VMS, there are multiple nonhormonal treatments for women who are either at too high a risk for HT or who favor other options, which are outlined in the NAMS 2015 nonhormonal management position statement.²⁷ Cognitive behavioral therapy (CBT) has been shown to decrease bother related to VMS but not frequency. Clinical hypnosis has been shown to reduce hot flash frequency and improve sleep. Paroxetine salt (7.5 mg/day) remains the only FDA nonhormonal-approved medication for treatment of moderate to severe vasomotor symptoms. Off label use of other selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors have been shown in studies to reduce VMS including paroxetine at slightly higher doses (10 mg/day–20 mg/day), citalopram (10 mg/day–20 mg/day), escitalopram (10 mg/day–20 mg/day), venlafaxine (37.5 mg/day–150 mg/day), and desvenlafaxine (50 mg/day–100 mg/day). Other treatments that could be considered include off-label use of gabapentin (900 mg/day–2,400 mg/day), oxybutynin (2.5–5 mg twice daily) or clonidine (0.1 mg/day–1 mg/day divided in doses) since they all have data demonstrating they are beneficial at reducing VMS.

Nonhormonal options that may be helpful but are recommended with caution due to lack of data include weight loss, mindfulness-based stress reduction, s-equol derivatives of soy isoflavones and a stellate ganglion block. Further evidence and studies are needed for the aforementioned options.²⁷

ALTERNATE CASE 2 Resolved

She may consider any of the nonhormonal options discussed. If she meets with a medical breast specialist to discuss her elevated risk of breast cancer and considers starting risk-reducing medications, particularly tamoxifen, you will want to avoid medications that have significant CPY 2D6 inhibition, such as paroxetine and fluoxetine. Safer choices would include venlafaxine, escitalopram, or citalopram.

The bottom line

In summary, the benefits and risks of HT in the treatment of VMS remain nuanced. For healthy women younger than 60 years of age and within 10 years from their last menstrual period, the benefits of HT largely outweigh the risks. Shared decision making, along with individualized and appropriate risk stratification specific for women, can guide appropriateness of HT prescribing. For those women who cannot take HT or choose not to, there are many nonhormonal options that will help manage their bothersome VMS. ●

CASE Healthy woman with hot flashes inquires about HT

A 54-year-old healthy woman with a history of hypothyroidism taking thyroid replacement medication comes in for her annual visit. Her last menstrual period was over 2 years ago and she reports severe hot flashes. They have greatly affected her quality of life and she must take frequent breaks at work. She wakes up frequently at night due to night sweats, which is impacting her sleep and, subsequently, her energy level. She has noted increased vaginal dryness so has been abstaining from sexual intercourse due to the discomfort. She has an intact uterus. Her family history is significant for heart disease, diagnosed in her mother at age 75.

On physical examination, she is normotensive and well-appearing. Her body mass index (BMI) is 21 kg/m². Labs obtained prior to her visit show normal renal and liver function. Her high-density lipid (HDL) level is 55 mg/dL, her low-density lipid (LDL) level is 80 mg/dL, and her triglyceride level is 100 mg/dL; HbA_1c is 5.5 mmol/mol.
 

She is interested in learning more about menopausal hormone therapy (HT) and whether or not she would be a candidate.

What information do you need to know to counsel and manage this patient?

Menopausal HT prescribing practices have changed over the last few decades as a better understanding of the risks and benefits of treatment have emerged. Prior to 2002, HT was commonly used for treatment of symptoms associated with menopause and was thought to have beneficial effects for chronic disease prevention.^1-4 After data from the Women’s Health Initiative (WHI) was released, concerns arose around the effect of HT on cardiovascular health and risk of breast cancer. As a result, HT prescriptions fell precipitously after around 2002.⁵ Since then, postintervention analysis and cumulative 18-year follow-up of WHI data, along with results from subsequent randomized controlled trials, including the Kronos Early Estrogen Prevention Study (KEEPS) and the Early Versus Late Intervention Trial with Estradiol (ELITE), have demonstrated a favorable safety profile for healthy women starting HT early in menopause (less than age 60, or within 10 years from their final menstrual period).^5-11

There are many types, formulations, and routes of HT, and the effects and risks differ for each (TABLE). For example, oral estrogen therapy, such as conjugated equine estrogens, portend a higher risk of adverse effects compared with transdermal formulations. Topical and transdermal estrogens bypass first-pass hepatic metabolism and thus are associated with a lower risk of venous thromboembolism (VTE) compared with oral formulations.^12-14 A progestogen such as micronized progesterone is used in postmenopausal women with a uterus to protect the endometrium from unopposed estrogen therapy (ET). While it comes in oral and transdermal forms, the oral formulation is most widely used and studied in the United States; transdermal forms do not provide adequate endometrial protection and should not be used in combination therapy.^15,16

Risks and benefits

Cardiovascular risk

Over time, the benefits and risks of HT use in menopausal patients have been further elucidated and defined, although they remain complex and dependent on patient clinical characteristics. HT remains the most effective treatment for vasomotor symptoms (VMS) and the genitourinary syndrome of menopause.^17,18 In 2002, concerns for increased cardiovascular disease (CVD) and breast cancer risk resulted in early cessation of the WHI trial. Since that time the risk of CVD in postmenopausal women taking HT has been found to be more nuanced. In fact, updates in the literature have shown that HT results in a reduction of coronary heart disease if started in healthy women younger than age 60 years within 10 years of menopause.^7,9-11 With this updated information, the North American Menopause society (NAMS), American College of Obstetricians and Gynecologists and the Endocrine Society have published guidelines supporting the initiation of HT for symptomatic healthy women: under the age of 60, within 10 years of menopause, and without contraindications. After age 60 years and further from menopause, the benefits and risks become less known.^18-20

Risk stratification allows for more comprehensive counseling in use of HT for treatment of bothersome VMS. From a cardiovascular health standpoint, calculating an atherosclerotic CVD (ASCVD) risk score helps to evaluate appropriateness of HT prescribing:

• For those with low 10-year CVD risk (<5%), either oral or transdermal HT is appropriate.
• For those with moderate 10-year CVD risk (5%-10%), transdermal HT is recommended over oral HT.
• For those with high 10-year CVD risk (>10%), HT is not recommended.^19,21

Breast cancer risk

Follow up since the initial WHI publication have shown that breast cancer risk is largely dependent on the formulation and route of HT used. Oral estrogen combined with a progestogen has been shown to increase the risk of invasive breast cancer, though very rarely.²² To put it into context, the absolute risk of breast cancer based on follow-up studies from WHI showed less than 1 additional case per 1,000 person years of use; less risk than associated with drinking 2 glasses of wine per day and similar to that of obesity and/or sedentary lifestyle.^23,24 Studies have shown estrogen treatment alone for postmenopausal women does not appear to increase the risk of breast cancer. In fact, follow-up data from WHI showed a nonsignificant reduction in breast cancer risk for those taking ET alone.²⁵

Breast cancer risk stratification is helpful when determining appropriateness of HT in postmenopausal women. Generally, if using risk stratification models for breast cancer (ie, Gail Risk model or international breast cancer intervention study [IBIS] tool), a patient who is average to moderate risk, HT can be offered with appropriate counseling. By contrast, a patient who is high risk should have a more detailed discussion about their risk (surveillance and risk-reducing treatments), and they may consider nonhormonal options for treatment of VMS. Women with a history of breast cancer should not be prescribed systemic HT.

Continue to: Additional HT benefits...

Additional HT benefits

The benefits of HT in postmenopausal women include improved bone health and reduction of fractures; reduction of risk for type 2 diabetes mellitus (T2DM); improvement of insulin sensitivity; improvement of lipid profiles with increased HDL and decreased LDL levels; and reduction of colon cancer risk.²⁵ For women aged younger than 60 years who start HT within 10 years of their last menstrual period, HT has been shown to cause a reduction in all-cause mortality. Important risks to counsel patients on when starting HT include the low risk of stroke and venous thromboembolism (VTE) when using oral formulations.²⁶

CASE Resolved

Her ASCVD risk score, based on her history, estimates her 10-year CVD risk to be low (<5%). Thus, from a cardiovascular standpoint, either oral or transdermal HT would be an appropriate option. Her IBIS 10-year score is 1.5%, placing her in a low-risk category for breast cancer based on her personal and family history. Given that she is less than 60 years of age and within 10 years of menopause, along with her low-risk stratification for CVD and breast cancer, she would be an appropriate patient to begin combined HT with an estrogen plus an oral progesterone, such as an estradiol patch 0.0375 mg twice weekly, along with oral micronized progesterone 100 mg nightly. The dose could be increased over time based on symptoms and tolerability of the treatment.

