Article

Case Report

An otherwise healthy 13-year-old boy was referred to pediatric dermatology with multiple asymptomatic erythematous papules throughout the trunk and arms of 6 months’ duration. He denied fevers, night sweats, or weight loss. A punch biopsy revealed a dense atypical lymphoid infiltrate with follicular prominence extending periadnexally and perivascularly, which was most consistent with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (Figures 1A and 1B). Cells were positive for Bcl-2, CD23, and CD20 (Figure 1C). Polymerase chain reaction analysis of the immunoglobulin heavy and κ chain gene rearrangements were positive, indicating the presence of a clonal B-cell expansion. The patient’s complete blood cell count, complete metabolic profile, serum lactate dehydrogenase, and erythrocyte sedimentation rate were within reference range. Lyme disease antibodies, Helicobacter pylori testing, thyroid function testing, thyroid antibodies, anti–Sjogren syndrome–related antigen A antibody, and anti–Sjogren syndrome–related antigen B were negative. Additionally, positron emission tomography (PET) with computed tomography (CT) revealed no abnormalities. He was diagnosed with stage T3b primary cutaneous marginal zone lymphoma (PCMZL) due to cutaneous involvement of 3 or more body regions.

The patient was started on clobetasol ointment 0.05% twice daily to the affected areas. After 2 months, he had progression of cutaneous disease, including increased number of lesions; erythema; and induration of lesions on the chest, back, and arms (Figure 2A) and was started on oral doxycycline 100 mg twice daily with subsequent notable improvement of the skin lesions at 2-week follow-up, including decreased erythema and induration of all lesions. He then received intralesional triamcinolone 20 mg/mL injections to 4 residual lesions; clobetasol ointment 0.05% twice daily was continued for the remaining lesions as needed for pruritus. He continued doxycycline for 4 months with further improvement of lesions (Figure 2B). Six months after discontinuing doxycycline, 2 small residual lesions remained on the left arm and back, but the patient did not develop any new or recurrent lesions.

Comment

Clinical Presentation—Primary cutaneous B-cell lymphomas include PCMZL, primary cutaneous follicle center lymphoma, and primary cutaneous large B-cell lymphoma. Primary cutaneous marginal zone lymphoma is an indolent extranodal B-cell lymphoma composed of small B cells, marginal zone cells, lymphoplasmacytoid cells, and mature plasma cells.¹

Primary cutaneous marginal zone lymphoma typically presents in the fourth to sixth decades of life and is rare in children, with fewer than 40 cases in patients younger than 20 years.² Amitay-Laish and colleagues² reported 29 patients with pediatric PCMZL ranging in age from 1 to 19.5 years at diagnosis, with the majority of patients diagnosed after 10 years of age. Clinically, patients present with multifocal, erythematous to brown, dermal papules, plaques, and nodules most commonly distributed on the trunk and arms. A retrospective review of 11 pediatric patients with PCMZL over a median of 5.5 years demonstrated that the clinical presentation, histopathology, molecular findings, and prognosis of pediatric PCMZL appears similar to adult PCMZL.² Cutaneous relapse is common, but extracutaneous spread is rare. The prognosis is excellent, with a disease-free survival rate of 93%.³

Diagnosis—The diagnosis of PCMZL requires histopathologic analysis of involved skin as well as exclusion of extracutaneous disease at the time of diagnosis during initial staging evaluation. Histologically there are nodular infiltrates of small lymphocytes in interfollicular compartments, reactive germinal centers, and clonality with monotypic immunoglobulin heavy chain genes.⁴ Laboratory workup should include complete blood cell count with differential, complete metabolic panel, and serum lactate dehydrogenase level. If lymphocytosis is present, flow cytometry of peripheral blood cells should be performed. Radiographic imaging with contrast-enhanced CT or PET/CT of the chest, abdomen, and pelvis should be performed for routine staging in most patients, with imaging of the neck recommended when cervical lymphadenopathy is detected.⁵ Patients with multifocal skin lesions should receive PET/CT to exclude systemic disease and assess lymph nodes. Bone marrow studies are not required for diagnosis.^5,6

Associated Conditions—Systemic marginal zone lymphoma has been associated with autoimmune conditions, including Hashimoto thyroiditis and Sjögren syndrome; however, this association has not been shown in PCMZL and was not found in our patient.^7,8Borrelia-positive serology has been described in cases of PCMZL in Europe. The pathogenesis has been speculated to be due to chronic antigen stimulation related to the geographic distribution of Borrelia species.⁹ In endemic areas, Borrelia testing with serology or DNA testing of skin is recommended; however, there has been no strong correlation between Borrelia burgdorferi and PCMZL found in North America or Asia.^9,10Helicobacter pylori has been associated with gastric mucosal-associated lymphatic tissue lymphoma, which responds well to antibiotic therapy. However, an association between PCMZL and H pylori has not been well described.¹¹

Management—Several treatment modalities have been attempted in patients with PCMZL with varying efficacy. Given the rarity of this disease, there is no standard therapy. Treatment options include radiation therapy, excision, topical steroids, intralesional steroids, intralesional rituximab, and antibiotics.^2,12-14 Case reports of pediatric patients have demonstrated improvement with excision,^15-19 intralesional steroids,^20,21 intralesional rituximab,²² and clobetasol cream.^23,24 In asymptomatic patients, watchful waiting often is employed given the overall indolent nature of PCMZL. Antibiotic therapy may be favored in Borrelia-positive cases. However, even in B burgdorferi–negative patients, there have been cases where there is response to antibiotics, particularly doxycycline.^2,15,25 We elected for a trial of doxycycline in our patient based on these prior reports, along with the overall favorable side-effect profile of doxycycline for adolescents and our patient’s widespread cutaneous involvement.

Doxycycline is utilized in pediatric patients 8 years and older for numerous indications, including treatment of acne, Rocky Mountain spotted fever, and Lyme disease. Use of doxycycline in younger patients typically is avoided given the risk for dental enamel hypoplasia, tooth discoloration, and possible delays in skeletal development. Originally utilized for its antibacterial effects as an intracellular inhibitor of protein synthesis, doxycycline has been repurposed for oncologic therapies. It has been shown to have cytotoxic and antiproliferative properties in various cancer cells and also may inhibit leukemic cell migration.²⁶ In PCMZL, doxycycline initially was utilized in Borrelia-positive patients in Europe and found to improve disease clearance.²⁷ In patients without Borrelia infection, doxycycline is thought to enhance apoptosis through caspase-3 activation along with p53 and Bax upregulation.²⁸

Intralesional triamcinolone alone may not be feasible in pediatric PCMZL patients because of widespread involvement, and doxycycline may be considered as a treatment option. Multiple low-risk treatment modalities may be used in conjunction to clear disease in pediatric patients, as demonstrated in our case.

Acknowledgment—We thank Ali Nael Amzajerdi, MD (Orange, California), for his contributions to the pathologic imaging in this report.

Case Report

An otherwise healthy 13-year-old boy was referred to pediatric dermatology with multiple asymptomatic erythematous papules throughout the trunk and arms of 6 months’ duration. He denied fevers, night sweats, or weight loss. A punch biopsy revealed a dense atypical lymphoid infiltrate with follicular prominence extending periadnexally and perivascularly, which was most consistent with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (Figures 1A and 1B). Cells were positive for Bcl-2, CD23, and CD20 (Figure 1C). Polymerase chain reaction analysis of the immunoglobulin heavy and κ chain gene rearrangements were positive, indicating the presence of a clonal B-cell expansion. The patient’s complete blood cell count, complete metabolic profile, serum lactate dehydrogenase, and erythrocyte sedimentation rate were within reference range. Lyme disease antibodies, Helicobacter pylori testing, thyroid function testing, thyroid antibodies, anti–Sjogren syndrome–related antigen A antibody, and anti–Sjogren syndrome–related antigen B were negative. Additionally, positron emission tomography (PET) with computed tomography (CT) revealed no abnormalities. He was diagnosed with stage T3b primary cutaneous marginal zone lymphoma (PCMZL) due to cutaneous involvement of 3 or more body regions.

The patient was started on clobetasol ointment 0.05% twice daily to the affected areas. After 2 months, he had progression of cutaneous disease, including increased number of lesions; erythema; and induration of lesions on the chest, back, and arms (Figure 2A) and was started on oral doxycycline 100 mg twice daily with subsequent notable improvement of the skin lesions at 2-week follow-up, including decreased erythema and induration of all lesions. He then received intralesional triamcinolone 20 mg/mL injections to 4 residual lesions; clobetasol ointment 0.05% twice daily was continued for the remaining lesions as needed for pruritus. He continued doxycycline for 4 months with further improvement of lesions (Figure 2B). Six months after discontinuing doxycycline, 2 small residual lesions remained on the left arm and back, but the patient did not develop any new or recurrent lesions.

Comment

Clinical Presentation—Primary cutaneous B-cell lymphomas include PCMZL, primary cutaneous follicle center lymphoma, and primary cutaneous large B-cell lymphoma. Primary cutaneous marginal zone lymphoma is an indolent extranodal B-cell lymphoma composed of small B cells, marginal zone cells, lymphoplasmacytoid cells, and mature plasma cells.¹

Primary cutaneous marginal zone lymphoma typically presents in the fourth to sixth decades of life and is rare in children, with fewer than 40 cases in patients younger than 20 years.² Amitay-Laish and colleagues² reported 29 patients with pediatric PCMZL ranging in age from 1 to 19.5 years at diagnosis, with the majority of patients diagnosed after 10 years of age. Clinically, patients present with multifocal, erythematous to brown, dermal papules, plaques, and nodules most commonly distributed on the trunk and arms. A retrospective review of 11 pediatric patients with PCMZL over a median of 5.5 years demonstrated that the clinical presentation, histopathology, molecular findings, and prognosis of pediatric PCMZL appears similar to adult PCMZL.² Cutaneous relapse is common, but extracutaneous spread is rare. The prognosis is excellent, with a disease-free survival rate of 93%.³

Diagnosis—The diagnosis of PCMZL requires histopathologic analysis of involved skin as well as exclusion of extracutaneous disease at the time of diagnosis during initial staging evaluation. Histologically there are nodular infiltrates of small lymphocytes in interfollicular compartments, reactive germinal centers, and clonality with monotypic immunoglobulin heavy chain genes.⁴ Laboratory workup should include complete blood cell count with differential, complete metabolic panel, and serum lactate dehydrogenase level. If lymphocytosis is present, flow cytometry of peripheral blood cells should be performed. Radiographic imaging with contrast-enhanced CT or PET/CT of the chest, abdomen, and pelvis should be performed for routine staging in most patients, with imaging of the neck recommended when cervical lymphadenopathy is detected.⁵ Patients with multifocal skin lesions should receive PET/CT to exclude systemic disease and assess lymph nodes. Bone marrow studies are not required for diagnosis.^5,6

Associated Conditions—Systemic marginal zone lymphoma has been associated with autoimmune conditions, including Hashimoto thyroiditis and Sjögren syndrome; however, this association has not been shown in PCMZL and was not found in our patient.^7,8Borrelia-positive serology has been described in cases of PCMZL in Europe. The pathogenesis has been speculated to be due to chronic antigen stimulation related to the geographic distribution of Borrelia species.⁹ In endemic areas, Borrelia testing with serology or DNA testing of skin is recommended; however, there has been no strong correlation between Borrelia burgdorferi and PCMZL found in North America or Asia.^9,10Helicobacter pylori has been associated with gastric mucosal-associated lymphatic tissue lymphoma, which responds well to antibiotic therapy. However, an association between PCMZL and H pylori has not been well described.¹¹

Management—Several treatment modalities have been attempted in patients with PCMZL with varying efficacy. Given the rarity of this disease, there is no standard therapy. Treatment options include radiation therapy, excision, topical steroids, intralesional steroids, intralesional rituximab, and antibiotics.^2,12-14 Case reports of pediatric patients have demonstrated improvement with excision,^15-19 intralesional steroids,^20,21 intralesional rituximab,²² and clobetasol cream.^23,24 In asymptomatic patients, watchful waiting often is employed given the overall indolent nature of PCMZL. Antibiotic therapy may be favored in Borrelia-positive cases. However, even in B burgdorferi–negative patients, there have been cases where there is response to antibiotics, particularly doxycycline.^2,15,25 We elected for a trial of doxycycline in our patient based on these prior reports, along with the overall favorable side-effect profile of doxycycline for adolescents and our patient’s widespread cutaneous involvement.

Doxycycline is utilized in pediatric patients 8 years and older for numerous indications, including treatment of acne, Rocky Mountain spotted fever, and Lyme disease. Use of doxycycline in younger patients typically is avoided given the risk for dental enamel hypoplasia, tooth discoloration, and possible delays in skeletal development. Originally utilized for its antibacterial effects as an intracellular inhibitor of protein synthesis, doxycycline has been repurposed for oncologic therapies. It has been shown to have cytotoxic and antiproliferative properties in various cancer cells and also may inhibit leukemic cell migration.²⁶ In PCMZL, doxycycline initially was utilized in Borrelia-positive patients in Europe and found to improve disease clearance.²⁷ In patients without Borrelia infection, doxycycline is thought to enhance apoptosis through caspase-3 activation along with p53 and Bax upregulation.²⁸

Intralesional triamcinolone alone may not be feasible in pediatric PCMZL patients because of widespread involvement, and doxycycline may be considered as a treatment option. Multiple low-risk treatment modalities may be used in conjunction to clear disease in pediatric patients, as demonstrated in our case.

Acknowledgment—We thank Ali Nael Amzajerdi, MD (Orange, California), for his contributions to the pathologic imaging in this report.

Case Report

An otherwise healthy 13-year-old boy was referred to pediatric dermatology with multiple asymptomatic erythematous papules throughout the trunk and arms of 6 months’ duration. He denied fevers, night sweats, or weight loss. A punch biopsy revealed a dense atypical lymphoid infiltrate with follicular prominence extending periadnexally and perivascularly, which was most consistent with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (Figures 1A and 1B). Cells were positive for Bcl-2, CD23, and CD20 (Figure 1C). Polymerase chain reaction analysis of the immunoglobulin heavy and κ chain gene rearrangements were positive, indicating the presence of a clonal B-cell expansion. The patient’s complete blood cell count, complete metabolic profile, serum lactate dehydrogenase, and erythrocyte sedimentation rate were within reference range. Lyme disease antibodies, Helicobacter pylori testing, thyroid function testing, thyroid antibodies, anti–Sjogren syndrome–related antigen A antibody, and anti–Sjogren syndrome–related antigen B were negative. Additionally, positron emission tomography (PET) with computed tomography (CT) revealed no abnormalities. He was diagnosed with stage T3b primary cutaneous marginal zone lymphoma (PCMZL) due to cutaneous involvement of 3 or more body regions.

The patient was started on clobetasol ointment 0.05% twice daily to the affected areas. After 2 months, he had progression of cutaneous disease, including increased number of lesions; erythema; and induration of lesions on the chest, back, and arms (Figure 2A) and was started on oral doxycycline 100 mg twice daily with subsequent notable improvement of the skin lesions at 2-week follow-up, including decreased erythema and induration of all lesions. He then received intralesional triamcinolone 20 mg/mL injections to 4 residual lesions; clobetasol ointment 0.05% twice daily was continued for the remaining lesions as needed for pruritus. He continued doxycycline for 4 months with further improvement of lesions (Figure 2B). Six months after discontinuing doxycycline, 2 small residual lesions remained on the left arm and back, but the patient did not develop any new or recurrent lesions.

Comment

Clinical Presentation—Primary cutaneous B-cell lymphomas include PCMZL, primary cutaneous follicle center lymphoma, and primary cutaneous large B-cell lymphoma. Primary cutaneous marginal zone lymphoma is an indolent extranodal B-cell lymphoma composed of small B cells, marginal zone cells, lymphoplasmacytoid cells, and mature plasma cells.¹

Primary cutaneous marginal zone lymphoma typically presents in the fourth to sixth decades of life and is rare in children, with fewer than 40 cases in patients younger than 20 years.² Amitay-Laish and colleagues² reported 29 patients with pediatric PCMZL ranging in age from 1 to 19.5 years at diagnosis, with the majority of patients diagnosed after 10 years of age. Clinically, patients present with multifocal, erythematous to brown, dermal papules, plaques, and nodules most commonly distributed on the trunk and arms. A retrospective review of 11 pediatric patients with PCMZL over a median of 5.5 years demonstrated that the clinical presentation, histopathology, molecular findings, and prognosis of pediatric PCMZL appears similar to adult PCMZL.² Cutaneous relapse is common, but extracutaneous spread is rare. The prognosis is excellent, with a disease-free survival rate of 93%.³

Diagnosis—The diagnosis of PCMZL requires histopathologic analysis of involved skin as well as exclusion of extracutaneous disease at the time of diagnosis during initial staging evaluation. Histologically there are nodular infiltrates of small lymphocytes in interfollicular compartments, reactive germinal centers, and clonality with monotypic immunoglobulin heavy chain genes.⁴ Laboratory workup should include complete blood cell count with differential, complete metabolic panel, and serum lactate dehydrogenase level. If lymphocytosis is present, flow cytometry of peripheral blood cells should be performed. Radiographic imaging with contrast-enhanced CT or PET/CT of the chest, abdomen, and pelvis should be performed for routine staging in most patients, with imaging of the neck recommended when cervical lymphadenopathy is detected.⁵ Patients with multifocal skin lesions should receive PET/CT to exclude systemic disease and assess lymph nodes. Bone marrow studies are not required for diagnosis.^5,6

Associated Conditions—Systemic marginal zone lymphoma has been associated with autoimmune conditions, including Hashimoto thyroiditis and Sjögren syndrome; however, this association has not been shown in PCMZL and was not found in our patient.^7,8Borrelia-positive serology has been described in cases of PCMZL in Europe. The pathogenesis has been speculated to be due to chronic antigen stimulation related to the geographic distribution of Borrelia species.⁹ In endemic areas, Borrelia testing with serology or DNA testing of skin is recommended; however, there has been no strong correlation between Borrelia burgdorferi and PCMZL found in North America or Asia.^9,10Helicobacter pylori has been associated with gastric mucosal-associated lymphatic tissue lymphoma, which responds well to antibiotic therapy. However, an association between PCMZL and H pylori has not been well described.¹¹

Management—Several treatment modalities have been attempted in patients with PCMZL with varying efficacy. Given the rarity of this disease, there is no standard therapy. Treatment options include radiation therapy, excision, topical steroids, intralesional steroids, intralesional rituximab, and antibiotics.^2,12-14 Case reports of pediatric patients have demonstrated improvement with excision,^15-19 intralesional steroids,^20,21 intralesional rituximab,²² and clobetasol cream.^23,24 In asymptomatic patients, watchful waiting often is employed given the overall indolent nature of PCMZL. Antibiotic therapy may be favored in Borrelia-positive cases. However, even in B burgdorferi–negative patients, there have been cases where there is response to antibiotics, particularly doxycycline.^2,15,25 We elected for a trial of doxycycline in our patient based on these prior reports, along with the overall favorable side-effect profile of doxycycline for adolescents and our patient’s widespread cutaneous involvement.

Doxycycline is utilized in pediatric patients 8 years and older for numerous indications, including treatment of acne, Rocky Mountain spotted fever, and Lyme disease. Use of doxycycline in younger patients typically is avoided given the risk for dental enamel hypoplasia, tooth discoloration, and possible delays in skeletal development. Originally utilized for its antibacterial effects as an intracellular inhibitor of protein synthesis, doxycycline has been repurposed for oncologic therapies. It has been shown to have cytotoxic and antiproliferative properties in various cancer cells and also may inhibit leukemic cell migration.²⁶ In PCMZL, doxycycline initially was utilized in Borrelia-positive patients in Europe and found to improve disease clearance.²⁷ In patients without Borrelia infection, doxycycline is thought to enhance apoptosis through caspase-3 activation along with p53 and Bax upregulation.²⁸

Intralesional triamcinolone alone may not be feasible in pediatric PCMZL patients because of widespread involvement, and doxycycline may be considered as a treatment option. Multiple low-risk treatment modalities may be used in conjunction to clear disease in pediatric patients, as demonstrated in our case.

Acknowledgment—We thank Ali Nael Amzajerdi, MD (Orange, California), for his contributions to the pathologic imaging in this report.

Individuals spend close to half of their lives preventing, or planning for, pregnancy. As such, contraception plays a major role in patient-provider interactions. Contraception counseling and management is a common scenario encountered in the general gynecologist’s practice. Luckily, we have two evidence-based guidelines developed by the US Centers for Disease Control and Prevention (CDC) that support the provision of contraceptive care:

1. US Medical Eligibility for Contraceptive Use (US-MEC),¹ which provides guidance on which patients can safely use a method
2. US Selected Practice Recommendations for Contraceptive Use (US-SPR),² which provides method-specific guidance on how to use a method (including how to: initiate or start a method; manage adherence issues, such as a missed pill, etc; and manage common issues like breakthrough bleeding). Both of these guidelines are updated routinely and are publicly available online or for free, through smartphone applications.

While most contraceptive care is straightforward, there are circumstances that require additional consideration. In this 3-part series we review 3 clinical cases, existing evidence to guide management decisions, and our recommendations. In part 1, we focus on restarting hormonal contraception after ulipristal acetate administration. In parts 2 and 3, we will discuss removal of a nonpalpable contraceptive implant and the consideration of a levonorgestrel-releasing intrauterine device (LNG-IUD) for emergency contraception.

CASE Meeting emergency and follow-up contraception needs

A 27-year-old woman (G0) presents to you after having unprotected intercourse 4 days ago. She does not formally track her menstrual cycles and is unsure when her last menstrual period was. She is not using contraception but is interested in starting a method. After counseling, she elects to take a dose of oral ulipristal acetate (UPA; Ella) now for emergency contraception and would like to start a combined oral contraceptive (COC) pill moving forward.

How soon after taking UPA should you tell her to start the combined hormonal pill?

Effectiveness of hormonal contraception following UPA

UPA does not appear to decrease the efficacy of COCs when started around the same time. However, immediately starting a hormonal contraceptive can decrease the effectiveness of UPA, and as such, it is recommended to take UPA and then abstain or use a backup method for 7 days before initiating a hormonal contraceptive method.¹ By obtaining some additional information from your patient and with the use of shared decision making, though, your patient may be able to start their contraceptive method earlier than 5 days after UPA.

What is UPA

UPA is a progesterone receptor modulator used for emergency contraception intenhded to prevent pregnancy after unprotected intercourse or contraceptive failure.³ It works by delaying follicular rupture at least 5 days, if taken before the peak of the luteinizing hormone (LH) surge. If taken after that timeframe, it does not work. Since UPA competes for the progesterone receptor, there is a concern that the effectiveness of UPA may be decreased if a progestin-containing form of contraception is started immediately after taking UPA, or vice versa.⁴ Several studies have now specifically looked at the interaction between UPA and progestin-containing contraceptives, including at how UPA is impacted by the contraceptive method, and conversely, how the contraceptive method is impacted by UPA.^5-8

Data on types of hormonal contraception. Brache and colleagues demonstrated that UPA users who started a desogestrel progestin-only pill (DSG POP) the next day had higher rates of ovulation within 5 days of taking UPA (45%), compared with those who the next day started a placebo pill (3%).⁶ This type of progestin-only pill is not available in the United States.

A study by Edelman and colleagues demonstrated similar findings in those starting a COC pill containing estrogen and progestin. When taking a COC two days after UPA use, more participants had evidence of follicular rupture in less than 5 days.⁵ It should be noted that these studies focused on ovulation, which—while necessary for conception to occur—is a surrogate biomarker for pregnancy risk. Additional studies have looked at the impact of UPA on the COC and have not found that UPA impacts ovulation suppression of the COC with its initiation or use.⁸

Considering unprotected intercourse and UPA timing. Of course, the risk of pregnancy is reliant on cycle timing plus the presence of viable sperm in the reproductive tract. Sperm have been shown to only be viable in the reproductive tract for 5 days, which could result in fertilization and subsequent pregnancy. Longevity of an egg is much shorter, at 12 to 24 hours after ovulation. For this patient, her exposure was 4 days ago, but sperm are only viable for approximately 5 days—she could consider taking the UPA now and then starting a COC earlier than 5 days since she only needs an extra day or two of protection from the UPA from the sperm in her reproductive tract. Your patient’s involvement in this decision making is paramount, as only they can prioritize their desire to avoid pregnancy from their recent act of unprotected intercourse versus their immediate needs for starting their method of contraception. It is important that individuals abstain from sexual activity or use an additional back-up method during the first 7 days of starting their method of contraception.

Continue to: Counseling considerations for the case patient...

For a patient planning to start or resume a hormonal contraceptive method after taking UPA, the waiting period recommended by the CDC (5 days) is most beneficial for patients who are uncertain about their menstrual cycle timing in relation to the act of unprotected intercourse that already occurred and need to prioritize maximum effectiveness of emergency contraception.

Patients with unsure cycle-sex timing planning to self-start or resume a short-term hormonal contraceptive method (eg, pills, patches, or rings), should be counseled to wait 5 days after the most recent act of unprotected sex, before taking their hormonal contraceptive method.⁷ Patients with unsure cycle-sex timing planning to use provider-dependent hormonal contraceptive methods (eg, those requiring a prescription, including a progestin-contraceptive implant or depot medroxyprogesterone acetate) should also be counseled to wait. Timing of levonorgestrel and copper intrauterine devices are addressed in part 3 of this series.

However, if your patient has a good understanding of their menstrual cycle, and the primary concern is exposure from subsequent sexual encounters and not the recent unprotected intercourse, it is advisable to provide UPA and immediately initiate a contraceptive method. One of the primary reasons for emergency contraception failure is that its effectiveness is limited to the most recent act of unprotected sexual intercourse and does not extend to subsequent acts throughout the month.

For these patients with sure cycle-sex timing who are planning to start or resume short-or long-term contraceptive methods, and whose primary concern is to prevent pregnancy risk from subsequent sexual encounters, immediately initiating a contraceptive method is advisable. For provider-dependent methods, we must weigh the risk of unintended pregnancy from the act of intercourse that already occurred (and the potential to increase that risk by initiating a method that could compromise UPA efficacy) versus the future risk of pregnancy if the patient cannot return for a contraception visit.⁷

In short, starting the contraceptive method at the time of UPA use can be considered after shared decision making with the patient and understanding what their primary concerns are.