ALTERNATE CASE 1 The patient has additional risk factors

Consider the patient case with the following additions to her history: the patient has a BMI of 34 kg/m², a history of well-controlled hypertension while taking amlodipine 5 mg, and an ASCVD risk score of 7.5%. She reports severe VMS that are greatly impacting her quality of life. How would your recommendations or counseling change?

Focus on healthy lifestyle

Obesity and hypertension, both common chronic conditions, pose additional risks to be accounted for when counseling on and approaching HT prescribing. Her alternate ASCVD risk score places her at moderate risk for CVD within 10 years, based on guidelines as discussed above. It would still be appropriate to offer her combined HT after a shared decision-making discussion that includes a focus on healthy lifestyle habits.

Consider transdermal HT in obese women

Longitudinal studies have found that weight gain is more a consequence of aging, regardless of menopausal status. Fat distribution and body composition changes are a menopause-related phenomenon driven by estrogen deficiency. HT has been shown to preserve lean body mass and reduce visceral adiposity, resulting in favorable effects of body composition. Still, obesity results in increased risk of CVD, VTE, and certain hormone-sensitive cancers.²⁷ When considering HT in obese patients, a transdermal estrogen route is preferred to reduce risks.

For women with hypertension, prescribe transdermal HT

Overall, studies have found that HT has a neutral effect on blood pressure.²⁵ When considering formulation of HT, micronized progesterone, dydrogesterone, and drospirenone seem to be most neutral and possibly even beneficial on blood pressure compared with synthetic progestins.²⁶ Oral estrogen is associated with increased vasoconstriction and/or increased sodium retention with resultant worsened regulation of blood pressure in women with hypertension, so transdermal estrogen is preferred for women with hypertension.²⁶ Hypertension is a component of the ASCVD risk score; factoring this into a patient’s clinical picture is important when discussing appropriateness of HT prescribing. To minimize risks, the transdermal route of estrogen is preferred for those with hypertension.

Continue to: ALTERNATE CASE 1 Resolved...

ALTERNATE CASE 1 Resolved

She has a moderate ASCVD risk score, is obese, and has a history of hypertension. Through shared decision making, you ultimately start her on transdermal estrogen and micronized progesterone to treat her quality-of-life-impacting VMS, a formulation that is most likely to mitigate the possible risks in her clinical case. You see her back in the clinic every 3-6 months to monitor her blood pressure.

ALTERNATE CASE 2 The patient has a high risk for breast cancer

The patient reveals further her significant family history of breast cancer in her maternal grandmother and mother, both diagnosed in their 50s. You calculate her risk of breast cancer with a model that incorporates family history. Her Tyrer Cuzick-IBIS 10-year risk score is >5% and lifetime risk is >20%, putting her at high risk for breast cancer. Since she has a uterus and would need concomitant progesterone therapy, her risk for breast cancer is higher than if she was taking ET alone. Ultimately, together you and the patient decide to trial nonhormonal options for her VMS.

What are nonhormonal options for treatment of VMS?

While HT remains the most effective treatment for VMS, there are multiple nonhormonal treatments for women who are either at too high a risk for HT or who favor other options, which are outlined in the NAMS 2015 nonhormonal management position statement.²⁷ Cognitive behavioral therapy (CBT) has been shown to decrease bother related to VMS but not frequency. Clinical hypnosis has been shown to reduce hot flash frequency and improve sleep. Paroxetine salt (7.5 mg/day) remains the only FDA nonhormonal-approved medication for treatment of moderate to severe vasomotor symptoms. Off label use of other selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors have been shown in studies to reduce VMS including paroxetine at slightly higher doses (10 mg/day–20 mg/day), citalopram (10 mg/day–20 mg/day), escitalopram (10 mg/day–20 mg/day), venlafaxine (37.5 mg/day–150 mg/day), and desvenlafaxine (50 mg/day–100 mg/day). Other treatments that could be considered include off-label use of gabapentin (900 mg/day–2,400 mg/day), oxybutynin (2.5–5 mg twice daily) or clonidine (0.1 mg/day–1 mg/day divided in doses) since they all have data demonstrating they are beneficial at reducing VMS.

Nonhormonal options that may be helpful but are recommended with caution due to lack of data include weight loss, mindfulness-based stress reduction, s-equol derivatives of soy isoflavones and a stellate ganglion block. Further evidence and studies are needed for the aforementioned options.²⁷

ALTERNATE CASE 2 Resolved

She may consider any of the nonhormonal options discussed. If she meets with a medical breast specialist to discuss her elevated risk of breast cancer and considers starting risk-reducing medications, particularly tamoxifen, you will want to avoid medications that have significant CPY 2D6 inhibition, such as paroxetine and fluoxetine. Safer choices would include venlafaxine, escitalopram, or citalopram.

The bottom line

In summary, the benefits and risks of HT in the treatment of VMS remain nuanced. For healthy women younger than 60 years of age and within 10 years from their last menstrual period, the benefits of HT largely outweigh the risks. Shared decision making, along with individualized and appropriate risk stratification specific for women, can guide appropriateness of HT prescribing. For those women who cannot take HT or choose not to, there are many nonhormonal options that will help manage their bothersome VMS. ●

Von Willebrand disease (VWD) represents the most common inherited bleeding disorder, with a prevalence of approximately 1 in 1,000 people. Type 1 disease, associated with a quantitative reduction in von Willebrand factor (VWF), is the most common type of VWD and accounts for approximately 70% of VWD patients enrolled in hemophilia treatment centers; transmission is autosomal dominant. Type 2 disease, associated with a qualitative defect in VWF, accounts for most of the remaining 30% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal dominant. Type 3 disease, associated with a near absence of VWF, accounts for less than 1% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal recessive.

Bruising and mucocutaneous bleeding (epistaxis, gingival bleeding, and bleeding after dental extraction) are the most common presenting symptoms of VWD. Because VWD substantially increases the risk of heavy menstrual bleeding (HMB) and, to some extent, intrapartum bleeding complications, and postpartum hemorrhage, women experience a disproportionate burden from VWD. Thus, ObGyns are likely to be called on to make treatment recommendations in VWD patients with these concerns.¹

In 2017, the American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia determined that among clinical issues related to VWD, updating guidelines for women with VWD represented the highest priority.² Accordingly, an international group of hematologists/coagulation specialists performed systematic literature reviews to address 3 questions faced by women with VWD and their clinicians:

• What are the most effective treatments for HMB?
• What is the safest approach for women desiring neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of tranexamic acid (TxA) on postpartum hemorrhage (PPH)?³

Evidence on management strategies for HMB in women with VWD

The prevalence of HMB in women with VWD ranges from 50% to 92%. Reports suggest that between 5% and 24% of women presenting with this symptom have VWD.³ However, the prevalence of VWD among women seeking care for HMB relates to referral patterns, with the prevalence of VWD substantially higher in patient populations who are referred to clinicians or centers that focus on care of patients with bleeding disorders.

The systematic review authors³ identified 2 comparative studies that assessed the treatment of HMB in women with VWD. One was a crossover trial that enrolled 116 VWD patients with HMB with a mean age of 36 years.⁴ All participants in this trial chose not to use combination oral contraceptives (COCs) as they had not experienced good results with prior COC use. Trial participants were randomly assigned to receive either intranasal desmopressin (DDAVP; a synthetic analog of the antidiuretic agent vasopressin, which stimulates the release of VWF from endothelial cells) or oral TxA therapy for 2 menstrual cycles. Participants then crossed over to the other drug for 2 additional cycles. Although both agents significantly reduced estimated menstrual blood loss, TxA was more effective in decreasing bleeding than intranasal DDAVP.⁴

In a retrospective cohort study, investigators compared COC use with intranasal DDAVP in 36 adolescents who had VWD and HMB.⁵ Participant follow-up ranged from 6 months to 4 years. The estimated efficacy of COCs and intranasal DDAVP was 86% and 77%, respectively, a difference that did not achieve statistical significance. Some of the adolescents who used intranasal DDAVP reported severe headaches and flushing.⁵

In addition, the systematic review authors³ identified 5 case series that described the use of the levonorgestrel (52 mg)-releasing intrauterine device (LNG 52 IUD) in women with VWD and HMB; 4 of these addressed the efficacy of progestin-releasing IUDs in reducing HMB in this patient population.^6-9 Using different approaches to define HMB, the authors of these reports followed between 7 and 26 patients with bleeding disorders (most with confirmed VWD) and HMB for variable amounts of time after placement of an LNG 52 IUD. Many of the women described in these case series had tried other HMB treatments, including COCs, without success. Although these 4 reports assessed different outcomes, all reported that placement of the LNG 52 IUD substantially reduced menstrual blood loss, often resulting in amenorrhea. Several of these reports also noted important improvements in quality of life following LNG 52 IUD placement. One case series reported LNG 52 IUD placement in 13 adolescents with VWD and HMB. The mean time to achieve amenorrhea or occasional spotting was 94 days.⁶

The fifth report, which followed 20 women (median age, 31 years) with HMB associated with VWD or other bleeding disorders who underwent LNG 52 IUD placement, aimed to describe IUD expulsions and malpositioned IUDs in this population. In this small group of patients, 3 IUD expulsions and 2 malpositioned IUDs were observed. Furthermore, an additional 5 women had their device removed prematurely due to patient dissatisfaction. Accordingly, the IUD continuation rate in this case series was only 50%.¹⁰

Evidence on management of pregnancy, delivery, and the postpartum period

Heavy menstrual bleeding is not the only challenge for women with VWD. While pregnancy is accompanied by higher levels of VWF, potentially offsetting the risk of bleeding at the time of delivery, the levels do not achieve the same magnitude as they would in unaffected women.¹¹ Women are at an increased risk of primary PPH^12,13 and, importantly, since VWF levels fall exponentially after delivery when women are still experiencing lochia,¹¹ they are at increased risk of secondary or delayed PPH.