Important point

Counsel on using backup barrier contraception after UPA

Oral emergency contraception only covers that one act of unprotected intercourse and does not continue to protect a patient from pregnancy for the rest of their cycle. When taken before ovulation, UPA works by delaying follicular development and rupture for at least 5 days. Patients who continue to have unprotected intercourse after taking UPA are at a high risk of an unintended pregnancy from this ‘stalled’ follicle that will eventually ovulate. Follicular maturation resumes after UPA’s effects wane, and the patient is primed for ovulation (and therefore unintended pregnancy) if ongoing unprotected intercourse occurs for the rest of their cycle.

Therefore, it is important to counsel patients on the need, if they do not desire a pregnancy, to abstain or start a method of contraception.

Final question

What about starting or resuming non–hormonal contraceptive methods?

Non-hormonal contraceptive methods can be started immediately with UPA use.¹

CASE Resolved

After shared decision making, the patient decides to start using the COC pill. You prescribe her both UPA for emergency contraception and a combined hormonal contraceptive pill. Given her unsure cycle-sex timing, she expresses to you that her most important priority is preventing unintended pregnancy. You counsel her to set a reminder on her phone to start taking the pill 5 days from her most recent act of unprotected intercourse. You also counsel her to use a back-up barrier method of contraception for 7 days after starting her COC pill. ●

Individuals spend close to half of their lives preventing, or planning for, pregnancy. As such, contraception plays a major role in patient-provider interactions. Contraception counseling and management is a common scenario encountered in the general gynecologist’s practice. Luckily, we have two evidence-based guidelines developed by the US Centers for Disease Control and Prevention (CDC) that support the provision of contraceptive care:

1. US Medical Eligibility for Contraceptive Use (US-MEC),¹ which provides guidance on which patients can safely use a method
2. US Selected Practice Recommendations for Contraceptive Use (US-SPR),² which provides method-specific guidance on how to use a method (including how to: initiate or start a method; manage adherence issues, such as a missed pill, etc; and manage common issues like breakthrough bleeding). Both of these guidelines are updated routinely and are publicly available online or for free, through smartphone applications.

While most contraceptive care is straightforward, there are circumstances that require additional consideration. In this 3-part series we review 3 clinical cases, existing evidence to guide management decisions, and our recommendations. In part 1, we focus on restarting hormonal contraception after ulipristal acetate administration. In parts 2 and 3, we will discuss removal of a nonpalpable contraceptive implant and the consideration of a levonorgestrel-releasing intrauterine device (LNG-IUD) for emergency contraception.

CASE Meeting emergency and follow-up contraception needs

A 27-year-old woman (G0) presents to you after having unprotected intercourse 4 days ago. She does not formally track her menstrual cycles and is unsure when her last menstrual period was. She is not using contraception but is interested in starting a method. After counseling, she elects to take a dose of oral ulipristal acetate (UPA; Ella) now for emergency contraception and would like to start a combined oral contraceptive (COC) pill moving forward.

How soon after taking UPA should you tell her to start the combined hormonal pill?

Effectiveness of hormonal contraception following UPA

UPA does not appear to decrease the efficacy of COCs when started around the same time. However, immediately starting a hormonal contraceptive can decrease the effectiveness of UPA, and as such, it is recommended to take UPA and then abstain or use a backup method for 7 days before initiating a hormonal contraceptive method.¹ By obtaining some additional information from your patient and with the use of shared decision making, though, your patient may be able to start their contraceptive method earlier than 5 days after UPA.

What is UPA

UPA is a progesterone receptor modulator used for emergency contraception intenhded to prevent pregnancy after unprotected intercourse or contraceptive failure.³ It works by delaying follicular rupture at least 5 days, if taken before the peak of the luteinizing hormone (LH) surge. If taken after that timeframe, it does not work. Since UPA competes for the progesterone receptor, there is a concern that the effectiveness of UPA may be decreased if a progestin-containing form of contraception is started immediately after taking UPA, or vice versa.⁴ Several studies have now specifically looked at the interaction between UPA and progestin-containing contraceptives, including at how UPA is impacted by the contraceptive method, and conversely, how the contraceptive method is impacted by UPA.^5-8

Data on types of hormonal contraception. Brache and colleagues demonstrated that UPA users who started a desogestrel progestin-only pill (DSG POP) the next day had higher rates of ovulation within 5 days of taking UPA (45%), compared with those who the next day started a placebo pill (3%).⁶ This type of progestin-only pill is not available in the United States.

A study by Edelman and colleagues demonstrated similar findings in those starting a COC pill containing estrogen and progestin. When taking a COC two days after UPA use, more participants had evidence of follicular rupture in less than 5 days.⁵ It should be noted that these studies focused on ovulation, which—while necessary for conception to occur—is a surrogate biomarker for pregnancy risk. Additional studies have looked at the impact of UPA on the COC and have not found that UPA impacts ovulation suppression of the COC with its initiation or use.⁸

Considering unprotected intercourse and UPA timing. Of course, the risk of pregnancy is reliant on cycle timing plus the presence of viable sperm in the reproductive tract. Sperm have been shown to only be viable in the reproductive tract for 5 days, which could result in fertilization and subsequent pregnancy. Longevity of an egg is much shorter, at 12 to 24 hours after ovulation. For this patient, her exposure was 4 days ago, but sperm are only viable for approximately 5 days—she could consider taking the UPA now and then starting a COC earlier than 5 days since she only needs an extra day or two of protection from the UPA from the sperm in her reproductive tract. Your patient’s involvement in this decision making is paramount, as only they can prioritize their desire to avoid pregnancy from their recent act of unprotected intercourse versus their immediate needs for starting their method of contraception. It is important that individuals abstain from sexual activity or use an additional back-up method during the first 7 days of starting their method of contraception.

Continue to: Counseling considerations for the case patient...

For a patient planning to start or resume a hormonal contraceptive method after taking UPA, the waiting period recommended by the CDC (5 days) is most beneficial for patients who are uncertain about their menstrual cycle timing in relation to the act of unprotected intercourse that already occurred and need to prioritize maximum effectiveness of emergency contraception.

Patients with unsure cycle-sex timing planning to self-start or resume a short-term hormonal contraceptive method (eg, pills, patches, or rings), should be counseled to wait 5 days after the most recent act of unprotected sex, before taking their hormonal contraceptive method.⁷ Patients with unsure cycle-sex timing planning to use provider-dependent hormonal contraceptive methods (eg, those requiring a prescription, including a progestin-contraceptive implant or depot medroxyprogesterone acetate) should also be counseled to wait. Timing of levonorgestrel and copper intrauterine devices are addressed in part 3 of this series.

However, if your patient has a good understanding of their menstrual cycle, and the primary concern is exposure from subsequent sexual encounters and not the recent unprotected intercourse, it is advisable to provide UPA and immediately initiate a contraceptive method. One of the primary reasons for emergency contraception failure is that its effectiveness is limited to the most recent act of unprotected sexual intercourse and does not extend to subsequent acts throughout the month.

For these patients with sure cycle-sex timing who are planning to start or resume short-or long-term contraceptive methods, and whose primary concern is to prevent pregnancy risk from subsequent sexual encounters, immediately initiating a contraceptive method is advisable. For provider-dependent methods, we must weigh the risk of unintended pregnancy from the act of intercourse that already occurred (and the potential to increase that risk by initiating a method that could compromise UPA efficacy) versus the future risk of pregnancy if the patient cannot return for a contraception visit.⁷

In short, starting the contraceptive method at the time of UPA use can be considered after shared decision making with the patient and understanding what their primary concerns are.

Important point

Counsel on using backup barrier contraception after UPA

Oral emergency contraception only covers that one act of unprotected intercourse and does not continue to protect a patient from pregnancy for the rest of their cycle. When taken before ovulation, UPA works by delaying follicular development and rupture for at least 5 days. Patients who continue to have unprotected intercourse after taking UPA are at a high risk of an unintended pregnancy from this ‘stalled’ follicle that will eventually ovulate. Follicular maturation resumes after UPA’s effects wane, and the patient is primed for ovulation (and therefore unintended pregnancy) if ongoing unprotected intercourse occurs for the rest of their cycle.

Therefore, it is important to counsel patients on the need, if they do not desire a pregnancy, to abstain or start a method of contraception.

Final question

What about starting or resuming non–hormonal contraceptive methods?

Non-hormonal contraceptive methods can be started immediately with UPA use.¹

CASE Resolved

After shared decision making, the patient decides to start using the COC pill. You prescribe her both UPA for emergency contraception and a combined hormonal contraceptive pill. Given her unsure cycle-sex timing, she expresses to you that her most important priority is preventing unintended pregnancy. You counsel her to set a reminder on her phone to start taking the pill 5 days from her most recent act of unprotected intercourse. You also counsel her to use a back-up barrier method of contraception for 7 days after starting her COC pill. ●

Individuals spend close to half of their lives preventing, or planning for, pregnancy. As such, contraception plays a major role in patient-provider interactions. Contraception counseling and management is a common scenario encountered in the general gynecologist’s practice. Luckily, we have two evidence-based guidelines developed by the US Centers for Disease Control and Prevention (CDC) that support the provision of contraceptive care:

1. US Medical Eligibility for Contraceptive Use (US-MEC),¹ which provides guidance on which patients can safely use a method
2. US Selected Practice Recommendations for Contraceptive Use (US-SPR),² which provides method-specific guidance on how to use a method (including how to: initiate or start a method; manage adherence issues, such as a missed pill, etc; and manage common issues like breakthrough bleeding). Both of these guidelines are updated routinely and are publicly available online or for free, through smartphone applications.

While most contraceptive care is straightforward, there are circumstances that require additional consideration. In this 3-part series we review 3 clinical cases, existing evidence to guide management decisions, and our recommendations. In part 1, we focus on restarting hormonal contraception after ulipristal acetate administration. In parts 2 and 3, we will discuss removal of a nonpalpable contraceptive implant and the consideration of a levonorgestrel-releasing intrauterine device (LNG-IUD) for emergency contraception.

CASE Meeting emergency and follow-up contraception needs

A 27-year-old woman (G0) presents to you after having unprotected intercourse 4 days ago. She does not formally track her menstrual cycles and is unsure when her last menstrual period was. She is not using contraception but is interested in starting a method. After counseling, she elects to take a dose of oral ulipristal acetate (UPA; Ella) now for emergency contraception and would like to start a combined oral contraceptive (COC) pill moving forward.

How soon after taking UPA should you tell her to start the combined hormonal pill?

Effectiveness of hormonal contraception following UPA

UPA does not appear to decrease the efficacy of COCs when started around the same time. However, immediately starting a hormonal contraceptive can decrease the effectiveness of UPA, and as such, it is recommended to take UPA and then abstain or use a backup method for 7 days before initiating a hormonal contraceptive method.¹ By obtaining some additional information from your patient and with the use of shared decision making, though, your patient may be able to start their contraceptive method earlier than 5 days after UPA.

What is UPA

UPA is a progesterone receptor modulator used for emergency contraception intenhded to prevent pregnancy after unprotected intercourse or contraceptive failure.³ It works by delaying follicular rupture at least 5 days, if taken before the peak of the luteinizing hormone (LH) surge. If taken after that timeframe, it does not work. Since UPA competes for the progesterone receptor, there is a concern that the effectiveness of UPA may be decreased if a progestin-containing form of contraception is started immediately after taking UPA, or vice versa.⁴ Several studies have now specifically looked at the interaction between UPA and progestin-containing contraceptives, including at how UPA is impacted by the contraceptive method, and conversely, how the contraceptive method is impacted by UPA.^5-8

Data on types of hormonal contraception. Brache and colleagues demonstrated that UPA users who started a desogestrel progestin-only pill (DSG POP) the next day had higher rates of ovulation within 5 days of taking UPA (45%), compared with those who the next day started a placebo pill (3%).⁶ This type of progestin-only pill is not available in the United States.

A study by Edelman and colleagues demonstrated similar findings in those starting a COC pill containing estrogen and progestin. When taking a COC two days after UPA use, more participants had evidence of follicular rupture in less than 5 days.⁵ It should be noted that these studies focused on ovulation, which—while necessary for conception to occur—is a surrogate biomarker for pregnancy risk. Additional studies have looked at the impact of UPA on the COC and have not found that UPA impacts ovulation suppression of the COC with its initiation or use.⁸

Considering unprotected intercourse and UPA timing. Of course, the risk of pregnancy is reliant on cycle timing plus the presence of viable sperm in the reproductive tract. Sperm have been shown to only be viable in the reproductive tract for 5 days, which could result in fertilization and subsequent pregnancy. Longevity of an egg is much shorter, at 12 to 24 hours after ovulation. For this patient, her exposure was 4 days ago, but sperm are only viable for approximately 5 days—she could consider taking the UPA now and then starting a COC earlier than 5 days since she only needs an extra day or two of protection from the UPA from the sperm in her reproductive tract. Your patient’s involvement in this decision making is paramount, as only they can prioritize their desire to avoid pregnancy from their recent act of unprotected intercourse versus their immediate needs for starting their method of contraception. It is important that individuals abstain from sexual activity or use an additional back-up method during the first 7 days of starting their method of contraception.

Continue to: Counseling considerations for the case patient...

For a patient planning to start or resume a hormonal contraceptive method after taking UPA, the waiting period recommended by the CDC (5 days) is most beneficial for patients who are uncertain about their menstrual cycle timing in relation to the act of unprotected intercourse that already occurred and need to prioritize maximum effectiveness of emergency contraception.

Patients with unsure cycle-sex timing planning to self-start or resume a short-term hormonal contraceptive method (eg, pills, patches, or rings), should be counseled to wait 5 days after the most recent act of unprotected sex, before taking their hormonal contraceptive method.⁷ Patients with unsure cycle-sex timing planning to use provider-dependent hormonal contraceptive methods (eg, those requiring a prescription, including a progestin-contraceptive implant or depot medroxyprogesterone acetate) should also be counseled to wait. Timing of levonorgestrel and copper intrauterine devices are addressed in part 3 of this series.

However, if your patient has a good understanding of their menstrual cycle, and the primary concern is exposure from subsequent sexual encounters and not the recent unprotected intercourse, it is advisable to provide UPA and immediately initiate a contraceptive method. One of the primary reasons for emergency contraception failure is that its effectiveness is limited to the most recent act of unprotected sexual intercourse and does not extend to subsequent acts throughout the month.

For these patients with sure cycle-sex timing who are planning to start or resume short-or long-term contraceptive methods, and whose primary concern is to prevent pregnancy risk from subsequent sexual encounters, immediately initiating a contraceptive method is advisable. For provider-dependent methods, we must weigh the risk of unintended pregnancy from the act of intercourse that already occurred (and the potential to increase that risk by initiating a method that could compromise UPA efficacy) versus the future risk of pregnancy if the patient cannot return for a contraception visit.⁷

In short, starting the contraceptive method at the time of UPA use can be considered after shared decision making with the patient and understanding what their primary concerns are.

Important point

Counsel on using backup barrier contraception after UPA

Oral emergency contraception only covers that one act of unprotected intercourse and does not continue to protect a patient from pregnancy for the rest of their cycle. When taken before ovulation, UPA works by delaying follicular development and rupture for at least 5 days. Patients who continue to have unprotected intercourse after taking UPA are at a high risk of an unintended pregnancy from this ‘stalled’ follicle that will eventually ovulate. Follicular maturation resumes after UPA’s effects wane, and the patient is primed for ovulation (and therefore unintended pregnancy) if ongoing unprotected intercourse occurs for the rest of their cycle.

Therefore, it is important to counsel patients on the need, if they do not desire a pregnancy, to abstain or start a method of contraception.

Final question

What about starting or resuming non–hormonal contraceptive methods?

Non-hormonal contraceptive methods can be started immediately with UPA use.¹

CASE Resolved

After shared decision making, the patient decides to start using the COC pill. You prescribe her both UPA for emergency contraception and a combined hormonal contraceptive pill. Given her unsure cycle-sex timing, she expresses to you that her most important priority is preventing unintended pregnancy. You counsel her to set a reminder on her phone to start taking the pill 5 days from her most recent act of unprotected intercourse. You also counsel her to use a back-up barrier method of contraception for 7 days after starting her COC pill. ●

CASE Pregnant woman asks about the RSV vaccine

A 28-year-old primigravid woman at 30 weeks’ gestation inquires about the new vaccine to protect her newborn baby against respiratory syncytial virus infection (RSV). Her neighbor’s daughter recently was hospitalized for the treatment of RSV, and she is understandably concerned about her own newborn. The patient is healthy, and she has never had any serious respiratory infection. She is taking no medications other than prenatal vitamins.

What advice should you give her? 

If you decide to administer this vaccine, what is the appropriate timing of administration?

Are there any maternal or fetal safety concerns related to use of this vaccine in pregnancy?
 

Respiratory syncytial virus (RSV) is a member of the Paramyxoviridae family. It is an enveloped, single-stranded RNA virus that is 150-300 nm in size. The virus codes for 10 virus-specific proteins. The 2 most important are the G protein, which enables the virus to attach to host cells, and the F protein, which facilitates the entry of the virus into the host cell by fusing the host and viral membranes. Two distinct subtypes exist: A and B. There is genetic variation within each subtype and between subtypes. These subtle genetic variations create the potential for reinfections, and hence, research has focused on development of a vaccine that covers both subtypes.¹

RSV is the most common cause of acute lower respiratory tract infection in infants younger than 6 months of age. In these children, RSV is one of the most prominent causes of death, with mortality particularly marked in low- and middle-resource countries as well as in children who were born premature and/or who are immunocompromised. RSV has its greatest impact during winter epidemics in temperate climates and during the rainy seasons in tropical climates. The virus rarely is encountered in the summer.¹ Among young children, RSV primarily is transmitted via close contact with contaminated fingers or fomites and by self-inoculation of the conjunctiva or anterior nares. The incubation period of the infection is 4 to 6 days, and viral shedding may persist for 2 weeks or longer. Most patients gradually recover within 1 to 2 weeks.¹ Adults who contract RSV usually have symptoms suggestive of a common cold; however, in older adults or those who have comorbidities, serious and potentially life-threatening lower respiratory tract infections may develop.

Recently, there have been 2 main approaches to the prevention and treatment of RSV in infants. One has been the development of monoclonal antibodies such as motavizumab, palivizumab, and nirsevimab. The other has been the development of a vaccine that could be administered to pregnant women and which could provide protection for the neonate in the early months of life.^2,3

In late August 2023, the US Food and Drug Administration (FDA) announced the approval of a new bivalent RSV prefusion F vaccine (ABRYSVO, Pfizer) intended for administration to pregnant women.⁴ Of note, previous efforts to develop whole-virus vaccines either have been ineffective or have potentiated the disease in infants who became infected; development of an effective vaccine had eluded scientists and clinicians for nearly 50 years.² Thus, the new vaccine that targets the F protein of the virus represents a major and welcomed breakthrough.

This article reviews the 3 most recent investigations that preceded the ultimate approval of this vaccine and discusses specific logistical issues related to vaccine administration.

Continue to: First step toward vaccine approval...

First step toward vaccine approval

Madhi and colleagues⁵ were among the first to conduct a large well-designed study to evaluate the effectiveness of maternal vaccination in preventing neonatal infection in the first few months of life. The authors enrolled more than 4,500 healthy pregnant women at 28 to 36 weeks of gestation and assigned them to receive either a single intramuscular dose of an RSV fusion (F) protein vaccine or placebo in a ratio of 2:1. The primary end point was a “medically significant lower respiratory tract infection” within the first 90 days of life. The percentage of infants who met the primary end point was low in both groups: 1.5% in the vaccine group and 2.4% in the placebo group (efficacy 39.4%). The efficacy of the vaccine in preventing lower respiratory tract infection with severe hypoxemia was 48.3% and 44.4% in preventing hospitalization. Although there were differences between the 2 groups, they did not meet the prespecified success criterion for efficacy. Vaccine recipients had more local injection site reactions (40.7% vs 9.9%); however, there was no difference in the frequency of other adverse effects.

Intermediate step: Continued assessment of vaccine safety and immunogenicity

The next important step in the development of the RSV vaccine was a study by Simoes et al,⁶ who conducted a phase 2b trial to determine the safety and immunogenicity of the RSVpreF vaccine. The authors randomly assigned pregnant women at 24 to 36 weeks of gestation to receive either 120 or 240 µg of RSVpreF vaccine or placebo. The key endpoints were the following: maternal and infant safety; the maternal-to-infant transplacental transfer ratio; and the presence of RSV A, B, and combined A/B neutralizing antibody in maternal serum and umbilical cord blood at delivery. The authors conducted a planned interim analysis that included 327 mothers who received the vaccine. The incidence of adverse effects was similar in mothers and infants in the vaccine compared with the placebo group. None of the adverse effects were judged to be serious. The transplacental neutralizing antibody transfer ratios ranged from 1.4 to 2.1 across a range of gestational ages. The vaccine elicited meaningful neutralizing titers of antibody in maternal serum even up to 7 weeks after immunization. The levels of neutralizing antibodies in umbilical cord blood did not vary substantially with respect to gestational age. A post hoc analysis showed that the transferred antibodies prevented medically-attended RSV-associated lower respiratory tract illnesses in the infants.

Final step: Convincing proof of efficacy

The most recent of the 3 studies, and the one that had the greatest impact in convincing the FDA to approve the vaccine, was the report by Kampmann and colleagues.⁷ The authors conducted a phase 3 prospective, randomized, double-blind trial in 18 different countries over 4 RSV seasons: 2 in the northern hemisphere and 2 in the southern hemisphere. They enrolled healthy pregnant women with singleton gestations at 24 to 36 weeks of gestation and assigned them in a 1:1 ratio to a single intramuscular injection of 120 µg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. They excluded patients with any recognized risk factor for an adverse pregnancy outcome, including preterm labor. The 2 primary efficacy endpoints were a medically-attended severe RSV–lower respiratory tract infection and any medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth.

The efficacy of the vaccine in preventing severe lower respiratory tract illness within 90 days of delivery was 81.8% (99.5% confidence interval [CI], 40.6–96.3). The efficacy within 180 days of delivery was 69.4% (97.58% CI, 44.3–84.1). These differences reached the study’s pre-established statistical criteria for success. The overall rate of lower respiratory tract infections was not significantly different. The frequencies of adverse effects in mothers and infants were similar in the vaccine and placebo groups. In particular, the frequency of preterm delivery in the vaccine group was 0.8%, compared with 0.6% in the placebo group (P = NS).

In previous reports to the FDA,⁴ the frequency rate of preterm delivery in RSV vaccine recipients was slightly increased in vaccine recipients compared with patients who received placebo. The difference among the groups was too small to infer a causal relationship; however, as a condition of vaccine approval, the FDA has required Pfizer to conduct a postmarketing study to be certain that administration of the vaccine does not increase the risk for preterm delivery.

Practical details

The new vaccine is a bivalent recombinant vaccine that elicits a robust antibody response against the F (fusion) protein of the virus. In addition to the F antigen, the vaccine contains the following buffer ingredients: tromethamine, sucrose, mannitol, polysorbate, and sodium chloride.⁸ There are no preservatives in the vaccine.

The vaccine should be administered in a single, 0.5 mL, intramuscular injection at 32 to 36 weeks of gestation. Patients who are allergic to any of the components of the vaccine should not be vaccinated. Patients with a mild upper respiratory tract infection may receive the vaccine. Administration should be delayed in patients who are moderately to severely ill. The vaccine may be administered at the same time as other vaccines, such as influenza or Tdap.

The most common side effects of the vaccine are local injection site reactions, such as pain, redness, or swelling. Some patients may experience mild systemic manifestations, including fatigue, fever, headache, nausea, diarrhea, arthralgias, and myalgias. According to the Centers for Disease Control and Prevention, the approximate wholesale acquisition cost of the vaccine is $320 for 1 injection.

CASE Resolution

This patient is healthy and has no contraindication to the new RSV vaccine. According to the FDA, the optimal time for administration of the vaccine is 32 to 36 weeks of gestation. The patient should anticipate very few side effects following the vaccination, and the vaccine has approximately 80% efficacy in preventing severe lower respiratory tract infection in her neonate. ●

CASE Pregnant woman asks about the RSV vaccine

A 28-year-old primigravid woman at 30 weeks’ gestation inquires about the new vaccine to protect her newborn baby against respiratory syncytial virus infection (RSV). Her neighbor’s daughter recently was hospitalized for the treatment of RSV, and she is understandably concerned about her own newborn. The patient is healthy, and she has never had any serious respiratory infection. She is taking no medications other than prenatal vitamins.

What advice should you give her? 

If you decide to administer this vaccine, what is the appropriate timing of administration?

Are there any maternal or fetal safety concerns related to use of this vaccine in pregnancy?
 

Respiratory syncytial virus (RSV) is a member of the Paramyxoviridae family. It is an enveloped, single-stranded RNA virus that is 150-300 nm in size. The virus codes for 10 virus-specific proteins. The 2 most important are the G protein, which enables the virus to attach to host cells, and the F protein, which facilitates the entry of the virus into the host cell by fusing the host and viral membranes. Two distinct subtypes exist: A and B. There is genetic variation within each subtype and between subtypes. These subtle genetic variations create the potential for reinfections, and hence, research has focused on development of a vaccine that covers both subtypes.¹

RSV is the most common cause of acute lower respiratory tract infection in infants younger than 6 months of age. In these children, RSV is one of the most prominent causes of death, with mortality particularly marked in low- and middle-resource countries as well as in children who were born premature and/or who are immunocompromised. RSV has its greatest impact during winter epidemics in temperate climates and during the rainy seasons in tropical climates. The virus rarely is encountered in the summer.¹ Among young children, RSV primarily is transmitted via close contact with contaminated fingers or fomites and by self-inoculation of the conjunctiva or anterior nares. The incubation period of the infection is 4 to 6 days, and viral shedding may persist for 2 weeks or longer. Most patients gradually recover within 1 to 2 weeks.¹ Adults who contract RSV usually have symptoms suggestive of a common cold; however, in older adults or those who have comorbidities, serious and potentially life-threatening lower respiratory tract infections may develop.