Two questions arise frequently in the care of women with VWD at the time of delivery and during the postpartum period:

• What is the safest approach for women who desire neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of TxA on PPH?

The second systematic review the authors performed³ focused on VWF levels in women receiving neuraxial anesthesia during labor. After screening 27 studies, the authors included 5 case series, which did not describe outcomes based on VWF levels but rather described the outcomes of women with VWF levels of greater than 0.50 IU/mL (> 50% of normal compared with a normal standard).

Meta-analysis showed that the proportion of anesthesia complications was 6%, which sounds high, but the range of complications was what would be expected in any population (hypotension, accidental dural puncture, inadequate anesthesia, and bloody tap with no further complications). No spinal, subdural, or epidural hematomas were noted.³ Such hematomas are an extremely rare complication of neuraxial anesthesia, occurring in only 1 in 200,000 or 1 in 250,000 obstetric patients^14,15; accordingly, an increase in the rate of hematomas among women with VWD could go undetected. The absence of hematomas among women with VWD as reported in the systematic review does not mean there is not an increase in the rate of hematomas in women with VWD. The relative risk is unknown and caution would be advised.

The third systematic review that the authors performed³ was on TxA treatment in the postpartum period. After screening 41 studies, the authors included 2 retrospective cohort studies.^16,17 The majority of the participants had VWD. With very-low-certainty evidence, the authors found that TxA reduces the risk of:

• severe primary PPH (risk ratio [RR], 0.36; 95% confidence interval [CI], 0.05–2.59)
• primary PPH (RR, 0.25; 95% CI, 0.04–1.75)
• secondary PPH (RR, 0.42; 95% CI, 0.02–0.91—does not cross 1.0).

Note that the 95% confidence intervals for severe as well as primary PPH crossed 1.0 and therefore these reductions in risk did not achieve statistical significance. Additionally, there was very-low-certainty evidence on the effect of TxA on blood transfusions, vaginal hematomas, blood loss, and thrombotic complications.³

Continue to: Our recommendations for HMB management...

 

 

Our recommendations for HMB management

When first evaluating any woman with HMB, it is important to check a blood count and ferritin level, if not already done. If there is any suggestion of iron deficiency (with or without anemia), we recommend oral iron supplementation. This is best accomplished with slow-release iron supplement formulations (or less expensive generic or house brands that contain less than 65 mg of elemental iron per tablet) taken every other day. Such preparations may cause fewer gastrointestinal adverse effects than other oral iron formulations.¹⁸ Although it may appear counterintuitive, oral iron is better absorbed (and also may cause fewer gastrointestinal adverse effects) when taken every other day.¹⁹

Initial management of HMB, whether or not a bleeding disorder is present, often consists or oral hormonal management. If no contraindications are present, we recommend initiation of a COC with a short hormone-free interval (for example, a 24/4 formulation). If contraindications to contraceptive doses of estrogen are present, continuous use of norethindrone acetate 5-mg tablets or off-label use of combination tablets with 5 µg of ethinyl estradiol and 1 mg of norethindrone acetate (a formulation approved for the treatment of menopausal symptoms) is appropriate.²⁰

Once a patient is established on oral hormonal management, placement of a levonorgestrel-releasing IUD should be considered. Given that expulsion rates may be higher in women with HMB, if feasible, consider using abdominal ultrasound guidance for IUD placement.

For women with VWD who fail first-line therapy (hormonal management) or are trying to become pregnant, TxA (two 650-mg tablets 3 times daily for up to 5 days during episodes of heavy flow) can reduce HMB.^20,21

Our recommendations for management of pregnancy and delivery

The second and third systematic reviews discussed above provide very limited guidance on comprehensive management. The care of the pregnant patient with VWD starts with assessment of VWF levels and making an accurate diagnosis. This usually requires the input of a hematologist or other expert in hemostasis. If no recent VWF levels are available, the ObGyn can obtain a von Willebrand panel that includes VWF antigen, VWF activity (most commonly ristocetin cofactor), and factor VIII.

Levels should be reassessed around 36 weeks’ gestation in anticipation of delivery. VWF levels increase during pregnancy; accordingly, in mild, type 1 VWD, half the time treatment is not necessary.¹¹ If VWF activity is less than 50 IU/dL (less than 50% of normal) at 36 weeks’ gestation, the patient should receive VWF concentrate (dosed in VWF units). This requires consultation with hematology and specialized pharmacy support.

For these reasons, the patient with a VWF level less than 50% should be delivered in a referral center with the necessary resources. Anesthesia should be aware of the patient. Unless they have sustained VWF and factor VIII levels greater than 50 IU/dL, neuraxial anesthesia should not be offered to pregnant women with VWD.

Due to the quantity of fluids administered during labor or at the time of delivery and the coexistent administration of oxytocin, desmopressin (synthetic vasopressin) should not be used without monitoring sodium levels, should not be dosed more than once, or should be avoided altogether due to the risk of water intoxication.

If the patient has sustained VWF and factor VIII levels greater than 50 IU/dL, she would be a candidate to deliver in her local hospital and receive neuraxial anesthesia.

Based on the best data we have for women with VWD, a patient with a VWF greater than 50 IU/dL is no more likely to experience PPH than other women.¹¹ Intravenous TxA can be used for prevention or treatment of immediate postpartum bleeding per protocol (1 g after cord clamp and 1 g 30 minutes or more later).²² Oral TxA can be used for prevention or treatment of delayed postpartum bleeding as per HMB. Regardless of the outcome of any testing during pregnancy, nonsteroidal anti-inflammatory drugs should be avoided postpartum and the patient should be monitored closely for bleeding.

Neonatal care

As for the fetus/neonate, the parents should be aware that the infant has a 50% chance of inheriting VWD. If the baby’s father has no history of bleeding, it is unlikely that the infant would be any more affected than the patient herself. Nonetheless, cord blood (in one or more light blue top tubes) should be obtained at the time of delivery and sent for a von Willebrand panel. If the infant is male, a circumcision should be postponed until VWD is ruled out. In addition, fetal invasive procedures should be avoided during labor. Fetal scalp electrode placement should be avoided. Operative vaginal delivery also should be avoided. Cesarean delivery would be preferred to operative vaginal delivery, but if operative vaginal delivery is unavoidable, use of forceps is preferred to vacuum extraction. ●

Von Willebrand disease (VWD) represents the most common inherited bleeding disorder, with a prevalence of approximately 1 in 1,000 people. Type 1 disease, associated with a quantitative reduction in von Willebrand factor (VWF), is the most common type of VWD and accounts for approximately 70% of VWD patients enrolled in hemophilia treatment centers; transmission is autosomal dominant. Type 2 disease, associated with a qualitative defect in VWF, accounts for most of the remaining 30% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal dominant. Type 3 disease, associated with a near absence of VWF, accounts for less than 1% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal recessive.

Bruising and mucocutaneous bleeding (epistaxis, gingival bleeding, and bleeding after dental extraction) are the most common presenting symptoms of VWD. Because VWD substantially increases the risk of heavy menstrual bleeding (HMB) and, to some extent, intrapartum bleeding complications, and postpartum hemorrhage, women experience a disproportionate burden from VWD. Thus, ObGyns are likely to be called on to make treatment recommendations in VWD patients with these concerns.¹

In 2017, the American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia determined that among clinical issues related to VWD, updating guidelines for women with VWD represented the highest priority.² Accordingly, an international group of hematologists/coagulation specialists performed systematic literature reviews to address 3 questions faced by women with VWD and their clinicians:

• What are the most effective treatments for HMB?
• What is the safest approach for women desiring neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of tranexamic acid (TxA) on postpartum hemorrhage (PPH)?³

Evidence on management strategies for HMB in women with VWD

The prevalence of HMB in women with VWD ranges from 50% to 92%. Reports suggest that between 5% and 24% of women presenting with this symptom have VWD.³ However, the prevalence of VWD among women seeking care for HMB relates to referral patterns, with the prevalence of VWD substantially higher in patient populations who are referred to clinicians or centers that focus on care of patients with bleeding disorders.