Recently, there have been 2 main approaches to the prevention and treatment of RSV in infants. One has been the development of monoclonal antibodies such as motavizumab, palivizumab, and nirsevimab. The other has been the development of a vaccine that could be administered to pregnant women and which could provide protection for the neonate in the early months of life.^2,3

In late August 2023, the US Food and Drug Administration (FDA) announced the approval of a new bivalent RSV prefusion F vaccine (ABRYSVO, Pfizer) intended for administration to pregnant women.⁴ Of note, previous efforts to develop whole-virus vaccines either have been ineffective or have potentiated the disease in infants who became infected; development of an effective vaccine had eluded scientists and clinicians for nearly 50 years.² Thus, the new vaccine that targets the F protein of the virus represents a major and welcomed breakthrough.

This article reviews the 3 most recent investigations that preceded the ultimate approval of this vaccine and discusses specific logistical issues related to vaccine administration.

Continue to: First step toward vaccine approval...

First step toward vaccine approval

Madhi and colleagues⁵ were among the first to conduct a large well-designed study to evaluate the effectiveness of maternal vaccination in preventing neonatal infection in the first few months of life. The authors enrolled more than 4,500 healthy pregnant women at 28 to 36 weeks of gestation and assigned them to receive either a single intramuscular dose of an RSV fusion (F) protein vaccine or placebo in a ratio of 2:1. The primary end point was a “medically significant lower respiratory tract infection” within the first 90 days of life. The percentage of infants who met the primary end point was low in both groups: 1.5% in the vaccine group and 2.4% in the placebo group (efficacy 39.4%). The efficacy of the vaccine in preventing lower respiratory tract infection with severe hypoxemia was 48.3% and 44.4% in preventing hospitalization. Although there were differences between the 2 groups, they did not meet the prespecified success criterion for efficacy. Vaccine recipients had more local injection site reactions (40.7% vs 9.9%); however, there was no difference in the frequency of other adverse effects.

Intermediate step: Continued assessment of vaccine safety and immunogenicity

The next important step in the development of the RSV vaccine was a study by Simoes et al,⁶ who conducted a phase 2b trial to determine the safety and immunogenicity of the RSVpreF vaccine. The authors randomly assigned pregnant women at 24 to 36 weeks of gestation to receive either 120 or 240 µg of RSVpreF vaccine or placebo. The key endpoints were the following: maternal and infant safety; the maternal-to-infant transplacental transfer ratio; and the presence of RSV A, B, and combined A/B neutralizing antibody in maternal serum and umbilical cord blood at delivery. The authors conducted a planned interim analysis that included 327 mothers who received the vaccine. The incidence of adverse effects was similar in mothers and infants in the vaccine compared with the placebo group. None of the adverse effects were judged to be serious. The transplacental neutralizing antibody transfer ratios ranged from 1.4 to 2.1 across a range of gestational ages. The vaccine elicited meaningful neutralizing titers of antibody in maternal serum even up to 7 weeks after immunization. The levels of neutralizing antibodies in umbilical cord blood did not vary substantially with respect to gestational age. A post hoc analysis showed that the transferred antibodies prevented medically-attended RSV-associated lower respiratory tract illnesses in the infants.

Final step: Convincing proof of efficacy

The most recent of the 3 studies, and the one that had the greatest impact in convincing the FDA to approve the vaccine, was the report by Kampmann and colleagues.⁷ The authors conducted a phase 3 prospective, randomized, double-blind trial in 18 different countries over 4 RSV seasons: 2 in the northern hemisphere and 2 in the southern hemisphere. They enrolled healthy pregnant women with singleton gestations at 24 to 36 weeks of gestation and assigned them in a 1:1 ratio to a single intramuscular injection of 120 µg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. They excluded patients with any recognized risk factor for an adverse pregnancy outcome, including preterm labor. The 2 primary efficacy endpoints were a medically-attended severe RSV–lower respiratory tract infection and any medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth.

The efficacy of the vaccine in preventing severe lower respiratory tract illness within 90 days of delivery was 81.8% (99.5% confidence interval [CI], 40.6–96.3). The efficacy within 180 days of delivery was 69.4% (97.58% CI, 44.3–84.1). These differences reached the study’s pre-established statistical criteria for success. The overall rate of lower respiratory tract infections was not significantly different. The frequencies of adverse effects in mothers and infants were similar in the vaccine and placebo groups. In particular, the frequency of preterm delivery in the vaccine group was 0.8%, compared with 0.6% in the placebo group (P = NS).

In previous reports to the FDA,⁴ the frequency rate of preterm delivery in RSV vaccine recipients was slightly increased in vaccine recipients compared with patients who received placebo. The difference among the groups was too small to infer a causal relationship; however, as a condition of vaccine approval, the FDA has required Pfizer to conduct a postmarketing study to be certain that administration of the vaccine does not increase the risk for preterm delivery.

Practical details

The new vaccine is a bivalent recombinant vaccine that elicits a robust antibody response against the F (fusion) protein of the virus. In addition to the F antigen, the vaccine contains the following buffer ingredients: tromethamine, sucrose, mannitol, polysorbate, and sodium chloride.⁸ There are no preservatives in the vaccine.

The vaccine should be administered in a single, 0.5 mL, intramuscular injection at 32 to 36 weeks of gestation. Patients who are allergic to any of the components of the vaccine should not be vaccinated. Patients with a mild upper respiratory tract infection may receive the vaccine. Administration should be delayed in patients who are moderately to severely ill. The vaccine may be administered at the same time as other vaccines, such as influenza or Tdap.

The most common side effects of the vaccine are local injection site reactions, such as pain, redness, or swelling. Some patients may experience mild systemic manifestations, including fatigue, fever, headache, nausea, diarrhea, arthralgias, and myalgias. According to the Centers for Disease Control and Prevention, the approximate wholesale acquisition cost of the vaccine is $320 for 1 injection.

CASE Resolution

This patient is healthy and has no contraindication to the new RSV vaccine. According to the FDA, the optimal time for administration of the vaccine is 32 to 36 weeks of gestation. The patient should anticipate very few side effects following the vaccination, and the vaccine has approximately 80% efficacy in preventing severe lower respiratory tract infection in her neonate. ●

CASE Pregnant woman asks about the RSV vaccine

A 28-year-old primigravid woman at 30 weeks’ gestation inquires about the new vaccine to protect her newborn baby against respiratory syncytial virus infection (RSV). Her neighbor’s daughter recently was hospitalized for the treatment of RSV, and she is understandably concerned about her own newborn. The patient is healthy, and she has never had any serious respiratory infection. She is taking no medications other than prenatal vitamins.

What advice should you give her? 

If you decide to administer this vaccine, what is the appropriate timing of administration?

Are there any maternal or fetal safety concerns related to use of this vaccine in pregnancy?
 

Respiratory syncytial virus (RSV) is a member of the Paramyxoviridae family. It is an enveloped, single-stranded RNA virus that is 150-300 nm in size. The virus codes for 10 virus-specific proteins. The 2 most important are the G protein, which enables the virus to attach to host cells, and the F protein, which facilitates the entry of the virus into the host cell by fusing the host and viral membranes. Two distinct subtypes exist: A and B. There is genetic variation within each subtype and between subtypes. These subtle genetic variations create the potential for reinfections, and hence, research has focused on development of a vaccine that covers both subtypes.¹

RSV is the most common cause of acute lower respiratory tract infection in infants younger than 6 months of age. In these children, RSV is one of the most prominent causes of death, with mortality particularly marked in low- and middle-resource countries as well as in children who were born premature and/or who are immunocompromised. RSV has its greatest impact during winter epidemics in temperate climates and during the rainy seasons in tropical climates. The virus rarely is encountered in the summer.¹ Among young children, RSV primarily is transmitted via close contact with contaminated fingers or fomites and by self-inoculation of the conjunctiva or anterior nares. The incubation period of the infection is 4 to 6 days, and viral shedding may persist for 2 weeks or longer. Most patients gradually recover within 1 to 2 weeks.¹ Adults who contract RSV usually have symptoms suggestive of a common cold; however, in older adults or those who have comorbidities, serious and potentially life-threatening lower respiratory tract infections may develop.

Recently, there have been 2 main approaches to the prevention and treatment of RSV in infants. One has been the development of monoclonal antibodies such as motavizumab, palivizumab, and nirsevimab. The other has been the development of a vaccine that could be administered to pregnant women and which could provide protection for the neonate in the early months of life.^2,3

In late August 2023, the US Food and Drug Administration (FDA) announced the approval of a new bivalent RSV prefusion F vaccine (ABRYSVO, Pfizer) intended for administration to pregnant women.⁴ Of note, previous efforts to develop whole-virus vaccines either have been ineffective or have potentiated the disease in infants who became infected; development of an effective vaccine had eluded scientists and clinicians for nearly 50 years.² Thus, the new vaccine that targets the F protein of the virus represents a major and welcomed breakthrough.

This article reviews the 3 most recent investigations that preceded the ultimate approval of this vaccine and discusses specific logistical issues related to vaccine administration.

Continue to: First step toward vaccine approval...

First step toward vaccine approval

Madhi and colleagues⁵ were among the first to conduct a large well-designed study to evaluate the effectiveness of maternal vaccination in preventing neonatal infection in the first few months of life. The authors enrolled more than 4,500 healthy pregnant women at 28 to 36 weeks of gestation and assigned them to receive either a single intramuscular dose of an RSV fusion (F) protein vaccine or placebo in a ratio of 2:1. The primary end point was a “medically significant lower respiratory tract infection” within the first 90 days of life. The percentage of infants who met the primary end point was low in both groups: 1.5% in the vaccine group and 2.4% in the placebo group (efficacy 39.4%). The efficacy of the vaccine in preventing lower respiratory tract infection with severe hypoxemia was 48.3% and 44.4% in preventing hospitalization. Although there were differences between the 2 groups, they did not meet the prespecified success criterion for efficacy. Vaccine recipients had more local injection site reactions (40.7% vs 9.9%); however, there was no difference in the frequency of other adverse effects.

Intermediate step: Continued assessment of vaccine safety and immunogenicity

The next important step in the development of the RSV vaccine was a study by Simoes et al,⁶ who conducted a phase 2b trial to determine the safety and immunogenicity of the RSVpreF vaccine. The authors randomly assigned pregnant women at 24 to 36 weeks of gestation to receive either 120 or 240 µg of RSVpreF vaccine or placebo. The key endpoints were the following: maternal and infant safety; the maternal-to-infant transplacental transfer ratio; and the presence of RSV A, B, and combined A/B neutralizing antibody in maternal serum and umbilical cord blood at delivery. The authors conducted a planned interim analysis that included 327 mothers who received the vaccine. The incidence of adverse effects was similar in mothers and infants in the vaccine compared with the placebo group. None of the adverse effects were judged to be serious. The transplacental neutralizing antibody transfer ratios ranged from 1.4 to 2.1 across a range of gestational ages. The vaccine elicited meaningful neutralizing titers of antibody in maternal serum even up to 7 weeks after immunization. The levels of neutralizing antibodies in umbilical cord blood did not vary substantially with respect to gestational age. A post hoc analysis showed that the transferred antibodies prevented medically-attended RSV-associated lower respiratory tract illnesses in the infants.

Final step: Convincing proof of efficacy

The most recent of the 3 studies, and the one that had the greatest impact in convincing the FDA to approve the vaccine, was the report by Kampmann and colleagues.⁷ The authors conducted a phase 3 prospective, randomized, double-blind trial in 18 different countries over 4 RSV seasons: 2 in the northern hemisphere and 2 in the southern hemisphere. They enrolled healthy pregnant women with singleton gestations at 24 to 36 weeks of gestation and assigned them in a 1:1 ratio to a single intramuscular injection of 120 µg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. They excluded patients with any recognized risk factor for an adverse pregnancy outcome, including preterm labor. The 2 primary efficacy endpoints were a medically-attended severe RSV–lower respiratory tract infection and any medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth.

The efficacy of the vaccine in preventing severe lower respiratory tract illness within 90 days of delivery was 81.8% (99.5% confidence interval [CI], 40.6–96.3). The efficacy within 180 days of delivery was 69.4% (97.58% CI, 44.3–84.1). These differences reached the study’s pre-established statistical criteria for success. The overall rate of lower respiratory tract infections was not significantly different. The frequencies of adverse effects in mothers and infants were similar in the vaccine and placebo groups. In particular, the frequency of preterm delivery in the vaccine group was 0.8%, compared with 0.6% in the placebo group (P = NS).

In previous reports to the FDA,⁴ the frequency rate of preterm delivery in RSV vaccine recipients was slightly increased in vaccine recipients compared with patients who received placebo. The difference among the groups was too small to infer a causal relationship; however, as a condition of vaccine approval, the FDA has required Pfizer to conduct a postmarketing study to be certain that administration of the vaccine does not increase the risk for preterm delivery.

Practical details

The new vaccine is a bivalent recombinant vaccine that elicits a robust antibody response against the F (fusion) protein of the virus. In addition to the F antigen, the vaccine contains the following buffer ingredients: tromethamine, sucrose, mannitol, polysorbate, and sodium chloride.⁸ There are no preservatives in the vaccine.

The vaccine should be administered in a single, 0.5 mL, intramuscular injection at 32 to 36 weeks of gestation. Patients who are allergic to any of the components of the vaccine should not be vaccinated. Patients with a mild upper respiratory tract infection may receive the vaccine. Administration should be delayed in patients who are moderately to severely ill. The vaccine may be administered at the same time as other vaccines, such as influenza or Tdap.

The most common side effects of the vaccine are local injection site reactions, such as pain, redness, or swelling. Some patients may experience mild systemic manifestations, including fatigue, fever, headache, nausea, diarrhea, arthralgias, and myalgias. According to the Centers for Disease Control and Prevention, the approximate wholesale acquisition cost of the vaccine is $320 for 1 injection.

CASE Resolution

This patient is healthy and has no contraindication to the new RSV vaccine. According to the FDA, the optimal time for administration of the vaccine is 32 to 36 weeks of gestation. The patient should anticipate very few side effects following the vaccination, and the vaccine has approximately 80% efficacy in preventing severe lower respiratory tract infection in her neonate. ●

Essential oils (EOs), which are concentrated plant-based oils, have become ubiquitous over the past decade. ­Given the far reach of EOs and their longtime use in traditional, complementary, alternative, and integrative medicine, it is imperative that clinicians have some knowledge of the potential benefits, risks, and overall efficacy.

Commonly used for aromatic benefits (aromatherapy), EOs are now also incorporated into a multitude of products promoting health and wellness. EOs are sold as individual products and can be a component in consumer goods such as cosmetics, body care/hygiene/beauty products, laundry detergents, insect repellents, over-the-counter medications, and food.

It is important to read ingredient labels before purchasing an essential oil. Reputable companies will identify the plant ingredient, usually by the formal Latin binomial name, and explain the extraction process.

The review that follows presents the most current evidence available. With that said, it’s important to keep in mind some caveats that relate to this evidence. First, the studies cited tend to have a small sample size. Second, a majority of these studies were conducted in countries where there appears to be a significant culture of EO use, which could contribute to confirmation bias. Finally, in a number of the studies, there is concern for publication bias as well as a discrepancy between calculated statistical significance and actual clinical relevance.

What are essential oils?

EOs generally are made by extracting the oil from leaves, bark, flowers, seeds/fruit, rinds, and/or roots by steaming or pressing parts of a plant. It can take several pounds of plant material to produce a single bottle of EO, which usually contains ≥ 15 to 30 mL (.5 to 1 oz).¹

Some commonly used EOs in the United States are lavender, peppermint, rose, clary sage, tea tree, eucalyptus, and citrus; however, there are approximately 300 EOs available.² EOs are used most often via topical application, inhalation, or ingestion.

As with any botanical agent, EOs are complex substances often containing a multitude of chemical compounds.¹ Because of the complex makeup of EOs, which often contain up to 100 volatile organic compounds, and their wide-ranging potential effects, applying the scientific method to study effectiveness poses a challenge that has limited their adoption in evidence-based practice.²

Availability and cost. EOs can be purchased at large retailers (eg, grocery stores, drug stores) and smaller health food stores, as well as on the Internet. Various EO vehicles, such as inhalers and topical creams, also can be purchased at these stores.

Continue to: The cost varies...

The cost varies enormously by manufacturer and type of plant used to make the EO. Common EOs such as peppermint and lavender oil generally cost $10 to $25, while rarer plant oils can cost $80 or more per bottle.

How safe are essential oils?

Patients may assume EOs are harmless because they are derived from natural plants and have been used medicinally for centuries. However, care must be taken with their use.

The safest way to use EOs is topically, although due to their highly concentrated nature, EOs should be diluted in an unscented neutral carrier oil such as coconut, jojoba, olive, or sweet almond.³ Ingestion of certain oils can cause hepatotoxicity, seizures, and even death.³ In fact, patients should speak with a knowledgeable physician before purchasing any oral EO capsules.

Whether used topically or ingested, all EOs carry risk for skin irritation and allergic reactions, and oral ingestion may result in some negative gastrointestinal (GI) adverse effects.⁴ A case report of 3 patients published in 2007 identified the potential for lavender and tea tree EOs to be endocrine disruptors.⁵

Inhalation of EOs may be harmful, as they emit many volatile organic compounds, some of which are considered potentially hazardous.⁶ At this time, there is insufficient evidence regarding inhaled EOs and their direct connection to respiratory health. It is reasonable to suggest, however, that the prolonged use of EOs and their use by patients who have lung conditions such as asthma or COPD should be avoided.⁷

Continue to: How are quality and purity assessed?

How are quality and purity assessed?

Like other dietary supplements, EOs are not regulated. No US regulatory agencies (eg, the US Food and Drug Administration [FDA] or Department of Agriculture [USDA]) certify or approve EOs for quality and purity. Bottles labeled with “QAI” for Quality Assurance International or “USDA Organic” will ensure the plant constituents used in the EO are from organic farming but do not attest to quality or purity.

Essential oils are one of the nonpharmacologic modalities that patients and clinicians have at their disposal for adjunctive treatment of migraine and tension-type headaches.

Manufacturers commonly use marketing terms such as “therapeutic grade” or “pure” to sell products, but again, these terms do not reflect the product’s quality or purity. A labeled single EO may contain contaminants, alcohol, or additional ingredients.⁷ When choosing to use EOs, identifying reputable brands is essential; one resource is the independent testing organization ConsumerLab.com.

It is important to assess the manufacturer and read ingredient labels before purchasing an EO to understand what the product contains. Reputable companies will identify the plant ingredient, usually by the formal Latin binomial name, and explain the extraction process. A more certain way to assess the quality and purity of an EO is to ask the manufacturer to provide a certificate of analysis and gas chromatography/mass spectroscopy (GC/MS) data for the specific product. Some manufacturers offer GC/MS test results on their website Quality page.⁸ Others have detailed information on quality and testing, and GC/MS test reports can be obtained.⁹ Yet another manufacturer has test results on a product page matching reports to batch codes.¹⁰

Which conditions have evidence of benefit from essential oils?

EOs currently are being studied for treatment of many conditions—including pain, GI disorders, behavioral health disorders, and women’s health issues. The TABLE summarizes the conditions treated, outcomes, and practical applications of EOs.^11-44

Pain

Headache. As an adjunct to available medications and procedures for headache treatment, EOs are one of the nonpharmacologic modalities that patients and clinicians have at their disposal for both migraine and ­tension-type headaches. A systematic review of 19 randomized controlled trials (RCTs) examining the effects of herbal ingredients for the acute treatment or prophylaxis of migraines found certain topically applied or inhaled EOs, such as peppermint and chamomile, to be effective for migraine pain alleviation; however, topically applied rose oil was not effective.^11-13 Note: “topical application” in these studies implies application of the EO to ≥ 1 of the following areas: temples, forehead, behind ears, or above upper lip/below the nose.

Continue to: One RCT with 120 patients...

One RCT with 120 patients evaluated diluted intranasal peppermint oil and found that it reduced migraine intensity at similar rates to intranasal lidocaine.¹³ In this study, patients were randomized to receive one of the following: 4% lidocaine, 1.5% peppermint EO, or placebo. Two drops of the intranasal intervention were self-administered while the patient was in a supine position with their head suspended off the edge of the surface on which they were lying. They were instructed to stay in this position for at least 30 seconds after administration.

With regard to tension headache treatment, there is limited literature on the use of EOs. One study found that a preparation of peppermint oil applied topically to the temples and forehead of study participants resulted in significant analgesic effect.¹⁴

Fibromyalgia. Usual treatments for fibromyalgia include exercise, antidepressant and anticonvulsant medications, and stress management. Evidence also supports the use of inhaled and topically applied (with and without massage) lavender oil to improve symptoms.²⁶ Positive effects may be related to the anal­gesic, anti-­inflammatory, sleep-regulating,­ and anxiety­-reducing effects of the major volatile compounds contained in lavender oil.

In one RCT with 42 patients with fibromyalgia, the use of inhaled lavender oil was shown to increase the perception of well-­being (assessed on the validated SF-36 Health Survey Questionnaire) after 4 weeks.²⁷ In this study, the patient applied 3 drops of an oil mixture, comprising 1 mL lavender EO and 10 mL of fixed neutral base oil, to the wrist and inhaled for 10 minutes before going to bed.

The use of a topical oil blend labeled “Oil 24” (containing camphor, rosemary, eucalyptus, peppermint, aloe vera, and lemon/orange) also has been shown to be more effective than placebo in managing fibromyalgia symptoms. A randomized controlled pilot study of 153 participants found that regular application of Oil 24 improved scores on pain scales and the Fibromyalgia Impact Questionnaire.²⁸

Continue to: GI disorders

GI disorders

Irritable bowel syndrome. Peppermint oil relaxes GI smooth muscle, which has led to investigation of its use in irritable bowel ­syndrome (IBS) symptom amelioration.¹⁷ One meta-analysis including 12 RCTs with 835 patients with undifferentiated IBS found that orally ingested peppermint EO capsules reduced patient-reported symptoms of either abdominal pain or global symptoms.¹⁸

One study utilized the Total IBS Symptom Score to evaluate symptom reduction in patients with IBS-D (with diarrhea) and IBS-M (mixed) using 180-mg peppermint EO capsules ingested 3 times daily. There was a significant improvement in abdominal pain/discomfort, bloating/distension, pain at evacuation, and bowel urgency.¹⁹ A reduction in symptoms was observed after the first 24 hours of treatment and at the end of the 4-week treatment period.

In another study, among the 190 patients meeting Rome IV criteria for general (nonspecific) IBS who were treated with 182-mg peppermint EO capsules, no statistically significant reduction in overall symptom relief was found (based on outcome measures by the FDA and European Medicines Agency). However, in a secondary outcome analysis, peppermint oil produced greater improvements than placebo for the alleviation of abdominal pain, discomfort, and general IBS severity.²⁰

Chemotherapy-induced nausea and vomiting. Patients with cancer undergoing chemotherapy often explore integrative medicine approaches, including aromatherapy, to ameliorate adverse effects and improve quality of life.³⁸ A few small studies have shown potential for the use of inhaled ginger oil to reduce nausea and vomiting severity and improve health-related quality-of-life measures in these patients.

Evidence supports the use of inhaled and topically applied lavender oil to improve fibromyalgia symptoms.

For example, a study with 60 participants found that inhaling ginger EO for 10 minutes was beneficial for reducing both nausea and vomiting.³⁹ A single-blind, controlled, ­randomized crossover study of 60 patients with breast cancer receiving chemotherapy showed that ginger EO inhaled 3 times per day for 2 minutes at a time can decrease the severity of nausea but had no effect on vomiting. The same study showed that health-­related quality of life improved with the ginger oil treatment.⁴⁰

Continue to: Other EOs such as cardamom...

Other EOs such as cardamom and peppermint show promise as an adjunctive treatment for chemotherapy-induced nausea and vomiting as well.³⁸

Postoperative nausea. A 2013 randomized trial of 303 patients examined the use of ginger EO, a blend of EOs (including ginger, spearmint, peppermint, and cardamom), and isopropyl alcohol. Both the single EO and EO blend significantly reduced the symptom of nausea. The number of antiemetic medications requested by patients receiving an EO also was significantly reduced compared to those receiving saline.¹⁵

The use of EOs to reduce nausea after cardiac operations was reviewed in an RCT of 60 surgical candidates using 10% peppermint oil via nebulization for 10 minutes.¹⁶ This technique was effective in reducing nausea during cardiac postoperative periods. Although the evidence for the use of EOs for postoperative nausea is not robust, it may be a useful and generally safe approach for this common issue.

Behavioral health

Insomnia. EOs have been used as a treatment for insomnia traditionally and in complementary, alternative, and integrative medicine. A 2014 systematic review of 15 quantitative studies, including 11 RCTs, evaluated the hypnotic effects of EOs through inhalation, finding the strongest evidence for lavender, jasmine, and peppermint oils.²⁹ The majority of the studies in the systematic review used the Pittsburgh Sleep Quality Index (PSQI) to evaluate EO effectiveness. A more recent 2021 systematic review and meta-analysis that evaluated 34 RCTs found that inhalation of EOs, most notably lavender aromatherapy, is effective in improving sleep problems such as insomnia.³⁰

Findings from multiple smaller RCTs were consistent with those of the aforementioned systematic reviews. For example, in a well-conducted parallel randomized double-blind placebo-controlled trial of 100 people using orally ingested lemon verbena, the authors concluded that this intervention can be a complementary therapy for improving sleep quality and reducing insomnia severity.³¹ Another RCT with 60 participants evaluated an inhaled EO blend (lemon, eucalyptus, tea tree, and peppermint) over 4 weeks and found lowered perceived stress and depression as well as better sleep quality, but no influence on objective physiologic data such as stress indices or immune states.³²

Continue to: In a 2020 randomized crossover...

In a 2020 randomized crossover placebo­controlled trial of 37 participants with diabetes reporting insomnia, inhaled lavender improved sleep quality and quantity, quality of life, and mood but not physiologic or metabolic measures, such as fasting glucose.³³ Findings were similar in a cohort of cardiac rehabilitation patients (n = 37) who were treated with either an inhaled combination of lavender, bergamot, and ylang ylang, or placebo; cotton balls infused with the intervention oil or placebo oil were placed at the patient’s bedside for 5 nights. Sleep quality of participants receiving intervention oil was significantly better than the sleep quality of participants receiving the placebo oil as measured by participant completion of the PSQI.³⁴

Anxiety is a common disorder that can be managed with nonpharmacologic treatments such as yoga, deep breathing, meditation, and EO therapy.^21,22 In a systematic review and meta-analysis, the inhaled and topical use (with or without massage) of lavender EO was shown to improve psychological and physical manifestations of anxiety.²³ Lavender EO is purported to affect the parasympathetic nervous system via anxiolytic, sedative, analgesic, and anticonvulsant properties.²⁴ One systematic review and meta-analysis evaluating the anxiolytic effect of both inhaled and topical lavender EO found improvement in several biomarkers and physiologic data including blood pressure, heart rate, and cortisol levels, as well as a reduction in self-reported levels of anxiety, compared with placebo.²⁵

Anxiety related to dental procedures is another area of study for the use of EOs. Two RCTs demonstrate statistically significant improvement in anxiety-related physiologic markers such as heart rate, blood pressure, and salivary cortisol levels in children who inhaled lavender EO during dental procedures.^41,42 In 1 of the RCTs, the intervention was described as 3 drops of 100% lavender EO applied to a cloth and inhaled over the course of 3 minutes.⁴¹ Additionally, 2 studies found that orange EO was beneficial for dental procedure–induced anxiety, reducing pulse rates, cortisol levels, and self-reported anxiety.^43,44

Dementia-related behavioral disturbances. A small, poorly designed study examining 2 EO blends—rosemary with lemon and lavender with orange—found some potential for improving cognitive function, especially in patients with Alzheimer disease.⁴⁵ A Cochrane review of 13 RCTs totaling 708 patients concluded that it is not certain from the available evidence that EO therapy benefits patients with dementia in long-term-care facilities and hospital wards.⁴⁶ Given that reporting of adverse events in the trials was poor, it is not possible to make conclusions about the risk vs benefit of EO therapy in this population.

Women’s health

Dysmenorrhea. Interest has grown in the use of EOs for dysmenorrhea symptom relief, and there is a small body of evidence demonstrating that a variety of oils—most notably lavender, rose, and clary sage—may reduce symptom severity. One meta-analysis of 9 RCTs and 12 controlled clinical trials including women with moderate-to-severe dysmenorrhea found that inhaled and/or topical use of singular or mixed lavender, clary sage, rose, marjoram, and cinnamon EOs demonstrated the strongest evidence of effectiveness in reducing menstrual cramping.³⁵

Continue to: In a randomized, double-blind clinical trial...

Use of an inhaled blend of lemon, eucalyptus, tea tree, and peppermint was associated with lower perceived stress and depression as well as better sleep quality.

In a randomized, double-blind clinical trial of 48 women, a cream-based blend of lavender, clary sage, and marjoram EO (used topically in a 2:1:1 ratio diluted in unscented cream at 3% concentration and applied daily via abdominal massage) reduced participants’ reported menstrual pain symptoms and duration of pain.³⁶ In a meta-analysis of 6 studies, topical abdominal application of EO (mainly lavender with or without other oils) with massage showed superiority over massage with placebo oils in reducing menstrual pain.³⁷ A reduction in pain, mood symptoms, and fatigue in women with premenstrual symptoms was seen in an RCT of 77 patients using 3 drops of inhaled lavender EO.⁴⁷

Labor. There is limited evidence for the use of EOs during labor. In an RCT of 104 women, patient-selected diffused EOs, including lavender, rose geranium, citrus, or jasmine, were found to help lower pain scores during the latent and early active phase of labor. There were no differences in labor augmentation, length of labor, perinatal outcomes, or need for additional pain medication.⁴⁸

Other uses

Antimicrobial support. Some common EOs that have demonstrated antimicrobial properties are oregano, thyme, clove, lavender, clary sage, garlic, and cinnamon.^49,50 Topical lemongrass and tea tree EOs have shown some degree of efficacy as an alternative treatment for acne, decolonization of methicillin-resistant Staphylococcus aureus, and superficial fungal infections.⁵¹ Support for an oral mixture of EOs labeled Myrtol (containing eucalyptus, citrus myrtle, and lavender) for viral acute bronchitis and sinusitis was found in a review of 7 studies.⁵² More research needs to be done before clear recommendations can be made on the use of EOs as antimicrobials, but the current data are encouraging.

Insect repellent. Reviews of the ­insect-repellent properties of EOs have shown promise and are in the public’s interest due to increasing awareness of the potential health and environmental hazards of synthetic repellents.⁵³ Individual compounds present in EOs such as citronella/lemongrass, basil, and eucalyptus species demonstrate high repellent activity.⁵⁴ Since EOs require frequent reapplication for efficacy due to their highly volatile nature, scientists are currently developing a means to prolong their protection time through cream-based formulations.⁵⁵

The bottom line

Because of the ubiquity of EOs, family physicians will undoubtedly be asked about them by patients, and it would be beneficial to feel comfortable discussing their most common uses. For most adult patients, the topical and periodic inhaled usage of EOs is generally safe.⁵⁶

There is a small body of evidence demonstrating that a variety of essential oils, most notably lavender, rose, and clary sage, may reduce dysmenorrhea symptom severity.

There is existing evidence of efficacy for a number of EOs, most strongly for lavender and peppermint. Future research into EOs should include higher-powered and higher-­quality studies in order to provide more conclusive evidence regarding the continued use of EOs for many common conditions. More evidence-based information on dosing, application/use regimens, and safety in long-term use also will help providers better instruct patients on how to utilize EOs effectively and safely. 

CORRESPONDENCE
Pooja Amy Shah, MD, Columbia University College of Physicians & Surgeons, 610 West 158th Street, New York, NY 10032; [email protected]

Essential oils (EOs), which are concentrated plant-based oils, have become ubiquitous over the past decade. ­Given the far reach of EOs and their longtime use in traditional, complementary, alternative, and integrative medicine, it is imperative that clinicians have some knowledge of the potential benefits, risks, and overall efficacy.

Commonly used for aromatic benefits (aromatherapy), EOs are now also incorporated into a multitude of products promoting health and wellness. EOs are sold as individual products and can be a component in consumer goods such as cosmetics, body care/hygiene/beauty products, laundry detergents, insect repellents, over-the-counter medications, and food.

It is important to read ingredient labels before purchasing an essential oil. Reputable companies will identify the plant ingredient, usually by the formal Latin binomial name, and explain the extraction process.

The review that follows presents the most current evidence available. With that said, it’s important to keep in mind some caveats that relate to this evidence. First, the studies cited tend to have a small sample size. Second, a majority of these studies were conducted in countries where there appears to be a significant culture of EO use, which could contribute to confirmation bias. Finally, in a number of the studies, there is concern for publication bias as well as a discrepancy between calculated statistical significance and actual clinical relevance.

What are essential oils?

EOs generally are made by extracting the oil from leaves, bark, flowers, seeds/fruit, rinds, and/or roots by steaming or pressing parts of a plant. It can take several pounds of plant material to produce a single bottle of EO, which usually contains ≥ 15 to 30 mL (.5 to 1 oz).¹

Some commonly used EOs in the United States are lavender, peppermint, rose, clary sage, tea tree, eucalyptus, and citrus; however, there are approximately 300 EOs available.² EOs are used most often via topical application, inhalation, or ingestion.

As with any botanical agent, EOs are complex substances often containing a multitude of chemical compounds.¹ Because of the complex makeup of EOs, which often contain up to 100 volatile organic compounds, and their wide-ranging potential effects, applying the scientific method to study effectiveness poses a challenge that has limited their adoption in evidence-based practice.²

Availability and cost. EOs can be purchased at large retailers (eg, grocery stores, drug stores) and smaller health food stores, as well as on the Internet. Various EO vehicles, such as inhalers and topical creams, also can be purchased at these stores.

Continue to: The cost varies...

The cost varies enormously by manufacturer and type of plant used to make the EO. Common EOs such as peppermint and lavender oil generally cost $10 to $25, while rarer plant oils can cost $80 or more per bottle.

How safe are essential oils?

Patients may assume EOs are harmless because they are derived from natural plants and have been used medicinally for centuries. However, care must be taken with their use.

The safest way to use EOs is topically, although due to their highly concentrated nature, EOs should be diluted in an unscented neutral carrier oil such as coconut, jojoba, olive, or sweet almond.³ Ingestion of certain oils can cause hepatotoxicity, seizures, and even death.³ In fact, patients should speak with a knowledgeable physician before purchasing any oral EO capsules.

Whether used topically or ingested, all EOs carry risk for skin irritation and allergic reactions, and oral ingestion may result in some negative gastrointestinal (GI) adverse effects.⁴ A case report of 3 patients published in 2007 identified the potential for lavender and tea tree EOs to be endocrine disruptors.⁵

Inhalation of EOs may be harmful, as they emit many volatile organic compounds, some of which are considered potentially hazardous.⁶ At this time, there is insufficient evidence regarding inhaled EOs and their direct connection to respiratory health. It is reasonable to suggest, however, that the prolonged use of EOs and their use by patients who have lung conditions such as asthma or COPD should be avoided.⁷

Continue to: How are quality and purity assessed?

How are quality and purity assessed?

Like other dietary supplements, EOs are not regulated. No US regulatory agencies (eg, the US Food and Drug Administration [FDA] or Department of Agriculture [USDA]) certify or approve EOs for quality and purity. Bottles labeled with “QAI” for Quality Assurance International or “USDA Organic” will ensure the plant constituents used in the EO are from organic farming but do not attest to quality or purity.

Essential oils are one of the nonpharmacologic modalities that patients and clinicians have at their disposal for adjunctive treatment of migraine and tension-type headaches.

Manufacturers commonly use marketing terms such as “therapeutic grade” or “pure” to sell products, but again, these terms do not reflect the product’s quality or purity. A labeled single EO may contain contaminants, alcohol, or additional ingredients.⁷ When choosing to use EOs, identifying reputable brands is essential; one resource is the independent testing organization ConsumerLab.com.

It is important to assess the manufacturer and read ingredient labels before purchasing an EO to understand what the product contains. Reputable companies will identify the plant ingredient, usually by the formal Latin binomial name, and explain the extraction process. A more certain way to assess the quality and purity of an EO is to ask the manufacturer to provide a certificate of analysis and gas chromatography/mass spectroscopy (GC/MS) data for the specific product. Some manufacturers offer GC/MS test results on their website Quality page.⁸ Others have detailed information on quality and testing, and GC/MS test reports can be obtained.⁹ Yet another manufacturer has test results on a product page matching reports to batch codes.¹⁰

Which conditions have evidence of benefit from essential oils?

EOs currently are being studied for treatment of many conditions—including pain, GI disorders, behavioral health disorders, and women’s health issues. The TABLE summarizes the conditions treated, outcomes, and practical applications of EOs.^11-44

Pain

Headache. As an adjunct to available medications and procedures for headache treatment, EOs are one of the nonpharmacologic modalities that patients and clinicians have at their disposal for both migraine and ­tension-type headaches. A systematic review of 19 randomized controlled trials (RCTs) examining the effects of herbal ingredients for the acute treatment or prophylaxis of migraines found certain topically applied or inhaled EOs, such as peppermint and chamomile, to be effective for migraine pain alleviation; however, topically applied rose oil was not effective.^11-13 Note: “topical application” in these studies implies application of the EO to ≥ 1 of the following areas: temples, forehead, behind ears, or above upper lip/below the nose.

Continue to: One RCT with 120 patients...

One RCT with 120 patients evaluated diluted intranasal peppermint oil and found that it reduced migraine intensity at similar rates to intranasal lidocaine.¹³ In this study, patients were randomized to receive one of the following: 4% lidocaine, 1.5% peppermint EO, or placebo. Two drops of the intranasal intervention were self-administered while the patient was in a supine position with their head suspended off the edge of the surface on which they were lying. They were instructed to stay in this position for at least 30 seconds after administration.

With regard to tension headache treatment, there is limited literature on the use of EOs. One study found that a preparation of peppermint oil applied topically to the temples and forehead of study participants resulted in significant analgesic effect.¹⁴

Fibromyalgia. Usual treatments for fibromyalgia include exercise, antidepressant and anticonvulsant medications, and stress management. Evidence also supports the use of inhaled and topically applied (with and without massage) lavender oil to improve symptoms.²⁶ Positive effects may be related to the anal­gesic, anti-­inflammatory, sleep-regulating,­ and anxiety­-reducing effects of the major volatile compounds contained in lavender oil.

In one RCT with 42 patients with fibromyalgia, the use of inhaled lavender oil was shown to increase the perception of well-­being (assessed on the validated SF-36 Health Survey Questionnaire) after 4 weeks.²⁷ In this study, the patient applied 3 drops of an oil mixture, comprising 1 mL lavender EO and 10 mL of fixed neutral base oil, to the wrist and inhaled for 10 minutes before going to bed.

The use of a topical oil blend labeled “Oil 24” (containing camphor, rosemary, eucalyptus, peppermint, aloe vera, and lemon/orange) also has been shown to be more effective than placebo in managing fibromyalgia symptoms. A randomized controlled pilot study of 153 participants found that regular application of Oil 24 improved scores on pain scales and the Fibromyalgia Impact Questionnaire.²⁸

Continue to: GI disorders

GI disorders

Irritable bowel syndrome. Peppermint oil relaxes GI smooth muscle, which has led to investigation of its use in irritable bowel ­syndrome (IBS) symptom amelioration.¹⁷ One meta-analysis including 12 RCTs with 835 patients with undifferentiated IBS found that orally ingested peppermint EO capsules reduced patient-reported symptoms of either abdominal pain or global symptoms.¹⁸

One study utilized the Total IBS Symptom Score to evaluate symptom reduction in patients with IBS-D (with diarrhea) and IBS-M (mixed) using 180-mg peppermint EO capsules ingested 3 times daily. There was a significant improvement in abdominal pain/discomfort, bloating/distension, pain at evacuation, and bowel urgency.¹⁹ A reduction in symptoms was observed after the first 24 hours of treatment and at the end of the 4-week treatment period.

In another study, among the 190 patients meeting Rome IV criteria for general (nonspecific) IBS who were treated with 182-mg peppermint EO capsules, no statistically significant reduction in overall symptom relief was found (based on outcome measures by the FDA and European Medicines Agency). However, in a secondary outcome analysis, peppermint oil produced greater improvements than placebo for the alleviation of abdominal pain, discomfort, and general IBS severity.²⁰

Chemotherapy-induced nausea and vomiting. Patients with cancer undergoing chemotherapy often explore integrative medicine approaches, including aromatherapy, to ameliorate adverse effects and improve quality of life.³⁸ A few small studies have shown potential for the use of inhaled ginger oil to reduce nausea and vomiting severity and improve health-related quality-of-life measures in these patients.

Evidence supports the use of inhaled and topically applied lavender oil to improve fibromyalgia symptoms.

For example, a study with 60 participants found that inhaling ginger EO for 10 minutes was beneficial for reducing both nausea and vomiting.³⁹ A single-blind, controlled, ­randomized crossover study of 60 patients with breast cancer receiving chemotherapy showed that ginger EO inhaled 3 times per day for 2 minutes at a time can decrease the severity of nausea but had no effect on vomiting. The same study showed that health-­related quality of life improved with the ginger oil treatment.⁴⁰

Continue to: Other EOs such as cardamom...

Other EOs such as cardamom and peppermint show promise as an adjunctive treatment for chemotherapy-induced nausea and vomiting as well.³⁸

Postoperative nausea. A 2013 randomized trial of 303 patients examined the use of ginger EO, a blend of EOs (including ginger, spearmint, peppermint, and cardamom), and isopropyl alcohol. Both the single EO and EO blend significantly reduced the symptom of nausea. The number of antiemetic medications requested by patients receiving an EO also was significantly reduced compared to those receiving saline.¹⁵

The use of EOs to reduce nausea after cardiac operations was reviewed in an RCT of 60 surgical candidates using 10% peppermint oil via nebulization for 10 minutes.¹⁶ This technique was effective in reducing nausea during cardiac postoperative periods. Although the evidence for the use of EOs for postoperative nausea is not robust, it may be a useful and generally safe approach for this common issue.

Behavioral health

Insomnia. EOs have been used as a treatment for insomnia traditionally and in complementary, alternative, and integrative medicine. A 2014 systematic review of 15 quantitative studies, including 11 RCTs, evaluated the hypnotic effects of EOs through inhalation, finding the strongest evidence for lavender, jasmine, and peppermint oils.²⁹ The majority of the studies in the systematic review used the Pittsburgh Sleep Quality Index (PSQI) to evaluate EO effectiveness. A more recent 2021 systematic review and meta-analysis that evaluated 34 RCTs found that inhalation of EOs, most notably lavender aromatherapy, is effective in improving sleep problems such as insomnia.³⁰

Findings from multiple smaller RCTs were consistent with those of the aforementioned systematic reviews. For example, in a well-conducted parallel randomized double-blind placebo-controlled trial of 100 people using orally ingested lemon verbena, the authors concluded that this intervention can be a complementary therapy for improving sleep quality and reducing insomnia severity.³¹ Another RCT with 60 participants evaluated an inhaled EO blend (lemon, eucalyptus, tea tree, and peppermint) over 4 weeks and found lowered perceived stress and depression as well as better sleep quality, but no influence on objective physiologic data such as stress indices or immune states.³²

Continue to: In a 2020 randomized crossover...

In a 2020 randomized crossover placebo­controlled trial of 37 participants with diabetes reporting insomnia, inhaled lavender improved sleep quality and quantity, quality of life, and mood but not physiologic or metabolic measures, such as fasting glucose.³³ Findings were similar in a cohort of cardiac rehabilitation patients (n = 37) who were treated with either an inhaled combination of lavender, bergamot, and ylang ylang, or placebo; cotton balls infused with the intervention oil or placebo oil were placed at the patient’s bedside for 5 nights. Sleep quality of participants receiving intervention oil was significantly better than the sleep quality of participants receiving the placebo oil as measured by participant completion of the PSQI.³⁴

Anxiety is a common disorder that can be managed with nonpharmacologic treatments such as yoga, deep breathing, meditation, and EO therapy.^21,22 In a systematic review and meta-analysis, the inhaled and topical use (with or without massage) of lavender EO was shown to improve psychological and physical manifestations of anxiety.²³ Lavender EO is purported to affect the parasympathetic nervous system via anxiolytic, sedative, analgesic, and anticonvulsant properties.²⁴ One systematic review and meta-analysis evaluating the anxiolytic effect of both inhaled and topical lavender EO found improvement in several biomarkers and physiologic data including blood pressure, heart rate, and cortisol levels, as well as a reduction in self-reported levels of anxiety, compared with placebo.²⁵

Anxiety related to dental procedures is another area of study for the use of EOs. Two RCTs demonstrate statistically significant improvement in anxiety-related physiologic markers such as heart rate, blood pressure, and salivary cortisol levels in children who inhaled lavender EO during dental procedures.^41,42 In 1 of the RCTs, the intervention was described as 3 drops of 100% lavender EO applied to a cloth and inhaled over the course of 3 minutes.⁴¹ Additionally, 2 studies found that orange EO was beneficial for dental procedure–induced anxiety, reducing pulse rates, cortisol levels, and self-reported anxiety.^43,44

Dementia-related behavioral disturbances. A small, poorly designed study examining 2 EO blends—rosemary with lemon and lavender with orange—found some potential for improving cognitive function, especially in patients with Alzheimer disease.⁴⁵ A Cochrane review of 13 RCTs totaling 708 patients concluded that it is not certain from the available evidence that EO therapy benefits patients with dementia in long-term-care facilities and hospital wards.⁴⁶ Given that reporting of adverse events in the trials was poor, it is not possible to make conclusions about the risk vs benefit of EO therapy in this population.

Women’s health

Dysmenorrhea. Interest has grown in the use of EOs for dysmenorrhea symptom relief, and there is a small body of evidence demonstrating that a variety of oils—most notably lavender, rose, and clary sage—may reduce symptom severity. One meta-analysis of 9 RCTs and 12 controlled clinical trials including women with moderate-to-severe dysmenorrhea found that inhaled and/or topical use of singular or mixed lavender, clary sage, rose, marjoram, and cinnamon EOs demonstrated the strongest evidence of effectiveness in reducing menstrual cramping.³⁵

Continue to: In a randomized, double-blind clinical trial...

Use of an inhaled blend of lemon, eucalyptus, tea tree, and peppermint was associated with lower perceived stress and depression as well as better sleep quality.

In a randomized, double-blind clinical trial of 48 women, a cream-based blend of lavender, clary sage, and marjoram EO (used topically in a 2:1:1 ratio diluted in unscented cream at 3% concentration and applied daily via abdominal massage) reduced participants’ reported menstrual pain symptoms and duration of pain.³⁶ In a meta-analysis of 6 studies, topical abdominal application of EO (mainly lavender with or without other oils) with massage showed superiority over massage with placebo oils in reducing menstrual pain.³⁷ A reduction in pain, mood symptoms, and fatigue in women with premenstrual symptoms was seen in an RCT of 77 patients using 3 drops of inhaled lavender EO.⁴⁷

Labor. There is limited evidence for the use of EOs during labor. In an RCT of 104 women, patient-selected diffused EOs, including lavender, rose geranium, citrus, or jasmine, were found to help lower pain scores during the latent and early active phase of labor. There were no differences in labor augmentation, length of labor, perinatal outcomes, or need for additional pain medication.⁴⁸

Other uses

Antimicrobial support. Some common EOs that have demonstrated antimicrobial properties are oregano, thyme, clove, lavender, clary sage, garlic, and cinnamon.^49,50 Topical lemongrass and tea tree EOs have shown some degree of efficacy as an alternative treatment for acne, decolonization of methicillin-resistant Staphylococcus aureus, and superficial fungal infections.⁵¹ Support for an oral mixture of EOs labeled Myrtol (containing eucalyptus, citrus myrtle, and lavender) for viral acute bronchitis and sinusitis was found in a review of 7 studies.⁵² More research needs to be done before clear recommendations can be made on the use of EOs as antimicrobials, but the current data are encouraging.

Insect repellent. Reviews of the ­insect-repellent properties of EOs have shown promise and are in the public’s interest due to increasing awareness of the potential health and environmental hazards of synthetic repellents.⁵³ Individual compounds present in EOs such as citronella/lemongrass, basil, and eucalyptus species demonstrate high repellent activity.⁵⁴ Since EOs require frequent reapplication for efficacy due to their highly volatile nature, scientists are currently developing a means to prolong their protection time through cream-based formulations.⁵⁵

The bottom line

Because of the ubiquity of EOs, family physicians will undoubtedly be asked about them by patients, and it would be beneficial to feel comfortable discussing their most common uses. For most adult patients, the topical and periodic inhaled usage of EOs is generally safe.⁵⁶

There is a small body of evidence demonstrating that a variety of essential oils, most notably lavender, rose, and clary sage, may reduce dysmenorrhea symptom severity.

There is existing evidence of efficacy for a number of EOs, most strongly for lavender and peppermint. Future research into EOs should include higher-powered and higher-­quality studies in order to provide more conclusive evidence regarding the continued use of EOs for many common conditions. More evidence-based information on dosing, application/use regimens, and safety in long-term use also will help providers better instruct patients on how to utilize EOs effectively and safely. 

CORRESPONDENCE
Pooja Amy Shah, MD, Columbia University College of Physicians & Surgeons, 610 West 158th Street, New York, NY 10032; [email protected]

Essential oils (EOs), which are concentrated plant-based oils, have become ubiquitous over the past decade. ­Given the far reach of EOs and their longtime use in traditional, complementary, alternative, and integrative medicine, it is imperative that clinicians have some knowledge of the potential benefits, risks, and overall efficacy.

Commonly used for aromatic benefits (aromatherapy), EOs are now also incorporated into a multitude of products promoting health and wellness. EOs are sold as individual products and can be a component in consumer goods such as cosmetics, body care/hygiene/beauty products, laundry detergents, insect repellents, over-the-counter medications, and food.

It is important to read ingredient labels before purchasing an essential oil. Reputable companies will identify the plant ingredient, usually by the formal Latin binomial name, and explain the extraction process.

The review that follows presents the most current evidence available. With that said, it’s important to keep in mind some caveats that relate to this evidence. First, the studies cited tend to have a small sample size. Second, a majority of these studies were conducted in countries where there appears to be a significant culture of EO use, which could contribute to confirmation bias. Finally, in a number of the studies, there is concern for publication bias as well as a discrepancy between calculated statistical significance and actual clinical relevance.

What are essential oils?

EOs generally are made by extracting the oil from leaves, bark, flowers, seeds/fruit, rinds, and/or roots by steaming or pressing parts of a plant. It can take several pounds of plant material to produce a single bottle of EO, which usually contains ≥ 15 to 30 mL (.5 to 1 oz).¹

Some commonly used EOs in the United States are lavender, peppermint, rose, clary sage, tea tree, eucalyptus, and citrus; however, there are approximately 300 EOs available.² EOs are used most often via topical application, inhalation, or ingestion.

As with any botanical agent, EOs are complex substances often containing a multitude of chemical compounds.¹ Because of the complex makeup of EOs, which often contain up to 100 volatile organic compounds, and their wide-ranging potential effects, applying the scientific method to study effectiveness poses a challenge that has limited their adoption in evidence-based practice.²

Availability and cost. EOs can be purchased at large retailers (eg, grocery stores, drug stores) and smaller health food stores, as well as on the Internet. Various EO vehicles, such as inhalers and topical creams, also can be purchased at these stores.

Continue to: The cost varies...

The cost varies enormously by manufacturer and type of plant used to make the EO. Common EOs such as peppermint and lavender oil generally cost $10 to $25, while rarer plant oils can cost $80 or more per bottle.

How safe are essential oils?

Patients may assume EOs are harmless because they are derived from natural plants and have been used medicinally for centuries. However, care must be taken with their use.

The safest way to use EOs is topically, although due to their highly concentrated nature, EOs should be diluted in an unscented neutral carrier oil such as coconut, jojoba, olive, or sweet almond.³ Ingestion of certain oils can cause hepatotoxicity, seizures, and even death.³ In fact, patients should speak with a knowledgeable physician before purchasing any oral EO capsules.