The systematic review authors³ identified 2 comparative studies that assessed the treatment of HMB in women with VWD. One was a crossover trial that enrolled 116 VWD patients with HMB with a mean age of 36 years.⁴ All participants in this trial chose not to use combination oral contraceptives (COCs) as they had not experienced good results with prior COC use. Trial participants were randomly assigned to receive either intranasal desmopressin (DDAVP; a synthetic analog of the antidiuretic agent vasopressin, which stimulates the release of VWF from endothelial cells) or oral TxA therapy for 2 menstrual cycles. Participants then crossed over to the other drug for 2 additional cycles. Although both agents significantly reduced estimated menstrual blood loss, TxA was more effective in decreasing bleeding than intranasal DDAVP.⁴

In a retrospective cohort study, investigators compared COC use with intranasal DDAVP in 36 adolescents who had VWD and HMB.⁵ Participant follow-up ranged from 6 months to 4 years. The estimated efficacy of COCs and intranasal DDAVP was 86% and 77%, respectively, a difference that did not achieve statistical significance. Some of the adolescents who used intranasal DDAVP reported severe headaches and flushing.⁵

In addition, the systematic review authors³ identified 5 case series that described the use of the levonorgestrel (52 mg)-releasing intrauterine device (LNG 52 IUD) in women with VWD and HMB; 4 of these addressed the efficacy of progestin-releasing IUDs in reducing HMB in this patient population.^6-9 Using different approaches to define HMB, the authors of these reports followed between 7 and 26 patients with bleeding disorders (most with confirmed VWD) and HMB for variable amounts of time after placement of an LNG 52 IUD. Many of the women described in these case series had tried other HMB treatments, including COCs, without success. Although these 4 reports assessed different outcomes, all reported that placement of the LNG 52 IUD substantially reduced menstrual blood loss, often resulting in amenorrhea. Several of these reports also noted important improvements in quality of life following LNG 52 IUD placement. One case series reported LNG 52 IUD placement in 13 adolescents with VWD and HMB. The mean time to achieve amenorrhea or occasional spotting was 94 days.⁶

The fifth report, which followed 20 women (median age, 31 years) with HMB associated with VWD or other bleeding disorders who underwent LNG 52 IUD placement, aimed to describe IUD expulsions and malpositioned IUDs in this population. In this small group of patients, 3 IUD expulsions and 2 malpositioned IUDs were observed. Furthermore, an additional 5 women had their device removed prematurely due to patient dissatisfaction. Accordingly, the IUD continuation rate in this case series was only 50%.¹⁰

Evidence on management of pregnancy, delivery, and the postpartum period

Heavy menstrual bleeding is not the only challenge for women with VWD. While pregnancy is accompanied by higher levels of VWF, potentially offsetting the risk of bleeding at the time of delivery, the levels do not achieve the same magnitude as they would in unaffected women.¹¹ Women are at an increased risk of primary PPH^12,13 and, importantly, since VWF levels fall exponentially after delivery when women are still experiencing lochia,¹¹ they are at increased risk of secondary or delayed PPH.

Two questions arise frequently in the care of women with VWD at the time of delivery and during the postpartum period:

• What is the safest approach for women who desire neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of TxA on PPH?

The second systematic review the authors performed³ focused on VWF levels in women receiving neuraxial anesthesia during labor. After screening 27 studies, the authors included 5 case series, which did not describe outcomes based on VWF levels but rather described the outcomes of women with VWF levels of greater than 0.50 IU/mL (> 50% of normal compared with a normal standard).

Meta-analysis showed that the proportion of anesthesia complications was 6%, which sounds high, but the range of complications was what would be expected in any population (hypotension, accidental dural puncture, inadequate anesthesia, and bloody tap with no further complications). No spinal, subdural, or epidural hematomas were noted.³ Such hematomas are an extremely rare complication of neuraxial anesthesia, occurring in only 1 in 200,000 or 1 in 250,000 obstetric patients^14,15; accordingly, an increase in the rate of hematomas among women with VWD could go undetected. The absence of hematomas among women with VWD as reported in the systematic review does not mean there is not an increase in the rate of hematomas in women with VWD. The relative risk is unknown and caution would be advised.

The third systematic review that the authors performed³ was on TxA treatment in the postpartum period. After screening 41 studies, the authors included 2 retrospective cohort studies.^16,17 The majority of the participants had VWD. With very-low-certainty evidence, the authors found that TxA reduces the risk of:

• severe primary PPH (risk ratio [RR], 0.36; 95% confidence interval [CI], 0.05–2.59)
• primary PPH (RR, 0.25; 95% CI, 0.04–1.75)
• secondary PPH (RR, 0.42; 95% CI, 0.02–0.91—does not cross 1.0).

Note that the 95% confidence intervals for severe as well as primary PPH crossed 1.0 and therefore these reductions in risk did not achieve statistical significance. Additionally, there was very-low-certainty evidence on the effect of TxA on blood transfusions, vaginal hematomas, blood loss, and thrombotic complications.³

Continue to: Our recommendations for HMB management...

 

 

Our recommendations for HMB management

When first evaluating any woman with HMB, it is important to check a blood count and ferritin level, if not already done. If there is any suggestion of iron deficiency (with or without anemia), we recommend oral iron supplementation. This is best accomplished with slow-release iron supplement formulations (or less expensive generic or house brands that contain less than 65 mg of elemental iron per tablet) taken every other day. Such preparations may cause fewer gastrointestinal adverse effects than other oral iron formulations.¹⁸ Although it may appear counterintuitive, oral iron is better absorbed (and also may cause fewer gastrointestinal adverse effects) when taken every other day.¹⁹

Initial management of HMB, whether or not a bleeding disorder is present, often consists or oral hormonal management. If no contraindications are present, we recommend initiation of a COC with a short hormone-free interval (for example, a 24/4 formulation). If contraindications to contraceptive doses of estrogen are present, continuous use of norethindrone acetate 5-mg tablets or off-label use of combination tablets with 5 µg of ethinyl estradiol and 1 mg of norethindrone acetate (a formulation approved for the treatment of menopausal symptoms) is appropriate.²⁰

Once a patient is established on oral hormonal management, placement of a levonorgestrel-releasing IUD should be considered. Given that expulsion rates may be higher in women with HMB, if feasible, consider using abdominal ultrasound guidance for IUD placement.

For women with VWD who fail first-line therapy (hormonal management) or are trying to become pregnant, TxA (two 650-mg tablets 3 times daily for up to 5 days during episodes of heavy flow) can reduce HMB.^20,21

Our recommendations for management of pregnancy and delivery

The second and third systematic reviews discussed above provide very limited guidance on comprehensive management. The care of the pregnant patient with VWD starts with assessment of VWF levels and making an accurate diagnosis. This usually requires the input of a hematologist or other expert in hemostasis. If no recent VWF levels are available, the ObGyn can obtain a von Willebrand panel that includes VWF antigen, VWF activity (most commonly ristocetin cofactor), and factor VIII.

Levels should be reassessed around 36 weeks’ gestation in anticipation of delivery. VWF levels increase during pregnancy; accordingly, in mild, type 1 VWD, half the time treatment is not necessary.¹¹ If VWF activity is less than 50 IU/dL (less than 50% of normal) at 36 weeks’ gestation, the patient should receive VWF concentrate (dosed in VWF units). This requires consultation with hematology and specialized pharmacy support.

For these reasons, the patient with a VWF level less than 50% should be delivered in a referral center with the necessary resources. Anesthesia should be aware of the patient. Unless they have sustained VWF and factor VIII levels greater than 50 IU/dL, neuraxial anesthesia should not be offered to pregnant women with VWD.

Due to the quantity of fluids administered during labor or at the time of delivery and the coexistent administration of oxytocin, desmopressin (synthetic vasopressin) should not be used without monitoring sodium levels, should not be dosed more than once, or should be avoided altogether due to the risk of water intoxication.

If the patient has sustained VWF and factor VIII levels greater than 50 IU/dL, she would be a candidate to deliver in her local hospital and receive neuraxial anesthesia.

Based on the best data we have for women with VWD, a patient with a VWF greater than 50 IU/dL is no more likely to experience PPH than other women.¹¹ Intravenous TxA can be used for prevention or treatment of immediate postpartum bleeding per protocol (1 g after cord clamp and 1 g 30 minutes or more later).²² Oral TxA can be used for prevention or treatment of delayed postpartum bleeding as per HMB. Regardless of the outcome of any testing during pregnancy, nonsteroidal anti-inflammatory drugs should be avoided postpartum and the patient should be monitored closely for bleeding.