Whether used topically or ingested, all EOs carry risk for skin irritation and allergic reactions, and oral ingestion may result in some negative gastrointestinal (GI) adverse effects.⁴ A case report of 3 patients published in 2007 identified the potential for lavender and tea tree EOs to be endocrine disruptors.⁵

Inhalation of EOs may be harmful, as they emit many volatile organic compounds, some of which are considered potentially hazardous.⁶ At this time, there is insufficient evidence regarding inhaled EOs and their direct connection to respiratory health. It is reasonable to suggest, however, that the prolonged use of EOs and their use by patients who have lung conditions such as asthma or COPD should be avoided.⁷

Continue to: How are quality and purity assessed?

How are quality and purity assessed?

Like other dietary supplements, EOs are not regulated. No US regulatory agencies (eg, the US Food and Drug Administration [FDA] or Department of Agriculture [USDA]) certify or approve EOs for quality and purity. Bottles labeled with “QAI” for Quality Assurance International or “USDA Organic” will ensure the plant constituents used in the EO are from organic farming but do not attest to quality or purity.

Essential oils are one of the nonpharmacologic modalities that patients and clinicians have at their disposal for adjunctive treatment of migraine and tension-type headaches.

Manufacturers commonly use marketing terms such as “therapeutic grade” or “pure” to sell products, but again, these terms do not reflect the product’s quality or purity. A labeled single EO may contain contaminants, alcohol, or additional ingredients.⁷ When choosing to use EOs, identifying reputable brands is essential; one resource is the independent testing organization ConsumerLab.com.

It is important to assess the manufacturer and read ingredient labels before purchasing an EO to understand what the product contains. Reputable companies will identify the plant ingredient, usually by the formal Latin binomial name, and explain the extraction process. A more certain way to assess the quality and purity of an EO is to ask the manufacturer to provide a certificate of analysis and gas chromatography/mass spectroscopy (GC/MS) data for the specific product. Some manufacturers offer GC/MS test results on their website Quality page.⁸ Others have detailed information on quality and testing, and GC/MS test reports can be obtained.⁹ Yet another manufacturer has test results on a product page matching reports to batch codes.¹⁰

Which conditions have evidence of benefit from essential oils?

EOs currently are being studied for treatment of many conditions—including pain, GI disorders, behavioral health disorders, and women’s health issues. The TABLE summarizes the conditions treated, outcomes, and practical applications of EOs.^11-44

Pain

Headache. As an adjunct to available medications and procedures for headache treatment, EOs are one of the nonpharmacologic modalities that patients and clinicians have at their disposal for both migraine and ­tension-type headaches. A systematic review of 19 randomized controlled trials (RCTs) examining the effects of herbal ingredients for the acute treatment or prophylaxis of migraines found certain topically applied or inhaled EOs, such as peppermint and chamomile, to be effective for migraine pain alleviation; however, topically applied rose oil was not effective.^11-13 Note: “topical application” in these studies implies application of the EO to ≥ 1 of the following areas: temples, forehead, behind ears, or above upper lip/below the nose.

Continue to: One RCT with 120 patients...

One RCT with 120 patients evaluated diluted intranasal peppermint oil and found that it reduced migraine intensity at similar rates to intranasal lidocaine.¹³ In this study, patients were randomized to receive one of the following: 4% lidocaine, 1.5% peppermint EO, or placebo. Two drops of the intranasal intervention were self-administered while the patient was in a supine position with their head suspended off the edge of the surface on which they were lying. They were instructed to stay in this position for at least 30 seconds after administration.

With regard to tension headache treatment, there is limited literature on the use of EOs. One study found that a preparation of peppermint oil applied topically to the temples and forehead of study participants resulted in significant analgesic effect.¹⁴

Fibromyalgia. Usual treatments for fibromyalgia include exercise, antidepressant and anticonvulsant medications, and stress management. Evidence also supports the use of inhaled and topically applied (with and without massage) lavender oil to improve symptoms.²⁶ Positive effects may be related to the anal­gesic, anti-­inflammatory, sleep-regulating,­ and anxiety­-reducing effects of the major volatile compounds contained in lavender oil.

In one RCT with 42 patients with fibromyalgia, the use of inhaled lavender oil was shown to increase the perception of well-­being (assessed on the validated SF-36 Health Survey Questionnaire) after 4 weeks.²⁷ In this study, the patient applied 3 drops of an oil mixture, comprising 1 mL lavender EO and 10 mL of fixed neutral base oil, to the wrist and inhaled for 10 minutes before going to bed.

The use of a topical oil blend labeled “Oil 24” (containing camphor, rosemary, eucalyptus, peppermint, aloe vera, and lemon/orange) also has been shown to be more effective than placebo in managing fibromyalgia symptoms. A randomized controlled pilot study of 153 participants found that regular application of Oil 24 improved scores on pain scales and the Fibromyalgia Impact Questionnaire.²⁸

Continue to: GI disorders

GI disorders

Irritable bowel syndrome. Peppermint oil relaxes GI smooth muscle, which has led to investigation of its use in irritable bowel ­syndrome (IBS) symptom amelioration.¹⁷ One meta-analysis including 12 RCTs with 835 patients with undifferentiated IBS found that orally ingested peppermint EO capsules reduced patient-reported symptoms of either abdominal pain or global symptoms.¹⁸

One study utilized the Total IBS Symptom Score to evaluate symptom reduction in patients with IBS-D (with diarrhea) and IBS-M (mixed) using 180-mg peppermint EO capsules ingested 3 times daily. There was a significant improvement in abdominal pain/discomfort, bloating/distension, pain at evacuation, and bowel urgency.¹⁹ A reduction in symptoms was observed after the first 24 hours of treatment and at the end of the 4-week treatment period.

In another study, among the 190 patients meeting Rome IV criteria for general (nonspecific) IBS who were treated with 182-mg peppermint EO capsules, no statistically significant reduction in overall symptom relief was found (based on outcome measures by the FDA and European Medicines Agency). However, in a secondary outcome analysis, peppermint oil produced greater improvements than placebo for the alleviation of abdominal pain, discomfort, and general IBS severity.²⁰

Chemotherapy-induced nausea and vomiting. Patients with cancer undergoing chemotherapy often explore integrative medicine approaches, including aromatherapy, to ameliorate adverse effects and improve quality of life.³⁸ A few small studies have shown potential for the use of inhaled ginger oil to reduce nausea and vomiting severity and improve health-related quality-of-life measures in these patients.

Evidence supports the use of inhaled and topically applied lavender oil to improve fibromyalgia symptoms.

For example, a study with 60 participants found that inhaling ginger EO for 10 minutes was beneficial for reducing both nausea and vomiting.³⁹ A single-blind, controlled, ­randomized crossover study of 60 patients with breast cancer receiving chemotherapy showed that ginger EO inhaled 3 times per day for 2 minutes at a time can decrease the severity of nausea but had no effect on vomiting. The same study showed that health-­related quality of life improved with the ginger oil treatment.⁴⁰

Continue to: Other EOs such as cardamom...

Other EOs such as cardamom and peppermint show promise as an adjunctive treatment for chemotherapy-induced nausea and vomiting as well.³⁸

Postoperative nausea. A 2013 randomized trial of 303 patients examined the use of ginger EO, a blend of EOs (including ginger, spearmint, peppermint, and cardamom), and isopropyl alcohol. Both the single EO and EO blend significantly reduced the symptom of nausea. The number of antiemetic medications requested by patients receiving an EO also was significantly reduced compared to those receiving saline.¹⁵

The use of EOs to reduce nausea after cardiac operations was reviewed in an RCT of 60 surgical candidates using 10% peppermint oil via nebulization for 10 minutes.¹⁶ This technique was effective in reducing nausea during cardiac postoperative periods. Although the evidence for the use of EOs for postoperative nausea is not robust, it may be a useful and generally safe approach for this common issue.

Behavioral health

Insomnia. EOs have been used as a treatment for insomnia traditionally and in complementary, alternative, and integrative medicine. A 2014 systematic review of 15 quantitative studies, including 11 RCTs, evaluated the hypnotic effects of EOs through inhalation, finding the strongest evidence for lavender, jasmine, and peppermint oils.²⁹ The majority of the studies in the systematic review used the Pittsburgh Sleep Quality Index (PSQI) to evaluate EO effectiveness. A more recent 2021 systematic review and meta-analysis that evaluated 34 RCTs found that inhalation of EOs, most notably lavender aromatherapy, is effective in improving sleep problems such as insomnia.³⁰

Findings from multiple smaller RCTs were consistent with those of the aforementioned systematic reviews. For example, in a well-conducted parallel randomized double-blind placebo-controlled trial of 100 people using orally ingested lemon verbena, the authors concluded that this intervention can be a complementary therapy for improving sleep quality and reducing insomnia severity.³¹ Another RCT with 60 participants evaluated an inhaled EO blend (lemon, eucalyptus, tea tree, and peppermint) over 4 weeks and found lowered perceived stress and depression as well as better sleep quality, but no influence on objective physiologic data such as stress indices or immune states.³²

Continue to: In a 2020 randomized crossover...

In a 2020 randomized crossover placebo­controlled trial of 37 participants with diabetes reporting insomnia, inhaled lavender improved sleep quality and quantity, quality of life, and mood but not physiologic or metabolic measures, such as fasting glucose.³³ Findings were similar in a cohort of cardiac rehabilitation patients (n = 37) who were treated with either an inhaled combination of lavender, bergamot, and ylang ylang, or placebo; cotton balls infused with the intervention oil or placebo oil were placed at the patient’s bedside for 5 nights. Sleep quality of participants receiving intervention oil was significantly better than the sleep quality of participants receiving the placebo oil as measured by participant completion of the PSQI.³⁴

Anxiety is a common disorder that can be managed with nonpharmacologic treatments such as yoga, deep breathing, meditation, and EO therapy.^21,22 In a systematic review and meta-analysis, the inhaled and topical use (with or without massage) of lavender EO was shown to improve psychological and physical manifestations of anxiety.²³ Lavender EO is purported to affect the parasympathetic nervous system via anxiolytic, sedative, analgesic, and anticonvulsant properties.²⁴ One systematic review and meta-analysis evaluating the anxiolytic effect of both inhaled and topical lavender EO found improvement in several biomarkers and physiologic data including blood pressure, heart rate, and cortisol levels, as well as a reduction in self-reported levels of anxiety, compared with placebo.²⁵

Anxiety related to dental procedures is another area of study for the use of EOs. Two RCTs demonstrate statistically significant improvement in anxiety-related physiologic markers such as heart rate, blood pressure, and salivary cortisol levels in children who inhaled lavender EO during dental procedures.^41,42 In 1 of the RCTs, the intervention was described as 3 drops of 100% lavender EO applied to a cloth and inhaled over the course of 3 minutes.⁴¹ Additionally, 2 studies found that orange EO was beneficial for dental procedure–induced anxiety, reducing pulse rates, cortisol levels, and self-reported anxiety.^43,44

Dementia-related behavioral disturbances. A small, poorly designed study examining 2 EO blends—rosemary with lemon and lavender with orange—found some potential for improving cognitive function, especially in patients with Alzheimer disease.⁴⁵ A Cochrane review of 13 RCTs totaling 708 patients concluded that it is not certain from the available evidence that EO therapy benefits patients with dementia in long-term-care facilities and hospital wards.⁴⁶ Given that reporting of adverse events in the trials was poor, it is not possible to make conclusions about the risk vs benefit of EO therapy in this population.

Women’s health

Dysmenorrhea. Interest has grown in the use of EOs for dysmenorrhea symptom relief, and there is a small body of evidence demonstrating that a variety of oils—most notably lavender, rose, and clary sage—may reduce symptom severity. One meta-analysis of 9 RCTs and 12 controlled clinical trials including women with moderate-to-severe dysmenorrhea found that inhaled and/or topical use of singular or mixed lavender, clary sage, rose, marjoram, and cinnamon EOs demonstrated the strongest evidence of effectiveness in reducing menstrual cramping.³⁵

Continue to: In a randomized, double-blind clinical trial...

Use of an inhaled blend of lemon, eucalyptus, tea tree, and peppermint was associated with lower perceived stress and depression as well as better sleep quality.

In a randomized, double-blind clinical trial of 48 women, a cream-based blend of lavender, clary sage, and marjoram EO (used topically in a 2:1:1 ratio diluted in unscented cream at 3% concentration and applied daily via abdominal massage) reduced participants’ reported menstrual pain symptoms and duration of pain.³⁶ In a meta-analysis of 6 studies, topical abdominal application of EO (mainly lavender with or without other oils) with massage showed superiority over massage with placebo oils in reducing menstrual pain.³⁷ A reduction in pain, mood symptoms, and fatigue in women with premenstrual symptoms was seen in an RCT of 77 patients using 3 drops of inhaled lavender EO.⁴⁷

Labor. There is limited evidence for the use of EOs during labor. In an RCT of 104 women, patient-selected diffused EOs, including lavender, rose geranium, citrus, or jasmine, were found to help lower pain scores during the latent and early active phase of labor. There were no differences in labor augmentation, length of labor, perinatal outcomes, or need for additional pain medication.⁴⁸

Other uses

Antimicrobial support. Some common EOs that have demonstrated antimicrobial properties are oregano, thyme, clove, lavender, clary sage, garlic, and cinnamon.^49,50 Topical lemongrass and tea tree EOs have shown some degree of efficacy as an alternative treatment for acne, decolonization of methicillin-resistant Staphylococcus aureus, and superficial fungal infections.⁵¹ Support for an oral mixture of EOs labeled Myrtol (containing eucalyptus, citrus myrtle, and lavender) for viral acute bronchitis and sinusitis was found in a review of 7 studies.⁵² More research needs to be done before clear recommendations can be made on the use of EOs as antimicrobials, but the current data are encouraging.

Insect repellent. Reviews of the ­insect-repellent properties of EOs have shown promise and are in the public’s interest due to increasing awareness of the potential health and environmental hazards of synthetic repellents.⁵³ Individual compounds present in EOs such as citronella/lemongrass, basil, and eucalyptus species demonstrate high repellent activity.⁵⁴ Since EOs require frequent reapplication for efficacy due to their highly volatile nature, scientists are currently developing a means to prolong their protection time through cream-based formulations.⁵⁵

The bottom line

Because of the ubiquity of EOs, family physicians will undoubtedly be asked about them by patients, and it would be beneficial to feel comfortable discussing their most common uses. For most adult patients, the topical and periodic inhaled usage of EOs is generally safe.⁵⁶

There is a small body of evidence demonstrating that a variety of essential oils, most notably lavender, rose, and clary sage, may reduce dysmenorrhea symptom severity.

There is existing evidence of efficacy for a number of EOs, most strongly for lavender and peppermint. Future research into EOs should include higher-powered and higher-­quality studies in order to provide more conclusive evidence regarding the continued use of EOs for many common conditions. More evidence-based information on dosing, application/use regimens, and safety in long-term use also will help providers better instruct patients on how to utilize EOs effectively and safely. 

CORRESPONDENCE
Pooja Amy Shah, MD, Columbia University College of Physicians & Surgeons, 610 West 158th Street, New York, NY 10032; [email protected]

The Diagnosis: Eczema Herpeticum

The patient’s condition with worsening facial edema and notable pain prompted a bedside Tzanck smear using a sample from the base of a deroofed forehead vesicle. In addition, a swab of a deroofed lesion was sent for herpes simplex virus and varicella-zoster virus (VZV) polymerase chain reaction (PCR) testing. The Tzanck smear demonstrated ballooning multinucleated syncytial giant cells and eosinophilic inclusion bodies (Figure), which are characteristic of certain herpesviruses including herpes simplex virus and VZV. He was started on intravenous acyclovir while PCR results were pending; the PCR test later confirmed positivity for herpes simplex virus type 1. Treatment was transitioned to oral valacyclovir once the lesions started crusting over. Notable healing and epithelialization of the lesions occurred during his hospital stay, and he was discharged home 5 days after starting treatment. He was counseled on autoinoculation, advised that he was considered infectious until all lesions had crusted over, and encouraged to employ frequent handwashing. Complete resolution of eczema herpeticum (EH) was noted at 3-week follow-up.

Eczema herpeticum (also known as Kaposi varicelliform eruption) is a potentially life-threatening disseminated cutaneous infection caused by herpes simplex virus types 1 and 2 in patients with pre-existing skin disease.¹ It typically presents as a complication of atopic dermatitis (AD) but also has been identified as a rare complication in other conditions that disrupt the normal skin barrier, including mycosis fungoides, pemphigus foliaceus, pemphigus vulgaris, Darier disease, pityriasis rubra pilaris, contact dermatitis, and seborrheic dermatitis.^1-4

The pathogenesis of EH is multifactorial. Disruption of the stratum corneum; impaired natural killer cell function; early-onset, untreated, or severe AD; disrupted skin microbiota with skewed colonization by Staphylococcus aureus; immunosuppressive AD therapies such as calcineurin inhibitors; eosinophilia; and helper T cell (T_H2) cytokine predominance all have been suggested to play a role in the development of EH.^5-8

As seen in our patient, EH presents with a sudden eruption of painful or pruritic, grouped, monomorphic, domeshaped vesicles with background swelling and erythema typically on the head, neck, and trunk. Vesicles then progress to punched-out erosions with overlying hemorrhagic crusting that can coalesce to form large denuded areas susceptible to superinfection with bacteria.⁹ Other accompanying symptoms include high fever, chills, malaise, and lymphadenopathy. Associated inflammation, classically described as erythema, may be difficult to discern in patients with darker skin and appears as hyperpigmentation; therefore, identification of clusters of monomorphic vesicles in areas of pre-existing dermatitis is particularly important for clinical diagnosis in people with darker skin types.

Various tests are available to confirm diagnosis in ambiguous cases. Bedside Tzanck smears can be performed rapidly and are considered positive if characteristic multinucleated giant cells are noted; however, they do not differentiate between the various herpesviruses. Direct fluorescent antibody testing of scraped lesions and viral cultures of swabbed vesicular fluid are equally effective in distinguishing between herpes simplex virus type 1, herpes simplex virus type 2, and VZV; PCR confirms the diagnosis with high specificity and sensitivity.¹⁰

In our patient, the initial differential diagnosis included EH, acute generalized exanthematous pustulosis, allergic contact dermatitis, and Orthopoxvirus infection. The positive Tzanck smear reduced the likelihood of a nonviral etiology. Additionally, worsening of the rash despite discontinuation of medications and utilization of topical steroids argued against acute generalized exanthematous pustulosis and allergic contact dermatitis. The laboratory findings reduced the likelihood of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, and PCR findings ultimately ruled out Orthopoxvirus infections. Additional differential diagnoses for EH include dermatitis herpetiformis; primary VZV infection; hand, foot, and mouth disease; disseminated zoster infection; disseminated molluscum contagiosum; and eczema coxsackium.

Complications of EH include scarring; herpetic keratitis due to corneal infection, which if left untreated can progress to blindness; and rarely death due to multiorgan failure or septicemia.¹¹ The traditional smallpox vaccine (ACAM2000) is contraindicated in patients with AD and EH, even when AD is in remission. These patients should avoid contact with recently vaccinated individuals.¹² An alternative vaccine—Jynneos (Bavarian Nordic)—is available for these patients and their family members.¹³ Clinicians should be aware of this guideline, especially given the recent mpox (monkeypox) outbreaks.

Mild cases of EH are more common, may sometimes go unnoticed, and self-resolve in healthy patients. Severe cases may require systemic antiviral therapy. Acyclovir and its prodrug valacyclovir are standard treatments for EH. Alternatively, foscarnet or cidofovir can be used in the treatment of acyclovir-resistant thymidine kinase– deficient herpes simplex virus and other acyclovirresistant cases.¹⁴ Any secondary bacterial superinfections, usually due to staphylococcal or streptococcal bacteria, should be treated with antibiotics. A thorough ophthalmologic evaluation should be performed for patients with periocular involvement of EH. Empiric treatment should be started immediately, given a relative low toxicity of systemic antiviral therapy and high morbidity and mortality associated with untreated widespread EH.

It is important to maintain a high index of clinical suspicion for EH, especially in patients with pre-existing conditions such as AD who present with systemic symptoms and facial vesicles, pustules, or erosions to ensure prompt diagnosis and appropriate treatment.

The Diagnosis: Eczema Herpeticum

The patient’s condition with worsening facial edema and notable pain prompted a bedside Tzanck smear using a sample from the base of a deroofed forehead vesicle. In addition, a swab of a deroofed lesion was sent for herpes simplex virus and varicella-zoster virus (VZV) polymerase chain reaction (PCR) testing. The Tzanck smear demonstrated ballooning multinucleated syncytial giant cells and eosinophilic inclusion bodies (Figure), which are characteristic of certain herpesviruses including herpes simplex virus and VZV. He was started on intravenous acyclovir while PCR results were pending; the PCR test later confirmed positivity for herpes simplex virus type 1. Treatment was transitioned to oral valacyclovir once the lesions started crusting over. Notable healing and epithelialization of the lesions occurred during his hospital stay, and he was discharged home 5 days after starting treatment. He was counseled on autoinoculation, advised that he was considered infectious until all lesions had crusted over, and encouraged to employ frequent handwashing. Complete resolution of eczema herpeticum (EH) was noted at 3-week follow-up.

Eczema herpeticum (also known as Kaposi varicelliform eruption) is a potentially life-threatening disseminated cutaneous infection caused by herpes simplex virus types 1 and 2 in patients with pre-existing skin disease.¹ It typically presents as a complication of atopic dermatitis (AD) but also has been identified as a rare complication in other conditions that disrupt the normal skin barrier, including mycosis fungoides, pemphigus foliaceus, pemphigus vulgaris, Darier disease, pityriasis rubra pilaris, contact dermatitis, and seborrheic dermatitis.^1-4

The pathogenesis of EH is multifactorial. Disruption of the stratum corneum; impaired natural killer cell function; early-onset, untreated, or severe AD; disrupted skin microbiota with skewed colonization by Staphylococcus aureus; immunosuppressive AD therapies such as calcineurin inhibitors; eosinophilia; and helper T cell (T_H2) cytokine predominance all have been suggested to play a role in the development of EH.^5-8

As seen in our patient, EH presents with a sudden eruption of painful or pruritic, grouped, monomorphic, domeshaped vesicles with background swelling and erythema typically on the head, neck, and trunk. Vesicles then progress to punched-out erosions with overlying hemorrhagic crusting that can coalesce to form large denuded areas susceptible to superinfection with bacteria.⁹ Other accompanying symptoms include high fever, chills, malaise, and lymphadenopathy. Associated inflammation, classically described as erythema, may be difficult to discern in patients with darker skin and appears as hyperpigmentation; therefore, identification of clusters of monomorphic vesicles in areas of pre-existing dermatitis is particularly important for clinical diagnosis in people with darker skin types.

Various tests are available to confirm diagnosis in ambiguous cases. Bedside Tzanck smears can be performed rapidly and are considered positive if characteristic multinucleated giant cells are noted; however, they do not differentiate between the various herpesviruses. Direct fluorescent antibody testing of scraped lesions and viral cultures of swabbed vesicular fluid are equally effective in distinguishing between herpes simplex virus type 1, herpes simplex virus type 2, and VZV; PCR confirms the diagnosis with high specificity and sensitivity.¹⁰

In our patient, the initial differential diagnosis included EH, acute generalized exanthematous pustulosis, allergic contact dermatitis, and Orthopoxvirus infection. The positive Tzanck smear reduced the likelihood of a nonviral etiology. Additionally, worsening of the rash despite discontinuation of medications and utilization of topical steroids argued against acute generalized exanthematous pustulosis and allergic contact dermatitis. The laboratory findings reduced the likelihood of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, and PCR findings ultimately ruled out Orthopoxvirus infections. Additional differential diagnoses for EH include dermatitis herpetiformis; primary VZV infection; hand, foot, and mouth disease; disseminated zoster infection; disseminated molluscum contagiosum; and eczema coxsackium.

Complications of EH include scarring; herpetic keratitis due to corneal infection, which if left untreated can progress to blindness; and rarely death due to multiorgan failure or septicemia.¹¹ The traditional smallpox vaccine (ACAM2000) is contraindicated in patients with AD and EH, even when AD is in remission. These patients should avoid contact with recently vaccinated individuals.¹² An alternative vaccine—Jynneos (Bavarian Nordic)—is available for these patients and their family members.¹³ Clinicians should be aware of this guideline, especially given the recent mpox (monkeypox) outbreaks.

Mild cases of EH are more common, may sometimes go unnoticed, and self-resolve in healthy patients. Severe cases may require systemic antiviral therapy. Acyclovir and its prodrug valacyclovir are standard treatments for EH. Alternatively, foscarnet or cidofovir can be used in the treatment of acyclovir-resistant thymidine kinase– deficient herpes simplex virus and other acyclovirresistant cases.¹⁴ Any secondary bacterial superinfections, usually due to staphylococcal or streptococcal bacteria, should be treated with antibiotics. A thorough ophthalmologic evaluation should be performed for patients with periocular involvement of EH. Empiric treatment should be started immediately, given a relative low toxicity of systemic antiviral therapy and high morbidity and mortality associated with untreated widespread EH.

It is important to maintain a high index of clinical suspicion for EH, especially in patients with pre-existing conditions such as AD who present with systemic symptoms and facial vesicles, pustules, or erosions to ensure prompt diagnosis and appropriate treatment.

The Diagnosis: Eczema Herpeticum

The patient’s condition with worsening facial edema and notable pain prompted a bedside Tzanck smear using a sample from the base of a deroofed forehead vesicle. In addition, a swab of a deroofed lesion was sent for herpes simplex virus and varicella-zoster virus (VZV) polymerase chain reaction (PCR) testing. The Tzanck smear demonstrated ballooning multinucleated syncytial giant cells and eosinophilic inclusion bodies (Figure), which are characteristic of certain herpesviruses including herpes simplex virus and VZV. He was started on intravenous acyclovir while PCR results were pending; the PCR test later confirmed positivity for herpes simplex virus type 1. Treatment was transitioned to oral valacyclovir once the lesions started crusting over. Notable healing and epithelialization of the lesions occurred during his hospital stay, and he was discharged home 5 days after starting treatment. He was counseled on autoinoculation, advised that he was considered infectious until all lesions had crusted over, and encouraged to employ frequent handwashing. Complete resolution of eczema herpeticum (EH) was noted at 3-week follow-up.