Neonatal care

As for the fetus/neonate, the parents should be aware that the infant has a 50% chance of inheriting VWD. If the baby’s father has no history of bleeding, it is unlikely that the infant would be any more affected than the patient herself. Nonetheless, cord blood (in one or more light blue top tubes) should be obtained at the time of delivery and sent for a von Willebrand panel. If the infant is male, a circumcision should be postponed until VWD is ruled out. In addition, fetal invasive procedures should be avoided during labor. Fetal scalp electrode placement should be avoided. Operative vaginal delivery also should be avoided. Cesarean delivery would be preferred to operative vaginal delivery, but if operative vaginal delivery is unavoidable, use of forceps is preferred to vacuum extraction. ●

Von Willebrand disease (VWD) represents the most common inherited bleeding disorder, with a prevalence of approximately 1 in 1,000 people. Type 1 disease, associated with a quantitative reduction in von Willebrand factor (VWF), is the most common type of VWD and accounts for approximately 70% of VWD patients enrolled in hemophilia treatment centers; transmission is autosomal dominant. Type 2 disease, associated with a qualitative defect in VWF, accounts for most of the remaining 30% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal dominant. Type 3 disease, associated with a near absence of VWF, accounts for less than 1% of VWD patients enrolled in hemophilia treatment centers; transmission is usually autosomal recessive.

Bruising and mucocutaneous bleeding (epistaxis, gingival bleeding, and bleeding after dental extraction) are the most common presenting symptoms of VWD. Because VWD substantially increases the risk of heavy menstrual bleeding (HMB) and, to some extent, intrapartum bleeding complications, and postpartum hemorrhage, women experience a disproportionate burden from VWD. Thus, ObGyns are likely to be called on to make treatment recommendations in VWD patients with these concerns.¹

In 2017, the American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia determined that among clinical issues related to VWD, updating guidelines for women with VWD represented the highest priority.² Accordingly, an international group of hematologists/coagulation specialists performed systematic literature reviews to address 3 questions faced by women with VWD and their clinicians:

• What are the most effective treatments for HMB?
• What is the safest approach for women desiring neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of tranexamic acid (TxA) on postpartum hemorrhage (PPH)?³

Evidence on management strategies for HMB in women with VWD

The prevalence of HMB in women with VWD ranges from 50% to 92%. Reports suggest that between 5% and 24% of women presenting with this symptom have VWD.³ However, the prevalence of VWD among women seeking care for HMB relates to referral patterns, with the prevalence of VWD substantially higher in patient populations who are referred to clinicians or centers that focus on care of patients with bleeding disorders.

The systematic review authors³ identified 2 comparative studies that assessed the treatment of HMB in women with VWD. One was a crossover trial that enrolled 116 VWD patients with HMB with a mean age of 36 years.⁴ All participants in this trial chose not to use combination oral contraceptives (COCs) as they had not experienced good results with prior COC use. Trial participants were randomly assigned to receive either intranasal desmopressin (DDAVP; a synthetic analog of the antidiuretic agent vasopressin, which stimulates the release of VWF from endothelial cells) or oral TxA therapy for 2 menstrual cycles. Participants then crossed over to the other drug for 2 additional cycles. Although both agents significantly reduced estimated menstrual blood loss, TxA was more effective in decreasing bleeding than intranasal DDAVP.⁴

In a retrospective cohort study, investigators compared COC use with intranasal DDAVP in 36 adolescents who had VWD and HMB.⁵ Participant follow-up ranged from 6 months to 4 years. The estimated efficacy of COCs and intranasal DDAVP was 86% and 77%, respectively, a difference that did not achieve statistical significance. Some of the adolescents who used intranasal DDAVP reported severe headaches and flushing.⁵

In addition, the systematic review authors³ identified 5 case series that described the use of the levonorgestrel (52 mg)-releasing intrauterine device (LNG 52 IUD) in women with VWD and HMB; 4 of these addressed the efficacy of progestin-releasing IUDs in reducing HMB in this patient population.^6-9 Using different approaches to define HMB, the authors of these reports followed between 7 and 26 patients with bleeding disorders (most with confirmed VWD) and HMB for variable amounts of time after placement of an LNG 52 IUD. Many of the women described in these case series had tried other HMB treatments, including COCs, without success. Although these 4 reports assessed different outcomes, all reported that placement of the LNG 52 IUD substantially reduced menstrual blood loss, often resulting in amenorrhea. Several of these reports also noted important improvements in quality of life following LNG 52 IUD placement. One case series reported LNG 52 IUD placement in 13 adolescents with VWD and HMB. The mean time to achieve amenorrhea or occasional spotting was 94 days.⁶

The fifth report, which followed 20 women (median age, 31 years) with HMB associated with VWD or other bleeding disorders who underwent LNG 52 IUD placement, aimed to describe IUD expulsions and malpositioned IUDs in this population. In this small group of patients, 3 IUD expulsions and 2 malpositioned IUDs were observed. Furthermore, an additional 5 women had their device removed prematurely due to patient dissatisfaction. Accordingly, the IUD continuation rate in this case series was only 50%.¹⁰

Evidence on management of pregnancy, delivery, and the postpartum period

Heavy menstrual bleeding is not the only challenge for women with VWD. While pregnancy is accompanied by higher levels of VWF, potentially offsetting the risk of bleeding at the time of delivery, the levels do not achieve the same magnitude as they would in unaffected women.¹¹ Women are at an increased risk of primary PPH^12,13 and, importantly, since VWF levels fall exponentially after delivery when women are still experiencing lochia,¹¹ they are at increased risk of secondary or delayed PPH.

Two questions arise frequently in the care of women with VWD at the time of delivery and during the postpartum period:

• What is the safest approach for women who desire neuraxial analgesia for intrapartum pain?
• What is the impact of postpartum administration of TxA on PPH?

The second systematic review the authors performed³ focused on VWF levels in women receiving neuraxial anesthesia during labor. After screening 27 studies, the authors included 5 case series, which did not describe outcomes based on VWF levels but rather described the outcomes of women with VWF levels of greater than 0.50 IU/mL (> 50% of normal compared with a normal standard).

Meta-analysis showed that the proportion of anesthesia complications was 6%, which sounds high, but the range of complications was what would be expected in any population (hypotension, accidental dural puncture, inadequate anesthesia, and bloody tap with no further complications). No spinal, subdural, or epidural hematomas were noted.³ Such hematomas are an extremely rare complication of neuraxial anesthesia, occurring in only 1 in 200,000 or 1 in 250,000 obstetric patients^14,15; accordingly, an increase in the rate of hematomas among women with VWD could go undetected. The absence of hematomas among women with VWD as reported in the systematic review does not mean there is not an increase in the rate of hematomas in women with VWD. The relative risk is unknown and caution would be advised.

The third systematic review that the authors performed³ was on TxA treatment in the postpartum period. After screening 41 studies, the authors included 2 retrospective cohort studies.^16,17 The majority of the participants had VWD. With very-low-certainty evidence, the authors found that TxA reduces the risk of:

• severe primary PPH (risk ratio [RR], 0.36; 95% confidence interval [CI], 0.05–2.59)
• primary PPH (RR, 0.25; 95% CI, 0.04–1.75)
• secondary PPH (RR, 0.42; 95% CI, 0.02–0.91—does not cross 1.0).

Note that the 95% confidence intervals for severe as well as primary PPH crossed 1.0 and therefore these reductions in risk did not achieve statistical significance. Additionally, there was very-low-certainty evidence on the effect of TxA on blood transfusions, vaginal hematomas, blood loss, and thrombotic complications.³

Continue to: Our recommendations for HMB management...

 

 

Our recommendations for HMB management

When first evaluating any woman with HMB, it is important to check a blood count and ferritin level, if not already done. If there is any suggestion of iron deficiency (with or without anemia), we recommend oral iron supplementation. This is best accomplished with slow-release iron supplement formulations (or less expensive generic or house brands that contain less than 65 mg of elemental iron per tablet) taken every other day. Such preparations may cause fewer gastrointestinal adverse effects than other oral iron formulations.¹⁸ Although it may appear counterintuitive, oral iron is better absorbed (and also may cause fewer gastrointestinal adverse effects) when taken every other day.¹⁹

Initial management of HMB, whether or not a bleeding disorder is present, often consists or oral hormonal management. If no contraindications are present, we recommend initiation of a COC with a short hormone-free interval (for example, a 24/4 formulation). If contraindications to contraceptive doses of estrogen are present, continuous use of norethindrone acetate 5-mg tablets or off-label use of combination tablets with 5 µg of ethinyl estradiol and 1 mg of norethindrone acetate (a formulation approved for the treatment of menopausal symptoms) is appropriate.²⁰

Once a patient is established on oral hormonal management, placement of a levonorgestrel-releasing IUD should be considered. Given that expulsion rates may be higher in women with HMB, if feasible, consider using abdominal ultrasound guidance for IUD placement.

For women with VWD who fail first-line therapy (hormonal management) or are trying to become pregnant, TxA (two 650-mg tablets 3 times daily for up to 5 days during episodes of heavy flow) can reduce HMB.^20,21

Our recommendations for management of pregnancy and delivery

The second and third systematic reviews discussed above provide very limited guidance on comprehensive management. The care of the pregnant patient with VWD starts with assessment of VWF levels and making an accurate diagnosis. This usually requires the input of a hematologist or other expert in hemostasis. If no recent VWF levels are available, the ObGyn can obtain a von Willebrand panel that includes VWF antigen, VWF activity (most commonly ristocetin cofactor), and factor VIII.

Levels should be reassessed around 36 weeks’ gestation in anticipation of delivery. VWF levels increase during pregnancy; accordingly, in mild, type 1 VWD, half the time treatment is not necessary.¹¹ If VWF activity is less than 50 IU/dL (less than 50% of normal) at 36 weeks’ gestation, the patient should receive VWF concentrate (dosed in VWF units). This requires consultation with hematology and specialized pharmacy support.

For these reasons, the patient with a VWF level less than 50% should be delivered in a referral center with the necessary resources. Anesthesia should be aware of the patient. Unless they have sustained VWF and factor VIII levels greater than 50 IU/dL, neuraxial anesthesia should not be offered to pregnant women with VWD.

Due to the quantity of fluids administered during labor or at the time of delivery and the coexistent administration of oxytocin, desmopressin (synthetic vasopressin) should not be used without monitoring sodium levels, should not be dosed more than once, or should be avoided altogether due to the risk of water intoxication.

If the patient has sustained VWF and factor VIII levels greater than 50 IU/dL, she would be a candidate to deliver in her local hospital and receive neuraxial anesthesia.

Based on the best data we have for women with VWD, a patient with a VWF greater than 50 IU/dL is no more likely to experience PPH than other women.¹¹ Intravenous TxA can be used for prevention or treatment of immediate postpartum bleeding per protocol (1 g after cord clamp and 1 g 30 minutes or more later).²² Oral TxA can be used for prevention or treatment of delayed postpartum bleeding as per HMB. Regardless of the outcome of any testing during pregnancy, nonsteroidal anti-inflammatory drugs should be avoided postpartum and the patient should be monitored closely for bleeding.

Neonatal care

As for the fetus/neonate, the parents should be aware that the infant has a 50% chance of inheriting VWD. If the baby’s father has no history of bleeding, it is unlikely that the infant would be any more affected than the patient herself. Nonetheless, cord blood (in one or more light blue top tubes) should be obtained at the time of delivery and sent for a von Willebrand panel. If the infant is male, a circumcision should be postponed until VWD is ruled out. In addition, fetal invasive procedures should be avoided during labor. Fetal scalp electrode placement should be avoided. Operative vaginal delivery also should be avoided. Cesarean delivery would be preferred to operative vaginal delivery, but if operative vaginal delivery is unavoidable, use of forceps is preferred to vacuum extraction. ●

Dermatology is one of the least diverse medical specialties with only 3% of dermatologists being Black and 4% Latinx.¹ Leading dermatology organizations have called for specialty-wide efforts to improve diversity, with a particular focus on the resident selection process.^2,3 Medical students who are underrepresented in medicine (UIM)(ie, those who identify as Black, Latinx, Native American, or Pacific Islander) face many potential barriers in applying to dermatology programs, including financial limitations, lack of support and mentorship, and less exposure to the specialty.^1,2,4 The COVID-19 pandemic introduced additional challenges in the residency application process with limitations on clinical, research, and volunteer experiences; decreased opportunities for in-person mentorship and away rotations; and a shift to virtual recruitment. Although there has been increased emphasis on recruiting diverse candidates to dermatology, the COVID-19 pandemic may have exacerbated existing barriers for UIM applicants.

We surveyed dermatology residency program directors (PDs) and applicants to evaluate how UIM students approach and fare in the dermatology residency application process as well as the effects of COVID-19 on the most recent application cycle. Herein, we report the results of our surveys with a focus on racial differences in the application process.

Methods

We administered 2 anonymous online surveys—one to 115 PDs through the Association of Professors of Dermatology (APD) email listserve and another to applicants who participated in the 2020-2021 dermatology residency application cycle through the Dermatology Interest Group Association (DIGA) listserve. The surveys were distributed from March 29 through May 23, 2021. There was no way to determine the number of dermatology applicants on the DIGA listserve. The surveys were reviewed and approved by the University of Southern California (Los Angeles, California) institutional review board (approval #UP-21-00118).

Participants were not required to answer every survey question; response rates varied by question. Survey responses with less than 10% completion were excluded from analysis. Data were collected, analyzed, and stored using Qualtrics, a secure online survey platform. The test of equal or given proportions in R studio was used to determine statistically significant differences between variables (P<.05 indicated statistical significance).

Results

The PD survey received 79 complete responses (83.5% complete responses, 73.8% response rate) and the applicant survey received 232 complete responses (83.6% complete responses).

Applicant Characteristics—Applicant characteristics are provided in the eTable; 13.2% and 8.4% of participants were Black and Latinx (including those who identify as Hispanic/Latino), respectively. Only 0.8% of respondents identified as American Indian or Alaskan Native and were excluded from the analysis due to the limited sample size. Those who identified as White, Asian, multiple races, or other and those who preferred not to answer were considered non-UIM participants.

Differences in family background were observed in our cohort, with UIM candidates more likely to have experienced disadvantages, defined as being the first in their family to attend college/graduate school, growing up in a rural area, being a first-generation immigrant, or qualifying as low income. Underrepresented in medicine applicants also were less likely to have a dermatology program at their medical school (both Black and Latinx) and to have been elected to honor societies such as Alpha Omega Alpha and the Gold Humanism Honor Society (Black only).

Underrepresented in medicine applicants were more likely to complete a research gap year (eTable). Most applicants who took research years did so to improve their chances of matching, regardless of their race/ethnicity. For those who did not complete a research year, Black applicants (46.7%) were more likely to base that decision on financial limitations compared to non-UIMs (18.6%, P<.0001). Interestingly, in the PD survey, only 4.5% of respondents considered completion of a research year extremely or very important when compiling rank lists.

Application Process and Match Outcomes—The Table highlights differences in how UIM applicants approached the application process. Black but not Latinx applicants were less likely to be first-time applicants to dermatology compared to non-UIM applicants. Black applicants (8.3%) were significantly less likely to apply to more than 100 programs compared to non-UIM applicants (29.5%, P=.0002). Underrepresented in medicine applicants received greater numbers of interviews despite applying to fewer programs overall.

There also were differences in how UIM candidates approached their rank lists, with Black and Latinx applicants prioritizing diversity of patient populations and program faculty as well as program missions and values (Figure).

In our cohort, UIM candidates were more likely than non-UIM to match, and Black applicants were most likely to match at one of their top 3 choices (Table). In the PD survey, 77.6% of PDs considered contribution to diversity an important factor when compiling their rank lists.

Comment

Applicant Background—Dermatology is a competitive specialty with a challenging application process² that has been further complicated by the COVID-19 pandemic. Our study elucidated how the 2020-2021 application cycle affected UIM dermatology applicants. Prior studies have found that UIM medical students were more likely to come from lower socioeconomic backgrounds; financial constraints pose a major barrier for UIM and low-income students interested in dermatology.^4-6 We found this to be true in our cohort, as Black and Latinx applicants were significantly more likely to come from disadvantaged backgrounds (P<.000008 and P=.006, respectively). Additionally, we found that Black applicants were more likely than any other group to indicate financial concerns as their primary reason for not taking a research gap year. 

Although most applicants who completed a research year did so to increase their chances of matching, a higher percentage of UIMs took research years compared to non-UIM applicants. This finding could indicate greater anxiety about matching among UIM applicants vs their non-UIM counterparts. Black students have faced discrimination in clinical grading,⁷ have perceived racial discrimination in residency interviews,^8,9 and have shown to be less likely to be elected to medical school honor societies.¹⁰ We found that UIM applicants were more likely to pursue a research year compared to other applicants,¹¹ possibly because they felt additional pressure to enhance their applications or because UIM candidates were less likely to have a home dermatology program. Expansion of mentorship programs, visiting student electives, and grants for UIMs may alleviate the need for these candidates to complete a research year and reduce disparities in the application process.

Factors Influencing Rank Lists for Applicants—In our cohort, UIMs were significantly more likely to rank diversity of patients (P<.0001 for Black applicants and P=.04 for Latinx applicants) and faculty (P<.001 for Black applicants and P<.001 for Latinx applicants) as important factors in choosing a residency program. Historically, dermatology has been disproportionately White in its physician workforce and patient population.^1,12 Students with lower incomes or who identify as minorities cite the lack of diversity in dermatology as a considerable barrier to pursuing a career in the specialty.^4,5 Service learning, pipeline programs aimed at early exposure to dermatology, and increased access to care for diverse patient populations are important measures to improve diversity in the dermatology workforce.^13-15 Residency programs should consider how to incorporate these aspects into didactic and clinical curricula to better recruit diverse candidates to the field.