Eczema herpeticum (also known as Kaposi varicelliform eruption) is a potentially life-threatening disseminated cutaneous infection caused by herpes simplex virus types 1 and 2 in patients with pre-existing skin disease.¹ It typically presents as a complication of atopic dermatitis (AD) but also has been identified as a rare complication in other conditions that disrupt the normal skin barrier, including mycosis fungoides, pemphigus foliaceus, pemphigus vulgaris, Darier disease, pityriasis rubra pilaris, contact dermatitis, and seborrheic dermatitis.^1-4

The pathogenesis of EH is multifactorial. Disruption of the stratum corneum; impaired natural killer cell function; early-onset, untreated, or severe AD; disrupted skin microbiota with skewed colonization by Staphylococcus aureus; immunosuppressive AD therapies such as calcineurin inhibitors; eosinophilia; and helper T cell (T_H2) cytokine predominance all have been suggested to play a role in the development of EH.^5-8

As seen in our patient, EH presents with a sudden eruption of painful or pruritic, grouped, monomorphic, domeshaped vesicles with background swelling and erythema typically on the head, neck, and trunk. Vesicles then progress to punched-out erosions with overlying hemorrhagic crusting that can coalesce to form large denuded areas susceptible to superinfection with bacteria.⁹ Other accompanying symptoms include high fever, chills, malaise, and lymphadenopathy. Associated inflammation, classically described as erythema, may be difficult to discern in patients with darker skin and appears as hyperpigmentation; therefore, identification of clusters of monomorphic vesicles in areas of pre-existing dermatitis is particularly important for clinical diagnosis in people with darker skin types.

Various tests are available to confirm diagnosis in ambiguous cases. Bedside Tzanck smears can be performed rapidly and are considered positive if characteristic multinucleated giant cells are noted; however, they do not differentiate between the various herpesviruses. Direct fluorescent antibody testing of scraped lesions and viral cultures of swabbed vesicular fluid are equally effective in distinguishing between herpes simplex virus type 1, herpes simplex virus type 2, and VZV; PCR confirms the diagnosis with high specificity and sensitivity.¹⁰

In our patient, the initial differential diagnosis included EH, acute generalized exanthematous pustulosis, allergic contact dermatitis, and Orthopoxvirus infection. The positive Tzanck smear reduced the likelihood of a nonviral etiology. Additionally, worsening of the rash despite discontinuation of medications and utilization of topical steroids argued against acute generalized exanthematous pustulosis and allergic contact dermatitis. The laboratory findings reduced the likelihood of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, and PCR findings ultimately ruled out Orthopoxvirus infections. Additional differential diagnoses for EH include dermatitis herpetiformis; primary VZV infection; hand, foot, and mouth disease; disseminated zoster infection; disseminated molluscum contagiosum; and eczema coxsackium.

Complications of EH include scarring; herpetic keratitis due to corneal infection, which if left untreated can progress to blindness; and rarely death due to multiorgan failure or septicemia.¹¹ The traditional smallpox vaccine (ACAM2000) is contraindicated in patients with AD and EH, even when AD is in remission. These patients should avoid contact with recently vaccinated individuals.¹² An alternative vaccine—Jynneos (Bavarian Nordic)—is available for these patients and their family members.¹³ Clinicians should be aware of this guideline, especially given the recent mpox (monkeypox) outbreaks.

Mild cases of EH are more common, may sometimes go unnoticed, and self-resolve in healthy patients. Severe cases may require systemic antiviral therapy. Acyclovir and its prodrug valacyclovir are standard treatments for EH. Alternatively, foscarnet or cidofovir can be used in the treatment of acyclovir-resistant thymidine kinase– deficient herpes simplex virus and other acyclovirresistant cases.¹⁴ Any secondary bacterial superinfections, usually due to staphylococcal or streptococcal bacteria, should be treated with antibiotics. A thorough ophthalmologic evaluation should be performed for patients with periocular involvement of EH. Empiric treatment should be started immediately, given a relative low toxicity of systemic antiviral therapy and high morbidity and mortality associated with untreated widespread EH.

It is important to maintain a high index of clinical suspicion for EH, especially in patients with pre-existing conditions such as AD who present with systemic symptoms and facial vesicles, pustules, or erosions to ensure prompt diagnosis and appropriate treatment.

Pathology showed noncaseating granulomas consistent with cutaneous sarcoidosis. Based on these biopsy findings, a chest x-ray was ordered, and it confirmed a pulmonary sarcoid. A multidisciplinary work-up (including cardiac evaluation, continued rheumatologic care, and evaluation by Hematology) addressed this new finding.

Sarcoidosis is a multisystem inflammatory disorder characterized by the development of granulomas that can arise in any organ, but frequently involve the skin and lungs. Patients with cutaneous disease develop smooth skin lesions, including flesh-colored to pink or brown papules on the face. Genetic and environmental factors are both thought to contribute to the disease.

Race is a significant factor in the development of disease. Hispanic and Asian patients are significantly less likely to develop the disease compared to White or Black patients. In the Black Women’s Health Study, incidence in Black women was 71 per 100,000.¹ Women are more likely to be affected than men.¹

Many patients with sarcoidosis have a mild course, but for others the disease may progress on the skin or include pulmonary, renal, neurologic, or cardiac disease. Sometimes sarcoidosis is fatal. Recurrence can occur at any point later in life. Race influences disease severity as well as incidence, with hospitalization being 9 times as likely in Black patients compared with White patients.² One recent study puts sarcoidosis mortality rates for Black women at 10 per million compared with 3 per million in Black men, and 1 per million in White women or men.³

Patients with disease limited to the skin may be treated with topical steroids such as clobetasol 0.05% cream or ointment or intralesional triamcinolone 10 mg/mL injected into affected lesions every 2 to 4 weeks. With pulmonary or other systemic disease, treatment may include various disease-modifying agents including prednisone, methotrexate, hydroxychloroquine, and TNF-alpha inhibitors. Because of the long-term adverse effects of systemic steroids, these agents are reserved for instances when pulmonary function is significantly impacted.

This patient had a reassuring cardiac and hematology work-up. Her pulmonary function was impacted sufficiently enough that her pulmonologist added a course of prednisone 10 mg daily tapered over 6 weeks. She had been on hydroxychloroquine 200 mg twice daily prior to the diagnosis of sarcoidosis for presumed mixed connective tissue disease and was continued on it for sarcoidosis after completing the prednisone taper. With these treatments, her facial lesions cleared and her breathing symptoms and fatigue improved. She remains under surveillance with a multidisciplinary team.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

Pathology showed noncaseating granulomas consistent with cutaneous sarcoidosis. Based on these biopsy findings, a chest x-ray was ordered, and it confirmed a pulmonary sarcoid. A multidisciplinary work-up (including cardiac evaluation, continued rheumatologic care, and evaluation by Hematology) addressed this new finding.

Sarcoidosis is a multisystem inflammatory disorder characterized by the development of granulomas that can arise in any organ, but frequently involve the skin and lungs. Patients with cutaneous disease develop smooth skin lesions, including flesh-colored to pink or brown papules on the face. Genetic and environmental factors are both thought to contribute to the disease.

Race is a significant factor in the development of disease. Hispanic and Asian patients are significantly less likely to develop the disease compared to White or Black patients. In the Black Women’s Health Study, incidence in Black women was 71 per 100,000.¹ Women are more likely to be affected than men.¹

Many patients with sarcoidosis have a mild course, but for others the disease may progress on the skin or include pulmonary, renal, neurologic, or cardiac disease. Sometimes sarcoidosis is fatal. Recurrence can occur at any point later in life. Race influences disease severity as well as incidence, with hospitalization being 9 times as likely in Black patients compared with White patients.² One recent study puts sarcoidosis mortality rates for Black women at 10 per million compared with 3 per million in Black men, and 1 per million in White women or men.³

Patients with disease limited to the skin may be treated with topical steroids such as clobetasol 0.05% cream or ointment or intralesional triamcinolone 10 mg/mL injected into affected lesions every 2 to 4 weeks. With pulmonary or other systemic disease, treatment may include various disease-modifying agents including prednisone, methotrexate, hydroxychloroquine, and TNF-alpha inhibitors. Because of the long-term adverse effects of systemic steroids, these agents are reserved for instances when pulmonary function is significantly impacted.

This patient had a reassuring cardiac and hematology work-up. Her pulmonary function was impacted sufficiently enough that her pulmonologist added a course of prednisone 10 mg daily tapered over 6 weeks. She had been on hydroxychloroquine 200 mg twice daily prior to the diagnosis of sarcoidosis for presumed mixed connective tissue disease and was continued on it for sarcoidosis after completing the prednisone taper. With these treatments, her facial lesions cleared and her breathing symptoms and fatigue improved. She remains under surveillance with a multidisciplinary team.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

Pathology showed noncaseating granulomas consistent with cutaneous sarcoidosis. Based on these biopsy findings, a chest x-ray was ordered, and it confirmed a pulmonary sarcoid. A multidisciplinary work-up (including cardiac evaluation, continued rheumatologic care, and evaluation by Hematology) addressed this new finding.

Sarcoidosis is a multisystem inflammatory disorder characterized by the development of granulomas that can arise in any organ, but frequently involve the skin and lungs. Patients with cutaneous disease develop smooth skin lesions, including flesh-colored to pink or brown papules on the face. Genetic and environmental factors are both thought to contribute to the disease.

Race is a significant factor in the development of disease. Hispanic and Asian patients are significantly less likely to develop the disease compared to White or Black patients. In the Black Women’s Health Study, incidence in Black women was 71 per 100,000.¹ Women are more likely to be affected than men.¹

Many patients with sarcoidosis have a mild course, but for others the disease may progress on the skin or include pulmonary, renal, neurologic, or cardiac disease. Sometimes sarcoidosis is fatal. Recurrence can occur at any point later in life. Race influences disease severity as well as incidence, with hospitalization being 9 times as likely in Black patients compared with White patients.² One recent study puts sarcoidosis mortality rates for Black women at 10 per million compared with 3 per million in Black men, and 1 per million in White women or men.³

Patients with disease limited to the skin may be treated with topical steroids such as clobetasol 0.05% cream or ointment or intralesional triamcinolone 10 mg/mL injected into affected lesions every 2 to 4 weeks. With pulmonary or other systemic disease, treatment may include various disease-modifying agents including prednisone, methotrexate, hydroxychloroquine, and TNF-alpha inhibitors. Because of the long-term adverse effects of systemic steroids, these agents are reserved for instances when pulmonary function is significantly impacted.

This patient had a reassuring cardiac and hematology work-up. Her pulmonary function was impacted sufficiently enough that her pulmonologist added a course of prednisone 10 mg daily tapered over 6 weeks. She had been on hydroxychloroquine 200 mg twice daily prior to the diagnosis of sarcoidosis for presumed mixed connective tissue disease and was continued on it for sarcoidosis after completing the prednisone taper. With these treatments, her facial lesions cleared and her breathing symptoms and fatigue improved. She remains under surveillance with a multidisciplinary team.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.

In October, the Diversity, Equity, and Inclusion in GI section of Gastroenterology and Clinical Gastroenterology and Hepatology features the article, “Parental Leave and Return-to-Work Policies: A Practical Model for Implementation in Gastroenterology.” 

The authors note that this article can serve as a roadmap for institutions and practices to create a parental leave policy and return-to-work environment that attracts talent and supports a diverse and thriving workforce. 

Despite a joint statement by the four main gastroenterology societies more than 25 years ago, few structural changes have been implemented to mandate a minimum of 12 weeks of parental leave for gastroenterologists. 

We asked one of the article’s authors, Dr. Lauren D. Feld, a few questions about the motivation behind this article and the movement at large.
 

Q: What motivated you and your coauthors to write this article?

A: “It was a pleasure working with my coauthors – an incredible team of gender equity experts – Drs. Amy S. Oxentenko, Dawn Sears, Aline Charabaty, Loren G. Rabinowitz, and Julie K. Silver. 

I’m grateful to Dr. May and Dr. Quezada for the invitation to write about the important topic of creating family-friendly work environments. My coauthors and I have noticed increasing support for women in gastroenterology.”

UMass

Q: Why is this issue important?

A: “Nationwide, women are leaving clinical and academic medicine at alarming rates. The incompatibility of parenthood with a traditional medical career has been identified as a major driver of retention issues across specialties. In addition to impacting retention, incompatibility with pregnancy and parenthood also impacts recruitment. Survey studies of internal medicine residents have identified concerns about family life as a major barrier to choosing gastroenterology as a specialty. Women in medicine have worked too hard to get to where they are to be excluded from or driven out of our field. 

Beyond the impact on the physicians, there is a major impact on patients. Studies have identified that women patients’ preference for a woman endoscopist as well as the difficulty in finding women endoscopists has created a barrier to colon cancer screening for women. Areas of research have also gone understudied because they primarily impact women patients. We must work towards equity for the benefit of both physicians and patients.”
 

Q: What actions can practicing GI doctors take now to help support better parental leave and return to work policies?

A: “Start by reviewing this article and asking your human resources for your employer’s policies in this area. If your employer doesn’t have a parental leave policy, or if their policy is inadequate, discuss the importance of this with your leadership. Describing the cost impact of physicians leaving practice is a good way to justify the cost investment to support family friendly policies.”

The authors recommend policies outlined in the paper be consistent across genders with attention to equity for the LGBTQ+ community. The blueprint for parental leave and return to work department policies includes:  

• Specific policies to support physicians during pregnancy, including endoscopy ergonomic accommodations. 
• Components of a parental leave policy such as duration and adjusted RVUs to account for leave. 
• Coverage models to consider during leave.  
• How to create a family friendly return to work, including modified overnight call during postpartum and autonomy over schedule.

In October, the Diversity, Equity, and Inclusion in GI section of Gastroenterology and Clinical Gastroenterology and Hepatology features the article, “Parental Leave and Return-to-Work Policies: A Practical Model for Implementation in Gastroenterology.” 

The authors note that this article can serve as a roadmap for institutions and practices to create a parental leave policy and return-to-work environment that attracts talent and supports a diverse and thriving workforce. 

Despite a joint statement by the four main gastroenterology societies more than 25 years ago, few structural changes have been implemented to mandate a minimum of 12 weeks of parental leave for gastroenterologists. 

We asked one of the article’s authors, Dr. Lauren D. Feld, a few questions about the motivation behind this article and the movement at large.
 

Q: What motivated you and your coauthors to write this article?

A: “It was a pleasure working with my coauthors – an incredible team of gender equity experts – Drs. Amy S. Oxentenko, Dawn Sears, Aline Charabaty, Loren G. Rabinowitz, and Julie K. Silver. 

I’m grateful to Dr. May and Dr. Quezada for the invitation to write about the important topic of creating family-friendly work environments. My coauthors and I have noticed increasing support for women in gastroenterology.”

UMass

Q: Why is this issue important?

A: “Nationwide, women are leaving clinical and academic medicine at alarming rates. The incompatibility of parenthood with a traditional medical career has been identified as a major driver of retention issues across specialties. In addition to impacting retention, incompatibility with pregnancy and parenthood also impacts recruitment. Survey studies of internal medicine residents have identified concerns about family life as a major barrier to choosing gastroenterology as a specialty. Women in medicine have worked too hard to get to where they are to be excluded from or driven out of our field. 

Beyond the impact on the physicians, there is a major impact on patients. Studies have identified that women patients’ preference for a woman endoscopist as well as the difficulty in finding women endoscopists has created a barrier to colon cancer screening for women. Areas of research have also gone understudied because they primarily impact women patients. We must work towards equity for the benefit of both physicians and patients.”
 

Q: What actions can practicing GI doctors take now to help support better parental leave and return to work policies?

A: “Start by reviewing this article and asking your human resources for your employer’s policies in this area. If your employer doesn’t have a parental leave policy, or if their policy is inadequate, discuss the importance of this with your leadership. Describing the cost impact of physicians leaving practice is a good way to justify the cost investment to support family friendly policies.”

The authors recommend policies outlined in the paper be consistent across genders with attention to equity for the LGBTQ+ community. The blueprint for parental leave and return to work department policies includes:  

• Specific policies to support physicians during pregnancy, including endoscopy ergonomic accommodations. 
• Components of a parental leave policy such as duration and adjusted RVUs to account for leave. 
• Coverage models to consider during leave.  
• How to create a family friendly return to work, including modified overnight call during postpartum and autonomy over schedule.

In October, the Diversity, Equity, and Inclusion in GI section of Gastroenterology and Clinical Gastroenterology and Hepatology features the article, “Parental Leave and Return-to-Work Policies: A Practical Model for Implementation in Gastroenterology.” 

The authors note that this article can serve as a roadmap for institutions and practices to create a parental leave policy and return-to-work environment that attracts talent and supports a diverse and thriving workforce. 

Despite a joint statement by the four main gastroenterology societies more than 25 years ago, few structural changes have been implemented to mandate a minimum of 12 weeks of parental leave for gastroenterologists. 

We asked one of the article’s authors, Dr. Lauren D. Feld, a few questions about the motivation behind this article and the movement at large.
 

Q: What motivated you and your coauthors to write this article?

A: “It was a pleasure working with my coauthors – an incredible team of gender equity experts – Drs. Amy S. Oxentenko, Dawn Sears, Aline Charabaty, Loren G. Rabinowitz, and Julie K. Silver. 

I’m grateful to Dr. May and Dr. Quezada for the invitation to write about the important topic of creating family-friendly work environments. My coauthors and I have noticed increasing support for women in gastroenterology.”

UMass

Q: Why is this issue important?

A: “Nationwide, women are leaving clinical and academic medicine at alarming rates. The incompatibility of parenthood with a traditional medical career has been identified as a major driver of retention issues across specialties. In addition to impacting retention, incompatibility with pregnancy and parenthood also impacts recruitment. Survey studies of internal medicine residents have identified concerns about family life as a major barrier to choosing gastroenterology as a specialty. Women in medicine have worked too hard to get to where they are to be excluded from or driven out of our field. 

Beyond the impact on the physicians, there is a major impact on patients. Studies have identified that women patients’ preference for a woman endoscopist as well as the difficulty in finding women endoscopists has created a barrier to colon cancer screening for women. Areas of research have also gone understudied because they primarily impact women patients. We must work towards equity for the benefit of both physicians and patients.”
 

Q: What actions can practicing GI doctors take now to help support better parental leave and return to work policies?

A: “Start by reviewing this article and asking your human resources for your employer’s policies in this area. If your employer doesn’t have a parental leave policy, or if their policy is inadequate, discuss the importance of this with your leadership. Describing the cost impact of physicians leaving practice is a good way to justify the cost investment to support family friendly policies.”

The authors recommend policies outlined in the paper be consistent across genders with attention to equity for the LGBTQ+ community. The blueprint for parental leave and return to work department policies includes:  

• Specific policies to support physicians during pregnancy, including endoscopy ergonomic accommodations. 
• Components of a parental leave policy such as duration and adjusted RVUs to account for leave. 
• Coverage models to consider during leave.  
• How to create a family friendly return to work, including modified overnight call during postpartum and autonomy over schedule.

Inpatient headache admissions are often considered a last-case scenario option for patients with chronic refractory migraine. Initially described by Raskin,¹ the admission typically consists of repetitive infusions of dihydroergotamine (DHE) with a pretreatment of antihistamine, neuroleptic, and other antinausea medications in addition to anti-inflammatory or steroid medications, IV fluids, and magnesium. Often this is superimposed on a continuous infusion of lidocaine or ketamine. One common concern is whether the use of DHE is safe for patients at a higher risk for vascular disease. Wang and colleagues reported on the incidence of cardiovascular adverse events in this population receiving repetitive intravenous DHE.

They present findings based on the Jefferson Headache Center (Philadelphia, Pennsylvania) Inpatient Headache Protocol, looking at patients admitted from January through October 2019. Of the 347 patients admitted during this period, 64 were identified as having either an elevated or low risk for atherosclerotic vascular disease. The degree of vascular risk was determined on the basis of an atherosclerotic cardiovascular disease calculation, using body mass index values, cholesterol level, and mean arterial blood pressure readings, as well as smoking and diabetes history. A score < 5.0% was designated low risk, while elevated risk included scores up to 20%. DHE was not offered to patients with a history of moderate to severe ischemic heart disease, coronary vasospasm, peripheral artery disease, Raynaud phenomenon, or ischemic stroke.

The primary outcome was treatment effectiveness, determined by an 11-point pain scale; secondary outcomes included tolerability, as defined by change in the patient's QTc (corrected QT interval) based on their daily ECG monitoring, the incidence of chest pain or shortness of breath, and whether DHE needed to be tapered or discontinued. The researchers noted that the elevated-vascular-risk group had fewer patients receiving the maximum dose of DHE and receiving less DHE over the course of their admission as compared with the low-risk group. They also reported lower response rates and less freedom from pain after admission. No clinically significant adverse events were noted in either group, and only three patients had sustained ECG changes from baseline.

DHE remains an effective treatment for the most chronic and refractory migraine cases, and it can be provided safely and effectively in an appropriately monitored setting. Although there still are contraindications for receiving DHE, those who can receive it may benefit significantly. Ideally, this should be done with cardiac clearance if there is any doubt regarding the vascular risk for any individual patient.

The frequency and severity of migraine can fluctuate due to a myriad of factors. When faced with worsening migraine, most healthcare providers ask their patients about specific triggers or other potential causes that may have led to the recent subacute worsening. Many healthcare providers will also investigate further, and when appropriate, order serum lab testing to determine whether any potential metabolic derangement, vitamin deficiency, or other abnormality could be contributing. Subclinical hypothyroidism is a common finding when investigating for these potential causes of worsening migraine, and often our internal medicine or endocrinology colleagues will discount these findings as "borderline" or still within normal limits. Dev and colleagues sought to determine whether low-dose thyroid replacement was beneficial for migraine prevention in this situation.

This study defined subclinical hypothyroidism as a thyroid-stimulating hormone (TSH) level of 4.5-10.0 mIU/L with a normal free thyroxine (T4), measured twice within 6 weeks for confirmation. Patients with prior thyroid disease were excluded from the study. Participants were randomly assigned to take 25 μg levothyroxine supplementation or placebo and were allowed to continue their migraine treatments. The primary outcomes were reduction in headache duration, frequency, severity, and Migraine Disability Assessment (MIDAS) score after 3 months.

A total of 87 patients with migraine and subclinical hypothyroidism were recruited, and the investigators noted a statistically significant improvement in all parameters (migraine frequency, severity, duration, MIDAS score) after 3 months of low-dose thyroid supplementation. This was maintained at a 3-month follow-up visit as well. TSH levels normalized in 87% of participants after repeat testing 3 months after the intervention.

When evaluating patients with worsening migraine who had been stable, it is wise to consider subclinical hypothyroidism as a potential etiology. Low-dose thyroid hormone supplementation appears to be well tolerated and effective for normalizing both TSH levels and, importantly, the migrainous exacerbation. Clinicians often will start or add preventive medications, ignoring the reason that there was an exacerbation in the first place, even though many of our colleagues choose not to treat this degree of hypothyroidism.

Many variants of migraine are better recognized and understood now; chief among these is vestibular migraine (VM). VM is a migraine subtype characterized by frequent or near-constant vestibular symptoms (vertigo, lightheadedness, disequilibrium, or rocking) with superimposed headache symptoms with some migrainous features. VM is generally considered to be more difficult to treat and more treatment-refractory than episodic or chronic migraine without vestibular symptoms. There are few treatments that are specific for this variant of migraine. Chen and colleagues sought to better understand the evidence of specific treatments for VM via meta-analysis.

Only randomized controlled trials were included in this meta-analysis; seven studies that specifically recruited patients with vestibular migraine using International Classification of Headache Disorders (ICHD) criteria were included. The outcomes of the studies were changes in frequency or severity of vestibular migraine attacks. The studies that were included were published from 2014 to 2022 and comprised multiple treatment comparisons, including metoprolol, venlafaxine, valproic acid, propranolol, flunarizine, a probiotic, and relaxation techniques.

Three interventions were noted to be significantly beneficial for VM prevention, specifically a decrease in migraine frequency: valproic acid, propranolol, and venlafaxine. Valproic acid yielded the greatest decrease in VM frequency among all interventions. None of the interventions were associated with improvement in VM severity, and none of the treatments were associated with significantly different adverse-event and dropout rates.

VM is widely thought to be underdiagnosed and should be considered more frequently. This includes situations in which the headache component of the patient's complaints is relatively mild but still associated with features of migraines, such as sensitivities to light and sound, nausea, or unilateral presentations of pain. There remain very few high-quality VM studies, but this meta-analysis should highlight potential treatment options and raise the profile for this diagnosis in order for further trials to be performed.

Additional Reference

1. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology. 1986;36(7):995-997. doi: 10.1212/WNL.36.7.995

Inpatient headache admissions are often considered a last-case scenario option for patients with chronic refractory migraine. Initially described by Raskin,¹ the admission typically consists of repetitive infusions of dihydroergotamine (DHE) with a pretreatment of antihistamine, neuroleptic, and other antinausea medications in addition to anti-inflammatory or steroid medications, IV fluids, and magnesium. Often this is superimposed on a continuous infusion of lidocaine or ketamine. One common concern is whether the use of DHE is safe for patients at a higher risk for vascular disease. Wang and colleagues reported on the incidence of cardiovascular adverse events in this population receiving repetitive intravenous DHE.

They present findings based on the Jefferson Headache Center (Philadelphia, Pennsylvania) Inpatient Headache Protocol, looking at patients admitted from January through October 2019. Of the 347 patients admitted during this period, 64 were identified as having either an elevated or low risk for atherosclerotic vascular disease. The degree of vascular risk was determined on the basis of an atherosclerotic cardiovascular disease calculation, using body mass index values, cholesterol level, and mean arterial blood pressure readings, as well as smoking and diabetes history. A score < 5.0% was designated low risk, while elevated risk included scores up to 20%. DHE was not offered to patients with a history of moderate to severe ischemic heart disease, coronary vasospasm, peripheral artery disease, Raynaud phenomenon, or ischemic stroke.

The primary outcome was treatment effectiveness, determined by an 11-point pain scale; secondary outcomes included tolerability, as defined by change in the patient's QTc (corrected QT interval) based on their daily ECG monitoring, the incidence of chest pain or shortness of breath, and whether DHE needed to be tapered or discontinued. The researchers noted that the elevated-vascular-risk group had fewer patients receiving the maximum dose of DHE and receiving less DHE over the course of their admission as compared with the low-risk group. They also reported lower response rates and less freedom from pain after admission. No clinically significant adverse events were noted in either group, and only three patients had sustained ECG changes from baseline.

DHE remains an effective treatment for the most chronic and refractory migraine cases, and it can be provided safely and effectively in an appropriately monitored setting. Although there still are contraindications for receiving DHE, those who can receive it may benefit significantly. Ideally, this should be done with cardiac clearance if there is any doubt regarding the vascular risk for any individual patient.

The frequency and severity of migraine can fluctuate due to a myriad of factors. When faced with worsening migraine, most healthcare providers ask their patients about specific triggers or other potential causes that may have led to the recent subacute worsening. Many healthcare providers will also investigate further, and when appropriate, order serum lab testing to determine whether any potential metabolic derangement, vitamin deficiency, or other abnormality could be contributing. Subclinical hypothyroidism is a common finding when investigating for these potential causes of worsening migraine, and often our internal medicine or endocrinology colleagues will discount these findings as "borderline" or still within normal limits. Dev and colleagues sought to determine whether low-dose thyroid replacement was beneficial for migraine prevention in this situation.

This study defined subclinical hypothyroidism as a thyroid-stimulating hormone (TSH) level of 4.5-10.0 mIU/L with a normal free thyroxine (T4), measured twice within 6 weeks for confirmation. Patients with prior thyroid disease were excluded from the study. Participants were randomly assigned to take 25 μg levothyroxine supplementation or placebo and were allowed to continue their migraine treatments. The primary outcomes were reduction in headache duration, frequency, severity, and Migraine Disability Assessment (MIDAS) score after 3 months.

A total of 87 patients with migraine and subclinical hypothyroidism were recruited, and the investigators noted a statistically significant improvement in all parameters (migraine frequency, severity, duration, MIDAS score) after 3 months of low-dose thyroid supplementation. This was maintained at a 3-month follow-up visit as well. TSH levels normalized in 87% of participants after repeat testing 3 months after the intervention.

When evaluating patients with worsening migraine who had been stable, it is wise to consider subclinical hypothyroidism as a potential etiology. Low-dose thyroid hormone supplementation appears to be well tolerated and effective for normalizing both TSH levels and, importantly, the migrainous exacerbation. Clinicians often will start or add preventive medications, ignoring the reason that there was an exacerbation in the first place, even though many of our colleagues choose not to treat this degree of hypothyroidism.

Many variants of migraine are better recognized and understood now; chief among these is vestibular migraine (VM). VM is a migraine subtype characterized by frequent or near-constant vestibular symptoms (vertigo, lightheadedness, disequilibrium, or rocking) with superimposed headache symptoms with some migrainous features. VM is generally considered to be more difficult to treat and more treatment-refractory than episodic or chronic migraine without vestibular symptoms. There are few treatments that are specific for this variant of migraine. Chen and colleagues sought to better understand the evidence of specific treatments for VM via meta-analysis.

Only randomized controlled trials were included in this meta-analysis; seven studies that specifically recruited patients with vestibular migraine using International Classification of Headache Disorders (ICHD) criteria were included. The outcomes of the studies were changes in frequency or severity of vestibular migraine attacks. The studies that were included were published from 2014 to 2022 and comprised multiple treatment comparisons, including metoprolol, venlafaxine, valproic acid, propranolol, flunarizine, a probiotic, and relaxation techniques.

Three interventions were noted to be significantly beneficial for VM prevention, specifically a decrease in migraine frequency: valproic acid, propranolol, and venlafaxine. Valproic acid yielded the greatest decrease in VM frequency among all interventions. None of the interventions were associated with improvement in VM severity, and none of the treatments were associated with significantly different adverse-event and dropout rates.

VM is widely thought to be underdiagnosed and should be considered more frequently. This includes situations in which the headache component of the patient's complaints is relatively mild but still associated with features of migraines, such as sensitivities to light and sound, nausea, or unilateral presentations of pain. There remain very few high-quality VM studies, but this meta-analysis should highlight potential treatment options and raise the profile for this diagnosis in order for further trials to be performed.

Additional Reference

1. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology. 1986;36(7):995-997. doi: 10.1212/WNL.36.7.995

Inpatient headache admissions are often considered a last-case scenario option for patients with chronic refractory migraine. Initially described by Raskin,¹ the admission typically consists of repetitive infusions of dihydroergotamine (DHE) with a pretreatment of antihistamine, neuroleptic, and other antinausea medications in addition to anti-inflammatory or steroid medications, IV fluids, and magnesium. Often this is superimposed on a continuous infusion of lidocaine or ketamine. One common concern is whether the use of DHE is safe for patients at a higher risk for vascular disease. Wang and colleagues reported on the incidence of cardiovascular adverse events in this population receiving repetitive intravenous DHE.

They present findings based on the Jefferson Headache Center (Philadelphia, Pennsylvania) Inpatient Headache Protocol, looking at patients admitted from January through October 2019. Of the 347 patients admitted during this period, 64 were identified as having either an elevated or low risk for atherosclerotic vascular disease. The degree of vascular risk was determined on the basis of an atherosclerotic cardiovascular disease calculation, using body mass index values, cholesterol level, and mean arterial blood pressure readings, as well as smoking and diabetes history. A score < 5.0% was designated low risk, while elevated risk included scores up to 20%. DHE was not offered to patients with a history of moderate to severe ischemic heart disease, coronary vasospasm, peripheral artery disease, Raynaud phenomenon, or ischemic stroke.

The primary outcome was treatment effectiveness, determined by an 11-point pain scale; secondary outcomes included tolerability, as defined by change in the patient's QTc (corrected QT interval) based on their daily ECG monitoring, the incidence of chest pain or shortness of breath, and whether DHE needed to be tapered or discontinued. The researchers noted that the elevated-vascular-risk group had fewer patients receiving the maximum dose of DHE and receiving less DHE over the course of their admission as compared with the low-risk group. They also reported lower response rates and less freedom from pain after admission. No clinically significant adverse events were noted in either group, and only three patients had sustained ECG changes from baseline.

DHE remains an effective treatment for the most chronic and refractory migraine cases, and it can be provided safely and effectively in an appropriately monitored setting. Although there still are contraindications for receiving DHE, those who can receive it may benefit significantly. Ideally, this should be done with cardiac clearance if there is any doubt regarding the vascular risk for any individual patient.

The frequency and severity of migraine can fluctuate due to a myriad of factors. When faced with worsening migraine, most healthcare providers ask their patients about specific triggers or other potential causes that may have led to the recent subacute worsening. Many healthcare providers will also investigate further, and when appropriate, order serum lab testing to determine whether any potential metabolic derangement, vitamin deficiency, or other abnormality could be contributing. Subclinical hypothyroidism is a common finding when investigating for these potential causes of worsening migraine, and often our internal medicine or endocrinology colleagues will discount these findings as "borderline" or still within normal limits. Dev and colleagues sought to determine whether low-dose thyroid replacement was beneficial for migraine prevention in this situation.

This study defined subclinical hypothyroidism as a thyroid-stimulating hormone (TSH) level of 4.5-10.0 mIU/L with a normal free thyroxine (T4), measured twice within 6 weeks for confirmation. Patients with prior thyroid disease were excluded from the study. Participants were randomly assigned to take 25 μg levothyroxine supplementation or placebo and were allowed to continue their migraine treatments. The primary outcomes were reduction in headache duration, frequency, severity, and Migraine Disability Assessment (MIDAS) score after 3 months.

A total of 87 patients with migraine and subclinical hypothyroidism were recruited, and the investigators noted a statistically significant improvement in all parameters (migraine frequency, severity, duration, MIDAS score) after 3 months of low-dose thyroid supplementation. This was maintained at a 3-month follow-up visit as well. TSH levels normalized in 87% of participants after repeat testing 3 months after the intervention.

When evaluating patients with worsening migraine who had been stable, it is wise to consider subclinical hypothyroidism as a potential etiology. Low-dose thyroid hormone supplementation appears to be well tolerated and effective for normalizing both TSH levels and, importantly, the migrainous exacerbation. Clinicians often will start or add preventive medications, ignoring the reason that there was an exacerbation in the first place, even though many of our colleagues choose not to treat this degree of hypothyroidism.

Many variants of migraine are better recognized and understood now; chief among these is vestibular migraine (VM). VM is a migraine subtype characterized by frequent or near-constant vestibular symptoms (vertigo, lightheadedness, disequilibrium, or rocking) with superimposed headache symptoms with some migrainous features. VM is generally considered to be more difficult to treat and more treatment-refractory than episodic or chronic migraine without vestibular symptoms. There are few treatments that are specific for this variant of migraine. Chen and colleagues sought to better understand the evidence of specific treatments for VM via meta-analysis.

Only randomized controlled trials were included in this meta-analysis; seven studies that specifically recruited patients with vestibular migraine using International Classification of Headache Disorders (ICHD) criteria were included. The outcomes of the studies were changes in frequency or severity of vestibular migraine attacks. The studies that were included were published from 2014 to 2022 and comprised multiple treatment comparisons, including metoprolol, venlafaxine, valproic acid, propranolol, flunarizine, a probiotic, and relaxation techniques.

Three interventions were noted to be significantly beneficial for VM prevention, specifically a decrease in migraine frequency: valproic acid, propranolol, and venlafaxine. Valproic acid yielded the greatest decrease in VM frequency among all interventions. None of the interventions were associated with improvement in VM severity, and none of the treatments were associated with significantly different adverse-event and dropout rates.

VM is widely thought to be underdiagnosed and should be considered more frequently. This includes situations in which the headache component of the patient's complaints is relatively mild but still associated with features of migraines, such as sensitivities to light and sound, nausea, or unilateral presentations of pain. There remain very few high-quality VM studies, but this meta-analysis should highlight potential treatment options and raise the profile for this diagnosis in order for further trials to be performed.

Additional Reference

1. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology. 1986;36(7):995-997. doi: 10.1212/WNL.36.7.995

This patient's symptoms go beyond just memory problems: She has difficulty with daily tasks, shows behavioral changes, and has significant communication difficulties — symptoms not found in mild cognitive impairment. While the patient has some behavioral changes, she does not exhibit the pronounced personality changes typical of frontotemporal dementia. Finally, the patient's cognitive decline is gradual and consistent without the stepwise progression typical of vascular dementia. Given the comprehensive presentation of the patient's symptoms and the results of her clinical investigations, middle-stage Alzheimer's disease is the most fitting diagnosis.

Alzheimer's disease is a progressive and irreversible brain disorder that affects memory, behavior, and cognitive skills. This condition causes the degeneration and death of brain cells, leading to various cognitive issues. Alzheimer's disease is the most common cause of dementia and accounts for 60%-80% of dementia cases. Although the exact cause is unknown, it is believed to result from genetic, lifestyle, and environmental factors. Alzheimer's disease progresses through stages — mild (early stage), moderate (middle stage), and severe (late stage) — and each stage has different signs and symptoms.

Alzheimer's disease is commonly observed in individuals 65 years or older, as age is the most significant risk factor. Another risk factor for Alzheimer's disease is family history; individuals who have parents or siblings with Alzheimer's disease are more likely to develop the disease. The risk increases with the number of family members diagnosed with the disease. Genetics also contribute to the development of Alzheimer's disease. Genes for developing Alzheimer's disease have been classified as deterministic and risk genes, which imply that they can cause the disease or increase the risk of developing it; however, the deterministic gene, which almost guarantees the occurrence of Alzheimer's, is rare and is found in less than 1% of cases. Experiencing a head injury is also a possible risk factor for Alzheimer's disease.

Accurate diagnosis of Alzheimer's disease requires a thorough history and physical examination. Gathering information from the patient's family and caregivers is important because some patients may not be aware of their condition. It is common for Alzheimer's disease patients to experience "sundowning," which causes confusion, agitation, and behavioral issues in the evening. A comprehensive physical examination, including a detailed neurologic and mental status exam, is necessary to determine the stage of the disease and rule out other conditions. Typically, the neurologic exam of Alzheimer's disease patients is normal.

Volumetric MRI is a recent technique that allows precise measurement of changes in brain volume. In Alzheimer's disease, shrinkage in the medial temporal lobe is visible through volumetric MRI. However, hippocampal atrophy is also a normal part of age-related memory decline, which raises doubts about the appropriateness of using volumetric MRI for early detection of Alzheimer's disease. The full potential of volumetric MRI in aiding the diagnosis of Alzheimer's disease is yet to be fully established.

Alzheimer's disease has no known cure, and treatment options are limited to addressing symptoms. Currently, three types of drugs are approved for treating the moderate or severe stages of the disease: cholinesterase inhibitors, partial N-methyl D-aspartate (NMDA) antagonists, and amyloid-directed antibodies. Cholinesterase inhibitors increase acetylcholine levels, a chemical crucial for cognitive functions such as memory and learning. NMDA antagonists (memantine) blocks NMDA receptors whose overactivation is implicated in Alzheimer's disease and related to synaptic dysfunction. Antiamyloid monoclonal antibodies bind to and promote the clearance of amyloid-beta peptides, thereby reducing amyloid plaques in the brain, which are associated with Alzheimer's disease.

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

This patient's symptoms go beyond just memory problems: She has difficulty with daily tasks, shows behavioral changes, and has significant communication difficulties — symptoms not found in mild cognitive impairment. While the patient has some behavioral changes, she does not exhibit the pronounced personality changes typical of frontotemporal dementia. Finally, the patient's cognitive decline is gradual and consistent without the stepwise progression typical of vascular dementia. Given the comprehensive presentation of the patient's symptoms and the results of her clinical investigations, middle-stage Alzheimer's disease is the most fitting diagnosis.

Alzheimer's disease is a progressive and irreversible brain disorder that affects memory, behavior, and cognitive skills. This condition causes the degeneration and death of brain cells, leading to various cognitive issues. Alzheimer's disease is the most common cause of dementia and accounts for 60%-80% of dementia cases. Although the exact cause is unknown, it is believed to result from genetic, lifestyle, and environmental factors. Alzheimer's disease progresses through stages — mild (early stage), moderate (middle stage), and severe (late stage) — and each stage has different signs and symptoms.

Alzheimer's disease is commonly observed in individuals 65 years or older, as age is the most significant risk factor. Another risk factor for Alzheimer's disease is family history; individuals who have parents or siblings with Alzheimer's disease are more likely to develop the disease. The risk increases with the number of family members diagnosed with the disease. Genetics also contribute to the development of Alzheimer's disease. Genes for developing Alzheimer's disease have been classified as deterministic and risk genes, which imply that they can cause the disease or increase the risk of developing it; however, the deterministic gene, which almost guarantees the occurrence of Alzheimer's, is rare and is found in less than 1% of cases. Experiencing a head injury is also a possible risk factor for Alzheimer's disease.

Accurate diagnosis of Alzheimer's disease requires a thorough history and physical examination. Gathering information from the patient's family and caregivers is important because some patients may not be aware of their condition. It is common for Alzheimer's disease patients to experience "sundowning," which causes confusion, agitation, and behavioral issues in the evening. A comprehensive physical examination, including a detailed neurologic and mental status exam, is necessary to determine the stage of the disease and rule out other conditions. Typically, the neurologic exam of Alzheimer's disease patients is normal.

Volumetric MRI is a recent technique that allows precise measurement of changes in brain volume. In Alzheimer's disease, shrinkage in the medial temporal lobe is visible through volumetric MRI. However, hippocampal atrophy is also a normal part of age-related memory decline, which raises doubts about the appropriateness of using volumetric MRI for early detection of Alzheimer's disease. The full potential of volumetric MRI in aiding the diagnosis of Alzheimer's disease is yet to be fully established.

Alzheimer's disease has no known cure, and treatment options are limited to addressing symptoms. Currently, three types of drugs are approved for treating the moderate or severe stages of the disease: cholinesterase inhibitors, partial N-methyl D-aspartate (NMDA) antagonists, and amyloid-directed antibodies. Cholinesterase inhibitors increase acetylcholine levels, a chemical crucial for cognitive functions such as memory and learning. NMDA antagonists (memantine) blocks NMDA receptors whose overactivation is implicated in Alzheimer's disease and related to synaptic dysfunction. Antiamyloid monoclonal antibodies bind to and promote the clearance of amyloid-beta peptides, thereby reducing amyloid plaques in the brain, which are associated with Alzheimer's disease.

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

This patient's symptoms go beyond just memory problems: She has difficulty with daily tasks, shows behavioral changes, and has significant communication difficulties — symptoms not found in mild cognitive impairment. While the patient has some behavioral changes, she does not exhibit the pronounced personality changes typical of frontotemporal dementia. Finally, the patient's cognitive decline is gradual and consistent without the stepwise progression typical of vascular dementia. Given the comprehensive presentation of the patient's symptoms and the results of her clinical investigations, middle-stage Alzheimer's disease is the most fitting diagnosis.

Alzheimer's disease is a progressive and irreversible brain disorder that affects memory, behavior, and cognitive skills. This condition causes the degeneration and death of brain cells, leading to various cognitive issues. Alzheimer's disease is the most common cause of dementia and accounts for 60%-80% of dementia cases. Although the exact cause is unknown, it is believed to result from genetic, lifestyle, and environmental factors. Alzheimer's disease progresses through stages — mild (early stage), moderate (middle stage), and severe (late stage) — and each stage has different signs and symptoms.

Alzheimer's disease is commonly observed in individuals 65 years or older, as age is the most significant risk factor. Another risk factor for Alzheimer's disease is family history; individuals who have parents or siblings with Alzheimer's disease are more likely to develop the disease. The risk increases with the number of family members diagnosed with the disease. Genetics also contribute to the development of Alzheimer's disease. Genes for developing Alzheimer's disease have been classified as deterministic and risk genes, which imply that they can cause the disease or increase the risk of developing it; however, the deterministic gene, which almost guarantees the occurrence of Alzheimer's, is rare and is found in less than 1% of cases. Experiencing a head injury is also a possible risk factor for Alzheimer's disease.

Accurate diagnosis of Alzheimer's disease requires a thorough history and physical examination. Gathering information from the patient's family and caregivers is important because some patients may not be aware of their condition. It is common for Alzheimer's disease patients to experience "sundowning," which causes confusion, agitation, and behavioral issues in the evening. A comprehensive physical examination, including a detailed neurologic and mental status exam, is necessary to determine the stage of the disease and rule out other conditions. Typically, the neurologic exam of Alzheimer's disease patients is normal.

Volumetric MRI is a recent technique that allows precise measurement of changes in brain volume. In Alzheimer's disease, shrinkage in the medial temporal lobe is visible through volumetric MRI. However, hippocampal atrophy is also a normal part of age-related memory decline, which raises doubts about the appropriateness of using volumetric MRI for early detection of Alzheimer's disease. The full potential of volumetric MRI in aiding the diagnosis of Alzheimer's disease is yet to be fully established.

Alzheimer's disease has no known cure, and treatment options are limited to addressing symptoms. Currently, three types of drugs are approved for treating the moderate or severe stages of the disease: cholinesterase inhibitors, partial N-methyl D-aspartate (NMDA) antagonists, and amyloid-directed antibodies. Cholinesterase inhibitors increase acetylcholine levels, a chemical crucial for cognitive functions such as memory and learning. NMDA antagonists (memantine) blocks NMDA receptors whose overactivation is implicated in Alzheimer's disease and related to synaptic dysfunction. Antiamyloid monoclonal antibodies bind to and promote the clearance of amyloid-beta peptides, thereby reducing amyloid plaques in the brain, which are associated with Alzheimer's disease.

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

CASE Anomalous findings on fetal anatomic survey

A 27-year-old previously healthy primigravid woman is at 18 weeks’ gestation. She is a first-grade schoolteacher. On her fetal anatomic survey, the estimated fetal weight was in the eighth percentile. Echogenic bowel and a small amount of ascitic fluid were noted in the fetal abdomen. The lateral and third ventricles were mildly dilated, the head circumference was 2 standard deviations below normal, and the placenta was slightly thickened and edematous.

What is the most likely diagnosis?

What diagnostic tests are indicated?

What management options are available for this patient?
 

Cytomegalovirus (CMV) is the most common of the perinatally transmitted infections, affecting 1% to 4% of all pregnancies. Although the virus typically causes either asymptomatic infection or only mild illness in immunocompetent individuals, it can cause life-threatening disease in immunocompromised persons and in the developing fetus. In this article, we review the virology and epidemiology of CMV infection and then focus on the key methods to diagnose infection in the mother and fetus. We conclude by considering measures that may be of at least modest value in treating CMV in pregnancy.

Virology of CMV infection

Cytomegalovirus is a double-stranded DNA virus in the Herpesviridae family. This ubiquitous virus is present in virtually all secretions and excretions of an infected host, including blood, urine, saliva, breast milk, genital secretions, and tissues and organs used for donation. Infection is transmitted through direct contact with any of the substances listed; contact with infected urine or saliva is the most common mode of transmission. Disease occurrence does not show seasonal variation.

After exposure, an incubation period of 28 to 60 days ensues, followed by development of viremia and clinical symptoms. In the majority of exposed individuals, CMV establishes a lifelong latent infection, and recurrent episodes of illness can occur as a result of reactivation of latent virus (also known as secondary infection) or, more rarely, infection with a new viral strain. In fact, most CMV illness episodes in pregnancy represent a reactivation of a previous infection rather than a new infection.

Following initial infection, both IgM (immunoglobulin M) and IgG (immunoglobulin G) antibodies develop rapidly and can be detected in blood within 1 to 2 weeks. IgM levels typically wane within 30 to 60 days, although persistence for several months is not unusual, and levels also can increase with viral reactivation (secondary infection). IgG antibodies typically persist for many years after a primary infection.

Intrauterine CMV infection occurs through hematogenous transplacental passage during maternal viremia. The risk of transmission and severity of fetal effects depend on whether or not the infection is primary or secondary in nature as well as the gestational age at fetal exposure.^1,2

Additionally, postnatal vertical transmission can occur through exposure to viral particles in genital secretions as well as breast milk. CMV acquired in the postnatal period rarely produces severe sequelae in a healthy term neonate, but it has been associated with an increased rate of complications in very low birth weight and premature newborns.³

Continue to: Who is at risk...

Who is at risk

Congenital CMV, which occurs in 2.1 to 7.7 per 10,000 live births in the United States, is both the most common congenital infection and the leading cause of nonhereditary congenital hearing loss in children.^4,5 The main reservoir of CMV in the United States is young children in day care settings, with approximately 50% of this population showing evidence of viral shedding in saliva.¹ Adult populations in North America have a high prevalence of CMV IgG antibodies indicative of prior infection, with rates reaching 50% to 80%. Among seronegative individuals aged 12 to 49, the rate of seroconversion is approximately 1 in 60 annually.⁶ Significant racial disparities have been noted in rates of seroprevalence and seroconversion, with higher rates of infection in non-Hispanic Black and Mexican American individuals.⁶ Overall, the rate of new CMV infection among pregnant women in the United States is 0.7% to 4%.⁷

Clinical manifestations

Manifestations of infection differ depending on whether or not infection is primary or recurrent (secondary) and whether or not the host is immunocompetent or has a compromised immune system. Unique manifestations develop in the fetus.

CMV infection in children and adults. Among individuals with a normal immune response, the typical course of CMV is either no symptoms or a mononucleosis-like illness. In symptomatic patients, the most common symptoms include malaise, fever, and night sweats, and the most common associated laboratory abnormalities are elevation in liver function tests and a decreased white blood cell count, with a predominance of lymphocytes.⁸

Immunocompromised individuals are at risk for significant morbidity and mortality resulting from CMV. Illness may be the result of reactivation of latent infection due to decreased immune function or may be acquired as a result of treatment such as transplantation of CMV-positive organs or tissues, including bone marrow. Virtually any organ system can be affected, with potential for permanent organ damage and death. Severe systemic infection also can occur.

CMV infection in the fetus and neonate. As noted previously, fetal infection develops as a result of transplacental passage coincident with maternal infection. The risk of CMV transmission to the fetus and the severity of fetal injury vary based on gestational age at fetal infection and whether or not maternal infection is primary or secondary.

In most studies, primary maternal infections are associated with higher rates of fetal infection and more severe fetal and neonatal disease manifestations.^2,7,9,10 Primary infections carry an overall 30% to 40% risk of transmission to the fetus.^7,11 The risk of fetal transmission is much lower with a recurrent infection and is usually less than 2%.¹¹ Due to their greater overall incidence, secondary infections account for the majority of cases of fetal and neonatal CMV disease.⁷ Importantly, although secondary infections generally have been regarded as having a lower risk and lower severity of fetal and neonatal disease, several recent studies have demonstrated rates of complications similar to, and even exceeding, those of primary infections.^12-15 The TABLE provides a summary of the risks of fetal transmission and symptomatic fetal infection based on trimester of pregnancy.^2,11,16-18

In the fetus, CMV may affect multiple organ systems. Among sonographic and magnetic resonance imaging (MRI) findings, central nervous system (CNS) anomalies are the most common.^19,20 These can include microcephaly, ventriculomegaly, and periventricular calcifications. The gastrointestinal system also is frequently affected, and findings include echogenic bowel, hepatosplenomegaly, and liver calcifications. Lastly, isolated effusions, placentomegaly, fetal growth restriction, and even frank hydrops can develop. More favorable neurologic outcomes have been demonstrated in infants with no prenatal brain imaging abnormalities.^20,21 However, the role of MRI in prenatal prognosis currently is not well defined.

FIGURE 1 illustrates selected sonographic findings associated with fetal CMV infection.

Continue to: Diagnosing CMV infection...