Equity in the Application Process—We found that Black applicants were more likely than non-UIM applicants to be reapplicants to dermatology; however, Black applicants in our study also were more likely to receive more interview invites, match into dermatology, and match into one of their top 3 programs. These findings are interesting, particularly given concerns about equity in the application process. It is possible that Black applicants who overcome barriers to applying to dermatology ultimately are more successful applicants. Recently, there has been an increased focus in the field on diversifying dermatology, which was further intensified last year.^2,3 Indicative of this shift, our PD survey showed that most programs reported that applicants’ contributions to diversity were important factors in the application process. Additionally, an emphasis by PDs on a holistic review of applications coupled with direct advocacy for increased representation may have contributed to the increased match rates for UIM applicants reported in our survey.

Latinx Applicants—Our study showed differences in how Latinx candidates fared in the application process; although Latinx applicants were more likely than their non-Latinx counterparts to match into dermatology, they were less likely than non-Latinx applicants to match into one of their top 3 programs. Given that Latinx encompasses ethnicity, not race, there may be a difference in how intentional focus on and advocacy for increasing diversity in dermatology affected different UIM applicant groups. Both race and ethnicity are social constructs rather than scientific categorizations; thus, it is difficult in survey studies such as ours to capture the intersectionality present across and between groups. Lastly, it is possible that the respondents to our applicant survey are not representative of the full cohort of UIM applicants.

Study Limitations—A major limitation of our study was that we did not have a method of reaching all dermatology applicants. Although our study shows promising results suggestive of increased diversity in the last application cycle, release of the National Resident Matching Program results from 2020-2021 with racially stratified data will be imperative to assess equity in the match process for all specialties and to confirm the generalizability of our results.

Dermatology is one of the least diverse medical specialties with only 3% of dermatologists being Black and 4% Latinx.¹ Leading dermatology organizations have called for specialty-wide efforts to improve diversity, with a particular focus on the resident selection process.^2,3 Medical students who are underrepresented in medicine (UIM)(ie, those who identify as Black, Latinx, Native American, or Pacific Islander) face many potential barriers in applying to dermatology programs, including financial limitations, lack of support and mentorship, and less exposure to the specialty.^1,2,4 The COVID-19 pandemic introduced additional challenges in the residency application process with limitations on clinical, research, and volunteer experiences; decreased opportunities for in-person mentorship and away rotations; and a shift to virtual recruitment. Although there has been increased emphasis on recruiting diverse candidates to dermatology, the COVID-19 pandemic may have exacerbated existing barriers for UIM applicants.

We surveyed dermatology residency program directors (PDs) and applicants to evaluate how UIM students approach and fare in the dermatology residency application process as well as the effects of COVID-19 on the most recent application cycle. Herein, we report the results of our surveys with a focus on racial differences in the application process.

Methods

We administered 2 anonymous online surveys—one to 115 PDs through the Association of Professors of Dermatology (APD) email listserve and another to applicants who participated in the 2020-2021 dermatology residency application cycle through the Dermatology Interest Group Association (DIGA) listserve. The surveys were distributed from March 29 through May 23, 2021. There was no way to determine the number of dermatology applicants on the DIGA listserve. The surveys were reviewed and approved by the University of Southern California (Los Angeles, California) institutional review board (approval #UP-21-00118).

Participants were not required to answer every survey question; response rates varied by question. Survey responses with less than 10% completion were excluded from analysis. Data were collected, analyzed, and stored using Qualtrics, a secure online survey platform. The test of equal or given proportions in R studio was used to determine statistically significant differences between variables (P<.05 indicated statistical significance).

Results

The PD survey received 79 complete responses (83.5% complete responses, 73.8% response rate) and the applicant survey received 232 complete responses (83.6% complete responses).

Applicant Characteristics—Applicant characteristics are provided in the eTable; 13.2% and 8.4% of participants were Black and Latinx (including those who identify as Hispanic/Latino), respectively. Only 0.8% of respondents identified as American Indian or Alaskan Native and were excluded from the analysis due to the limited sample size. Those who identified as White, Asian, multiple races, or other and those who preferred not to answer were considered non-UIM participants.

Differences in family background were observed in our cohort, with UIM candidates more likely to have experienced disadvantages, defined as being the first in their family to attend college/graduate school, growing up in a rural area, being a first-generation immigrant, or qualifying as low income. Underrepresented in medicine applicants also were less likely to have a dermatology program at their medical school (both Black and Latinx) and to have been elected to honor societies such as Alpha Omega Alpha and the Gold Humanism Honor Society (Black only).

Underrepresented in medicine applicants were more likely to complete a research gap year (eTable). Most applicants who took research years did so to improve their chances of matching, regardless of their race/ethnicity. For those who did not complete a research year, Black applicants (46.7%) were more likely to base that decision on financial limitations compared to non-UIMs (18.6%, P<.0001). Interestingly, in the PD survey, only 4.5% of respondents considered completion of a research year extremely or very important when compiling rank lists.

Application Process and Match Outcomes—The Table highlights differences in how UIM applicants approached the application process. Black but not Latinx applicants were less likely to be first-time applicants to dermatology compared to non-UIM applicants. Black applicants (8.3%) were significantly less likely to apply to more than 100 programs compared to non-UIM applicants (29.5%, P=.0002). Underrepresented in medicine applicants received greater numbers of interviews despite applying to fewer programs overall.

There also were differences in how UIM candidates approached their rank lists, with Black and Latinx applicants prioritizing diversity of patient populations and program faculty as well as program missions and values (Figure).

In our cohort, UIM candidates were more likely than non-UIM to match, and Black applicants were most likely to match at one of their top 3 choices (Table). In the PD survey, 77.6% of PDs considered contribution to diversity an important factor when compiling their rank lists.

Comment

Applicant Background—Dermatology is a competitive specialty with a challenging application process² that has been further complicated by the COVID-19 pandemic. Our study elucidated how the 2020-2021 application cycle affected UIM dermatology applicants. Prior studies have found that UIM medical students were more likely to come from lower socioeconomic backgrounds; financial constraints pose a major barrier for UIM and low-income students interested in dermatology.^4-6 We found this to be true in our cohort, as Black and Latinx applicants were significantly more likely to come from disadvantaged backgrounds (P<.000008 and P=.006, respectively). Additionally, we found that Black applicants were more likely than any other group to indicate financial concerns as their primary reason for not taking a research gap year. 

Although most applicants who completed a research year did so to increase their chances of matching, a higher percentage of UIMs took research years compared to non-UIM applicants. This finding could indicate greater anxiety about matching among UIM applicants vs their non-UIM counterparts. Black students have faced discrimination in clinical grading,⁷ have perceived racial discrimination in residency interviews,^8,9 and have shown to be less likely to be elected to medical school honor societies.¹⁰ We found that UIM applicants were more likely to pursue a research year compared to other applicants,¹¹ possibly because they felt additional pressure to enhance their applications or because UIM candidates were less likely to have a home dermatology program. Expansion of mentorship programs, visiting student electives, and grants for UIMs may alleviate the need for these candidates to complete a research year and reduce disparities in the application process.

Factors Influencing Rank Lists for Applicants—In our cohort, UIMs were significantly more likely to rank diversity of patients (P<.0001 for Black applicants and P=.04 for Latinx applicants) and faculty (P<.001 for Black applicants and P<.001 for Latinx applicants) as important factors in choosing a residency program. Historically, dermatology has been disproportionately White in its physician workforce and patient population.^1,12 Students with lower incomes or who identify as minorities cite the lack of diversity in dermatology as a considerable barrier to pursuing a career in the specialty.^4,5 Service learning, pipeline programs aimed at early exposure to dermatology, and increased access to care for diverse patient populations are important measures to improve diversity in the dermatology workforce.^13-15 Residency programs should consider how to incorporate these aspects into didactic and clinical curricula to better recruit diverse candidates to the field.

Equity in the Application Process—We found that Black applicants were more likely than non-UIM applicants to be reapplicants to dermatology; however, Black applicants in our study also were more likely to receive more interview invites, match into dermatology, and match into one of their top 3 programs. These findings are interesting, particularly given concerns about equity in the application process. It is possible that Black applicants who overcome barriers to applying to dermatology ultimately are more successful applicants. Recently, there has been an increased focus in the field on diversifying dermatology, which was further intensified last year.^2,3 Indicative of this shift, our PD survey showed that most programs reported that applicants’ contributions to diversity were important factors in the application process. Additionally, an emphasis by PDs on a holistic review of applications coupled with direct advocacy for increased representation may have contributed to the increased match rates for UIM applicants reported in our survey.

Latinx Applicants—Our study showed differences in how Latinx candidates fared in the application process; although Latinx applicants were more likely than their non-Latinx counterparts to match into dermatology, they were less likely than non-Latinx applicants to match into one of their top 3 programs. Given that Latinx encompasses ethnicity, not race, there may be a difference in how intentional focus on and advocacy for increasing diversity in dermatology affected different UIM applicant groups. Both race and ethnicity are social constructs rather than scientific categorizations; thus, it is difficult in survey studies such as ours to capture the intersectionality present across and between groups. Lastly, it is possible that the respondents to our applicant survey are not representative of the full cohort of UIM applicants.

Study Limitations—A major limitation of our study was that we did not have a method of reaching all dermatology applicants. Although our study shows promising results suggestive of increased diversity in the last application cycle, release of the National Resident Matching Program results from 2020-2021 with racially stratified data will be imperative to assess equity in the match process for all specialties and to confirm the generalizability of our results.

Dermatology is one of the least diverse medical specialties with only 3% of dermatologists being Black and 4% Latinx.¹ Leading dermatology organizations have called for specialty-wide efforts to improve diversity, with a particular focus on the resident selection process.^2,3 Medical students who are underrepresented in medicine (UIM)(ie, those who identify as Black, Latinx, Native American, or Pacific Islander) face many potential barriers in applying to dermatology programs, including financial limitations, lack of support and mentorship, and less exposure to the specialty.^1,2,4 The COVID-19 pandemic introduced additional challenges in the residency application process with limitations on clinical, research, and volunteer experiences; decreased opportunities for in-person mentorship and away rotations; and a shift to virtual recruitment. Although there has been increased emphasis on recruiting diverse candidates to dermatology, the COVID-19 pandemic may have exacerbated existing barriers for UIM applicants.

We surveyed dermatology residency program directors (PDs) and applicants to evaluate how UIM students approach and fare in the dermatology residency application process as well as the effects of COVID-19 on the most recent application cycle. Herein, we report the results of our surveys with a focus on racial differences in the application process.

Methods

We administered 2 anonymous online surveys—one to 115 PDs through the Association of Professors of Dermatology (APD) email listserve and another to applicants who participated in the 2020-2021 dermatology residency application cycle through the Dermatology Interest Group Association (DIGA) listserve. The surveys were distributed from March 29 through May 23, 2021. There was no way to determine the number of dermatology applicants on the DIGA listserve. The surveys were reviewed and approved by the University of Southern California (Los Angeles, California) institutional review board (approval #UP-21-00118).

Participants were not required to answer every survey question; response rates varied by question. Survey responses with less than 10% completion were excluded from analysis. Data were collected, analyzed, and stored using Qualtrics, a secure online survey platform. The test of equal or given proportions in R studio was used to determine statistically significant differences between variables (P<.05 indicated statistical significance).

Results

The PD survey received 79 complete responses (83.5% complete responses, 73.8% response rate) and the applicant survey received 232 complete responses (83.6% complete responses).

Applicant Characteristics—Applicant characteristics are provided in the eTable; 13.2% and 8.4% of participants were Black and Latinx (including those who identify as Hispanic/Latino), respectively. Only 0.8% of respondents identified as American Indian or Alaskan Native and were excluded from the analysis due to the limited sample size. Those who identified as White, Asian, multiple races, or other and those who preferred not to answer were considered non-UIM participants.

Differences in family background were observed in our cohort, with UIM candidates more likely to have experienced disadvantages, defined as being the first in their family to attend college/graduate school, growing up in a rural area, being a first-generation immigrant, or qualifying as low income. Underrepresented in medicine applicants also were less likely to have a dermatology program at their medical school (both Black and Latinx) and to have been elected to honor societies such as Alpha Omega Alpha and the Gold Humanism Honor Society (Black only).

Underrepresented in medicine applicants were more likely to complete a research gap year (eTable). Most applicants who took research years did so to improve their chances of matching, regardless of their race/ethnicity. For those who did not complete a research year, Black applicants (46.7%) were more likely to base that decision on financial limitations compared to non-UIMs (18.6%, P<.0001). Interestingly, in the PD survey, only 4.5% of respondents considered completion of a research year extremely or very important when compiling rank lists.

Application Process and Match Outcomes—The Table highlights differences in how UIM applicants approached the application process. Black but not Latinx applicants were less likely to be first-time applicants to dermatology compared to non-UIM applicants. Black applicants (8.3%) were significantly less likely to apply to more than 100 programs compared to non-UIM applicants (29.5%, P=.0002). Underrepresented in medicine applicants received greater numbers of interviews despite applying to fewer programs overall.

There also were differences in how UIM candidates approached their rank lists, with Black and Latinx applicants prioritizing diversity of patient populations and program faculty as well as program missions and values (Figure).

In our cohort, UIM candidates were more likely than non-UIM to match, and Black applicants were most likely to match at one of their top 3 choices (Table). In the PD survey, 77.6% of PDs considered contribution to diversity an important factor when compiling their rank lists.

Comment

Applicant Background—Dermatology is a competitive specialty with a challenging application process² that has been further complicated by the COVID-19 pandemic. Our study elucidated how the 2020-2021 application cycle affected UIM dermatology applicants. Prior studies have found that UIM medical students were more likely to come from lower socioeconomic backgrounds; financial constraints pose a major barrier for UIM and low-income students interested in dermatology.^4-6 We found this to be true in our cohort, as Black and Latinx applicants were significantly more likely to come from disadvantaged backgrounds (P<.000008 and P=.006, respectively). Additionally, we found that Black applicants were more likely than any other group to indicate financial concerns as their primary reason for not taking a research gap year. 

Although most applicants who completed a research year did so to increase their chances of matching, a higher percentage of UIMs took research years compared to non-UIM applicants. This finding could indicate greater anxiety about matching among UIM applicants vs their non-UIM counterparts. Black students have faced discrimination in clinical grading,⁷ have perceived racial discrimination in residency interviews,^8,9 and have shown to be less likely to be elected to medical school honor societies.¹⁰ We found that UIM applicants were more likely to pursue a research year compared to other applicants,¹¹ possibly because they felt additional pressure to enhance their applications or because UIM candidates were less likely to have a home dermatology program. Expansion of mentorship programs, visiting student electives, and grants for UIMs may alleviate the need for these candidates to complete a research year and reduce disparities in the application process.

Factors Influencing Rank Lists for Applicants—In our cohort, UIMs were significantly more likely to rank diversity of patients (P<.0001 for Black applicants and P=.04 for Latinx applicants) and faculty (P<.001 for Black applicants and P<.001 for Latinx applicants) as important factors in choosing a residency program. Historically, dermatology has been disproportionately White in its physician workforce and patient population.^1,12 Students with lower incomes or who identify as minorities cite the lack of diversity in dermatology as a considerable barrier to pursuing a career in the specialty.^4,5 Service learning, pipeline programs aimed at early exposure to dermatology, and increased access to care for diverse patient populations are important measures to improve diversity in the dermatology workforce.^13-15 Residency programs should consider how to incorporate these aspects into didactic and clinical curricula to better recruit diverse candidates to the field.

Equity in the Application Process—We found that Black applicants were more likely than non-UIM applicants to be reapplicants to dermatology; however, Black applicants in our study also were more likely to receive more interview invites, match into dermatology, and match into one of their top 3 programs. These findings are interesting, particularly given concerns about equity in the application process. It is possible that Black applicants who overcome barriers to applying to dermatology ultimately are more successful applicants. Recently, there has been an increased focus in the field on diversifying dermatology, which was further intensified last year.^2,3 Indicative of this shift, our PD survey showed that most programs reported that applicants’ contributions to diversity were important factors in the application process. Additionally, an emphasis by PDs on a holistic review of applications coupled with direct advocacy for increased representation may have contributed to the increased match rates for UIM applicants reported in our survey.

Latinx Applicants—Our study showed differences in how Latinx candidates fared in the application process; although Latinx applicants were more likely than their non-Latinx counterparts to match into dermatology, they were less likely than non-Latinx applicants to match into one of their top 3 programs. Given that Latinx encompasses ethnicity, not race, there may be a difference in how intentional focus on and advocacy for increasing diversity in dermatology affected different UIM applicant groups. Both race and ethnicity are social constructs rather than scientific categorizations; thus, it is difficult in survey studies such as ours to capture the intersectionality present across and between groups. Lastly, it is possible that the respondents to our applicant survey are not representative of the full cohort of UIM applicants.

Study Limitations—A major limitation of our study was that we did not have a method of reaching all dermatology applicants. Although our study shows promising results suggestive of increased diversity in the last application cycle, release of the National Resident Matching Program results from 2020-2021 with racially stratified data will be imperative to assess equity in the match process for all specialties and to confirm the generalizability of our results.