Diagnosing CMV infection

Maternal infection

If maternal CMV infection is suspected based on a symptomatic illness or an abnormal fetal ultrasound exam, the first diagnostic test should be an assessment of IgM and IgG serology. If the former test results are positive and the latter negative, the diagnosis of acute CMV infection is confirmed. A positive serum CMV DNA polymerase chain reaction (PCR) test adds additional assurance that the diagnosis is correct. Primary infection, as noted above, poses the greatest risk of serious injury to the fetus.¹

A frequent diagnostic dilemma arises when both the IgM and IgG antibody are positive. Remember that CMV IgM antibody can remain positive for 9 to 12 months after a primary infection and can reappear in the maternal serum in the face of a recurrent or reactivated infection. When confronted by both a positive IgM and positive IgG result, the clinician should then order IgG avidity testing. If the avidity is low to moderate, which reflects poor binding of antibody to the virus, the patient likely has an acute infection. If the avidity is high, which reflects enhanced binding of antibody to virus, the patient probably has a recurrent or reactivated infection; this scenario poses less danger to the developing fetus. The presence of CMV DNA in serum is also more consistent with acute infection, although viremia still can occur with recurrent infection. FIGURE 2 presents a suggested algorithm for the diagnosis of CMV in the pregnant patient.¹

If a diagnosis of maternal CMV infection is confirmed, liver function tests should be obtained to determine if CMV hepatitis is present. If the liver function tests are abnormal, a coagulation profile also should be performed to identify the mother who might be at risk for peripartum hemorrhage.

Fetal infection

The single best test for confirmation of congenital CMV infection is detection of viral DNA and quantitation of viral load in the amniotic fluid by PCR. If the amniocentesis is performed prior to 20 weeks’ gestation and is negative, the test should be repeated in approximately 4 weeks.^1,19,24

Detection of viral DNA indicates congenital infection. The ultimate task, however, is to determine if the infection has injured the fetus. Detailed ultrasound examination is the key to identifying fetal injury. As noted previously, the principal ultrasonographic findings that suggest congenital CMV infection include^{2,19,20,21,25}:

• hydropic placenta
• fetal growth restriction
• microcephaly (head circumference more than 3 standard deviations below the mean)
• periventricular calcifications
• enlarged liver
• echogenic bowel
• ascites
• fetal hydrops.

Management: Evidence on CMV hyperimmune globulin, valacyclovir

If the immunocompetent mother has clinical manifestations of infection, she should receive symptomatic treatment. She should be encouraged to rest as much as possible, stay well hydrated, and use acetaminophen (1,000 mg every 6 to 8 hours) as needed for malaise and fever.

However, if the mother is immunocompromised and has signs of serious complications, such as chorioretinitis, hepatitis, or pneumonia, more aggressive therapy is indicated. Drugs used in this setting include foscarnet and ganciclovir and are best prescribed in consultation with a medical infectious disease specialist.

At this time, no consistently effective therapy for congenital infection is available. Therefore, if a patient has primary CMV infection in the first half of pregnancy, particularly in the first trimester, she should be counseled that the risk of fetal infection is approximately 40% and that approximately 5% to 15% of infants will be severely affected at birth. Given this information, some patients may opt for pregnancy termination.

In 2005, a report from Nigro and colleagues stimulated great hope that CMV-specific hyperimmune globulin (CytoGam) might be of value for both treatment and prophylaxis for congenital infection.²⁶ These authors studied 157 women with confirmed primary CMV infection. One-hundred forty-eight women were asymptomatic and were identified by routine serologic screening, 8 had symptomatic infection, and 1 was identified because of abnormal fetal ultrasound findings. Forty-five women had CMV detected in amniotic fluid by PCR or culture more than 6 weeks before study enrollment. Thirty-one of these women were treated with intravenous hyperimmune globulin (200 U or 200 mg/kg maternal body weight); 14 declined treatment. Seven of the latter women had infants who were acutely symptomatic at the time of delivery; only 1 of the 31 treated women had an affected neonate (adjusted odds ratio [OR], 0.02; P<.001). In this same study, 84 women did not have a diagnostic amniocentesis because their infection occurred within 6 weeks of enrollment, their gestational age was less than 20 weeks, or they declined the procedure. Thirty-seven of these women received hyperimmune globulin (100 U or 100 mg/kg) every month until delivery, and 47 declined treatment. Six of the treated women delivered infected infants compared with 19 of the untreated women (adjusted OR, 0.32; P<.04).

Although these results were quite encouraging, several problems existed with the study’s design, as noted in an editorial that accompanied the study’s publication.²⁷ First, the study was not randomized or placebo controlled. Second, patients were not stratified based on the severity of fetal ultrasound abnormalities. Third, the dosing of hyperimmune globulin varied; 9 of the 31 patients in the treatment group received additional infusions of drug into either the amniotic fluid or fetal umbilical vein. Moreover, patients in the prophylaxis group actually received a higher cumulative dose of hyperimmune globulin than patients in the treatment group.

Two subsequent investigations that were better designed were unable to verify the effectiveness of hyperimmune globulin. In 2014, Revello and colleagues reported the results of a prospective, randomized, placebo-controlled, double-blinded study of 124 women at 5 to 26 weeks’ gestation with confirmed primary CMV infection.²⁸ The rate of congenital infection was 30% in the group treated with hyperimmune globulin and 44% in the placebo group (P=.13). There also was no significant difference in the concentration of serum CMV DNA in treated versus untreated mothers. Moreover, the number of adverse obstetric events (preterm delivery, fetal growth restriction, intrahepatic cholestasis of pregnancy, and postpartum preeclampsia) in the treatment group was higher than in the placebo group, 13% versus 2%.

In 2021, Hughes and colleagues published the results of a multicenter, double-blind trial in 399 women who had a diagnosis of primary CMV infection before 23 weeks’ gestation.²⁹ The primary outcome was defined as a composite of congenital CMV infection or fetal/neonatal death. An adverse primary outcome occurred in 22.7% of the patients who received hyperimmune globulin and 19.4% of those who received placebo (relative risk, 1.17; 95% confidence interval [CI], 0.80–1.72; P=.42).
 

Continue to: Jacquemard and colleagues...

Jacquemard and colleagues then proposed a different approach.³⁰ In a small pilot study of 20 patients, these authors used high doses of oral valacylovir (2 g 4 times daily) and documented therapeutic drug concentrations and a decline in CMV viral load in fetal serum. Patients were not stratified by severity of fetal injury at onset of treatment, so the authors were unable to define which fetuses were most likely to benefit from treatment.

In a follow-up investigation, Leruez-Ville and colleagues reported another small series in which high-dose oral valacyclovir (8 g daily) was used for treatment.³¹ They excluded fetuses with severe brain anomalies and fetuses with no sonographic evidence of injury. The median gestational age at diagnosis was 26 weeks. Thirty-four of 43 treated fetuses were free of injury at birth. In addition, the viral load in the neonate’s serum decreased significantly after treatment, and the platelet count increased. The authors then compared these outcomes to a historical cohort and confirmed that treatment increased the proportion of asymptomatic neonates from 43% without treatment to 82% with treatment (P<.05 with no overlapping confidence intervals).

We conclude from these investigations that hyperimmune globulin is unlikely to be of value in treating congenital CMV infection, especially if the fetus already has sonographic findings of severe injury. High-dose oral valacyclovir also is unlikely to be of value in severely affected fetuses, particularly those with evidence of CNS injury. However, antiviral therapy may be of modest value in situations when the fetus is less severely injured.

Preventive measures

Since no definitive treatment is available for congenital CMV infection, our efforts as clinicians should focus on measures that may prevent transmission of infection to the pregnant patient. These measures include:

• Encouraging patients to use careful handwashing techniques when handling infant diapers and toys.
• Encouraging patients to adopt safe sexual practices if not already engaged in a mutually faithful, monogamous relationship.
• Using CMV-negative blood when transfusing a pregnant woman or a fetus.

At the present time, unfortunately, a readily available and highly effective therapy for prevention of CMV infection is not available.

CASE Congenital infection diagnosed

The ultrasound findings are most consistent with congenital CMV infection, especially given the patient’s work as an elementary schoolteacher. The diagnosis of maternal infection is best established by conventional serology (positive IgM, negative IgM) and detection of viral DNA in maternal blood by PCR testing. The diagnosis of congenital infection is best confirmed by documentation of viral DNA in the amniotic fluid by PCR testing. Given that this fetus already has evidence of moderate to severe injury, no treatment is likely to be effective in reversing the abnormal ultrasound findings. Pregnancy termination may be an option, depending upon the patient’s desires and the legal restrictions prevalent in the patient’s geographic area. ●

CASE Anomalous findings on fetal anatomic survey

A 27-year-old previously healthy primigravid woman is at 18 weeks’ gestation. She is a first-grade schoolteacher. On her fetal anatomic survey, the estimated fetal weight was in the eighth percentile. Echogenic bowel and a small amount of ascitic fluid were noted in the fetal abdomen. The lateral and third ventricles were mildly dilated, the head circumference was 2 standard deviations below normal, and the placenta was slightly thickened and edematous.

What is the most likely diagnosis?

What diagnostic tests are indicated?

What management options are available for this patient?
 

Cytomegalovirus (CMV) is the most common of the perinatally transmitted infections, affecting 1% to 4% of all pregnancies. Although the virus typically causes either asymptomatic infection or only mild illness in immunocompetent individuals, it can cause life-threatening disease in immunocompromised persons and in the developing fetus. In this article, we review the virology and epidemiology of CMV infection and then focus on the key methods to diagnose infection in the mother and fetus. We conclude by considering measures that may be of at least modest value in treating CMV in pregnancy.

Virology of CMV infection

Cytomegalovirus is a double-stranded DNA virus in the Herpesviridae family. This ubiquitous virus is present in virtually all secretions and excretions of an infected host, including blood, urine, saliva, breast milk, genital secretions, and tissues and organs used for donation. Infection is transmitted through direct contact with any of the substances listed; contact with infected urine or saliva is the most common mode of transmission. Disease occurrence does not show seasonal variation.

After exposure, an incubation period of 28 to 60 days ensues, followed by development of viremia and clinical symptoms. In the majority of exposed individuals, CMV establishes a lifelong latent infection, and recurrent episodes of illness can occur as a result of reactivation of latent virus (also known as secondary infection) or, more rarely, infection with a new viral strain. In fact, most CMV illness episodes in pregnancy represent a reactivation of a previous infection rather than a new infection.

Following initial infection, both IgM (immunoglobulin M) and IgG (immunoglobulin G) antibodies develop rapidly and can be detected in blood within 1 to 2 weeks. IgM levels typically wane within 30 to 60 days, although persistence for several months is not unusual, and levels also can increase with viral reactivation (secondary infection). IgG antibodies typically persist for many years after a primary infection.

Intrauterine CMV infection occurs through hematogenous transplacental passage during maternal viremia. The risk of transmission and severity of fetal effects depend on whether or not the infection is primary or secondary in nature as well as the gestational age at fetal exposure.^1,2

Additionally, postnatal vertical transmission can occur through exposure to viral particles in genital secretions as well as breast milk. CMV acquired in the postnatal period rarely produces severe sequelae in a healthy term neonate, but it has been associated with an increased rate of complications in very low birth weight and premature newborns.³

Continue to: Who is at risk...

Who is at risk

Congenital CMV, which occurs in 2.1 to 7.7 per 10,000 live births in the United States, is both the most common congenital infection and the leading cause of nonhereditary congenital hearing loss in children.^4,5 The main reservoir of CMV in the United States is young children in day care settings, with approximately 50% of this population showing evidence of viral shedding in saliva.¹ Adult populations in North America have a high prevalence of CMV IgG antibodies indicative of prior infection, with rates reaching 50% to 80%. Among seronegative individuals aged 12 to 49, the rate of seroconversion is approximately 1 in 60 annually.⁶ Significant racial disparities have been noted in rates of seroprevalence and seroconversion, with higher rates of infection in non-Hispanic Black and Mexican American individuals.⁶ Overall, the rate of new CMV infection among pregnant women in the United States is 0.7% to 4%.⁷

Clinical manifestations

Manifestations of infection differ depending on whether or not infection is primary or recurrent (secondary) and whether or not the host is immunocompetent or has a compromised immune system. Unique manifestations develop in the fetus.

CMV infection in children and adults. Among individuals with a normal immune response, the typical course of CMV is either no symptoms or a mononucleosis-like illness. In symptomatic patients, the most common symptoms include malaise, fever, and night sweats, and the most common associated laboratory abnormalities are elevation in liver function tests and a decreased white blood cell count, with a predominance of lymphocytes.⁸

Immunocompromised individuals are at risk for significant morbidity and mortality resulting from CMV. Illness may be the result of reactivation of latent infection due to decreased immune function or may be acquired as a result of treatment such as transplantation of CMV-positive organs or tissues, including bone marrow. Virtually any organ system can be affected, with potential for permanent organ damage and death. Severe systemic infection also can occur.

CMV infection in the fetus and neonate. As noted previously, fetal infection develops as a result of transplacental passage coincident with maternal infection. The risk of CMV transmission to the fetus and the severity of fetal injury vary based on gestational age at fetal infection and whether or not maternal infection is primary or secondary.

In most studies, primary maternal infections are associated with higher rates of fetal infection and more severe fetal and neonatal disease manifestations.^2,7,9,10 Primary infections carry an overall 30% to 40% risk of transmission to the fetus.^7,11 The risk of fetal transmission is much lower with a recurrent infection and is usually less than 2%.¹¹ Due to their greater overall incidence, secondary infections account for the majority of cases of fetal and neonatal CMV disease.⁷ Importantly, although secondary infections generally have been regarded as having a lower risk and lower severity of fetal and neonatal disease, several recent studies have demonstrated rates of complications similar to, and even exceeding, those of primary infections.^12-15 The TABLE provides a summary of the risks of fetal transmission and symptomatic fetal infection based on trimester of pregnancy.^2,11,16-18

In the fetus, CMV may affect multiple organ systems. Among sonographic and magnetic resonance imaging (MRI) findings, central nervous system (CNS) anomalies are the most common.^19,20 These can include microcephaly, ventriculomegaly, and periventricular calcifications. The gastrointestinal system also is frequently affected, and findings include echogenic bowel, hepatosplenomegaly, and liver calcifications. Lastly, isolated effusions, placentomegaly, fetal growth restriction, and even frank hydrops can develop. More favorable neurologic outcomes have been demonstrated in infants with no prenatal brain imaging abnormalities.^20,21 However, the role of MRI in prenatal prognosis currently is not well defined.

FIGURE 1 illustrates selected sonographic findings associated with fetal CMV infection.

Continue to: Diagnosing CMV infection...

Diagnosing CMV infection

Maternal infection

If maternal CMV infection is suspected based on a symptomatic illness or an abnormal fetal ultrasound exam, the first diagnostic test should be an assessment of IgM and IgG serology. If the former test results are positive and the latter negative, the diagnosis of acute CMV infection is confirmed. A positive serum CMV DNA polymerase chain reaction (PCR) test adds additional assurance that the diagnosis is correct. Primary infection, as noted above, poses the greatest risk of serious injury to the fetus.¹

A frequent diagnostic dilemma arises when both the IgM and IgG antibody are positive. Remember that CMV IgM antibody can remain positive for 9 to 12 months after a primary infection and can reappear in the maternal serum in the face of a recurrent or reactivated infection. When confronted by both a positive IgM and positive IgG result, the clinician should then order IgG avidity testing. If the avidity is low to moderate, which reflects poor binding of antibody to the virus, the patient likely has an acute infection. If the avidity is high, which reflects enhanced binding of antibody to virus, the patient probably has a recurrent or reactivated infection; this scenario poses less danger to the developing fetus. The presence of CMV DNA in serum is also more consistent with acute infection, although viremia still can occur with recurrent infection. FIGURE 2 presents a suggested algorithm for the diagnosis of CMV in the pregnant patient.¹

If a diagnosis of maternal CMV infection is confirmed, liver function tests should be obtained to determine if CMV hepatitis is present. If the liver function tests are abnormal, a coagulation profile also should be performed to identify the mother who might be at risk for peripartum hemorrhage.

Fetal infection

The single best test for confirmation of congenital CMV infection is detection of viral DNA and quantitation of viral load in the amniotic fluid by PCR. If the amniocentesis is performed prior to 20 weeks’ gestation and is negative, the test should be repeated in approximately 4 weeks.^1,19,24

Detection of viral DNA indicates congenital infection. The ultimate task, however, is to determine if the infection has injured the fetus. Detailed ultrasound examination is the key to identifying fetal injury. As noted previously, the principal ultrasonographic findings that suggest congenital CMV infection include^{2,19,20,21,25}:

• hydropic placenta
• fetal growth restriction
• microcephaly (head circumference more than 3 standard deviations below the mean)
• periventricular calcifications
• enlarged liver
• echogenic bowel
• ascites
• fetal hydrops.

Management: Evidence on CMV hyperimmune globulin, valacyclovir

If the immunocompetent mother has clinical manifestations of infection, she should receive symptomatic treatment. She should be encouraged to rest as much as possible, stay well hydrated, and use acetaminophen (1,000 mg every 6 to 8 hours) as needed for malaise and fever.

However, if the mother is immunocompromised and has signs of serious complications, such as chorioretinitis, hepatitis, or pneumonia, more aggressive therapy is indicated. Drugs used in this setting include foscarnet and ganciclovir and are best prescribed in consultation with a medical infectious disease specialist.

At this time, no consistently effective therapy for congenital infection is available. Therefore, if a patient has primary CMV infection in the first half of pregnancy, particularly in the first trimester, she should be counseled that the risk of fetal infection is approximately 40% and that approximately 5% to 15% of infants will be severely affected at birth. Given this information, some patients may opt for pregnancy termination.

In 2005, a report from Nigro and colleagues stimulated great hope that CMV-specific hyperimmune globulin (CytoGam) might be of value for both treatment and prophylaxis for congenital infection.²⁶ These authors studied 157 women with confirmed primary CMV infection. One-hundred forty-eight women were asymptomatic and were identified by routine serologic screening, 8 had symptomatic infection, and 1 was identified because of abnormal fetal ultrasound findings. Forty-five women had CMV detected in amniotic fluid by PCR or culture more than 6 weeks before study enrollment. Thirty-one of these women were treated with intravenous hyperimmune globulin (200 U or 200 mg/kg maternal body weight); 14 declined treatment. Seven of the latter women had infants who were acutely symptomatic at the time of delivery; only 1 of the 31 treated women had an affected neonate (adjusted odds ratio [OR], 0.02; P<.001). In this same study, 84 women did not have a diagnostic amniocentesis because their infection occurred within 6 weeks of enrollment, their gestational age was less than 20 weeks, or they declined the procedure. Thirty-seven of these women received hyperimmune globulin (100 U or 100 mg/kg) every month until delivery, and 47 declined treatment. Six of the treated women delivered infected infants compared with 19 of the untreated women (adjusted OR, 0.32; P<.04).

Although these results were quite encouraging, several problems existed with the study’s design, as noted in an editorial that accompanied the study’s publication.²⁷ First, the study was not randomized or placebo controlled. Second, patients were not stratified based on the severity of fetal ultrasound abnormalities. Third, the dosing of hyperimmune globulin varied; 9 of the 31 patients in the treatment group received additional infusions of drug into either the amniotic fluid or fetal umbilical vein. Moreover, patients in the prophylaxis group actually received a higher cumulative dose of hyperimmune globulin than patients in the treatment group.

Two subsequent investigations that were better designed were unable to verify the effectiveness of hyperimmune globulin. In 2014, Revello and colleagues reported the results of a prospective, randomized, placebo-controlled, double-blinded study of 124 women at 5 to 26 weeks’ gestation with confirmed primary CMV infection.²⁸ The rate of congenital infection was 30% in the group treated with hyperimmune globulin and 44% in the placebo group (P=.13). There also was no significant difference in the concentration of serum CMV DNA in treated versus untreated mothers. Moreover, the number of adverse obstetric events (preterm delivery, fetal growth restriction, intrahepatic cholestasis of pregnancy, and postpartum preeclampsia) in the treatment group was higher than in the placebo group, 13% versus 2%.

In 2021, Hughes and colleagues published the results of a multicenter, double-blind trial in 399 women who had a diagnosis of primary CMV infection before 23 weeks’ gestation.²⁹ The primary outcome was defined as a composite of congenital CMV infection or fetal/neonatal death. An adverse primary outcome occurred in 22.7% of the patients who received hyperimmune globulin and 19.4% of those who received placebo (relative risk, 1.17; 95% confidence interval [CI], 0.80–1.72; P=.42).
 

Continue to: Jacquemard and colleagues...

Jacquemard and colleagues then proposed a different approach.³⁰ In a small pilot study of 20 patients, these authors used high doses of oral valacylovir (2 g 4 times daily) and documented therapeutic drug concentrations and a decline in CMV viral load in fetal serum. Patients were not stratified by severity of fetal injury at onset of treatment, so the authors were unable to define which fetuses were most likely to benefit from treatment.

In a follow-up investigation, Leruez-Ville and colleagues reported another small series in which high-dose oral valacyclovir (8 g daily) was used for treatment.³¹ They excluded fetuses with severe brain anomalies and fetuses with no sonographic evidence of injury. The median gestational age at diagnosis was 26 weeks. Thirty-four of 43 treated fetuses were free of injury at birth. In addition, the viral load in the neonate’s serum decreased significantly after treatment, and the platelet count increased. The authors then compared these outcomes to a historical cohort and confirmed that treatment increased the proportion of asymptomatic neonates from 43% without treatment to 82% with treatment (P<.05 with no overlapping confidence intervals).

We conclude from these investigations that hyperimmune globulin is unlikely to be of value in treating congenital CMV infection, especially if the fetus already has sonographic findings of severe injury. High-dose oral valacyclovir also is unlikely to be of value in severely affected fetuses, particularly those with evidence of CNS injury. However, antiviral therapy may be of modest value in situations when the fetus is less severely injured.

Preventive measures

Since no definitive treatment is available for congenital CMV infection, our efforts as clinicians should focus on measures that may prevent transmission of infection to the pregnant patient. These measures include:

• Encouraging patients to use careful handwashing techniques when handling infant diapers and toys.
• Encouraging patients to adopt safe sexual practices if not already engaged in a mutually faithful, monogamous relationship.
• Using CMV-negative blood when transfusing a pregnant woman or a fetus.

At the present time, unfortunately, a readily available and highly effective therapy for prevention of CMV infection is not available.

CASE Congenital infection diagnosed

The ultrasound findings are most consistent with congenital CMV infection, especially given the patient’s work as an elementary schoolteacher. The diagnosis of maternal infection is best established by conventional serology (positive IgM, negative IgM) and detection of viral DNA in maternal blood by PCR testing. The diagnosis of congenital infection is best confirmed by documentation of viral DNA in the amniotic fluid by PCR testing. Given that this fetus already has evidence of moderate to severe injury, no treatment is likely to be effective in reversing the abnormal ultrasound findings. Pregnancy termination may be an option, depending upon the patient’s desires and the legal restrictions prevalent in the patient’s geographic area. ●

CASE Anomalous findings on fetal anatomic survey

A 27-year-old previously healthy primigravid woman is at 18 weeks’ gestation. She is a first-grade schoolteacher. On her fetal anatomic survey, the estimated fetal weight was in the eighth percentile. Echogenic bowel and a small amount of ascitic fluid were noted in the fetal abdomen. The lateral and third ventricles were mildly dilated, the head circumference was 2 standard deviations below normal, and the placenta was slightly thickened and edematous.

What is the most likely diagnosis?

What diagnostic tests are indicated?

What management options are available for this patient?
 

Cytomegalovirus (CMV) is the most common of the perinatally transmitted infections, affecting 1% to 4% of all pregnancies. Although the virus typically causes either asymptomatic infection or only mild illness in immunocompetent individuals, it can cause life-threatening disease in immunocompromised persons and in the developing fetus. In this article, we review the virology and epidemiology of CMV infection and then focus on the key methods to diagnose infection in the mother and fetus. We conclude by considering measures that may be of at least modest value in treating CMV in pregnancy.

Virology of CMV infection

Cytomegalovirus is a double-stranded DNA virus in the Herpesviridae family. This ubiquitous virus is present in virtually all secretions and excretions of an infected host, including blood, urine, saliva, breast milk, genital secretions, and tissues and organs used for donation. Infection is transmitted through direct contact with any of the substances listed; contact with infected urine or saliva is the most common mode of transmission. Disease occurrence does not show seasonal variation.

After exposure, an incubation period of 28 to 60 days ensues, followed by development of viremia and clinical symptoms. In the majority of exposed individuals, CMV establishes a lifelong latent infection, and recurrent episodes of illness can occur as a result of reactivation of latent virus (also known as secondary infection) or, more rarely, infection with a new viral strain. In fact, most CMV illness episodes in pregnancy represent a reactivation of a previous infection rather than a new infection.

Following initial infection, both IgM (immunoglobulin M) and IgG (immunoglobulin G) antibodies develop rapidly and can be detected in blood within 1 to 2 weeks. IgM levels typically wane within 30 to 60 days, although persistence for several months is not unusual, and levels also can increase with viral reactivation (secondary infection). IgG antibodies typically persist for many years after a primary infection.

Intrauterine CMV infection occurs through hematogenous transplacental passage during maternal viremia. The risk of transmission and severity of fetal effects depend on whether or not the infection is primary or secondary in nature as well as the gestational age at fetal exposure.^1,2

Additionally, postnatal vertical transmission can occur through exposure to viral particles in genital secretions as well as breast milk. CMV acquired in the postnatal period rarely produces severe sequelae in a healthy term neonate, but it has been associated with an increased rate of complications in very low birth weight and premature newborns.³

Continue to: Who is at risk...

Who is at risk

Congenital CMV, which occurs in 2.1 to 7.7 per 10,000 live births in the United States, is both the most common congenital infection and the leading cause of nonhereditary congenital hearing loss in children.^4,5 The main reservoir of CMV in the United States is young children in day care settings, with approximately 50% of this population showing evidence of viral shedding in saliva.¹ Adult populations in North America have a high prevalence of CMV IgG antibodies indicative of prior infection, with rates reaching 50% to 80%. Among seronegative individuals aged 12 to 49, the rate of seroconversion is approximately 1 in 60 annually.⁶ Significant racial disparities have been noted in rates of seroprevalence and seroconversion, with higher rates of infection in non-Hispanic Black and Mexican American individuals.⁶ Overall, the rate of new CMV infection among pregnant women in the United States is 0.7% to 4%.⁷

Clinical manifestations

Manifestations of infection differ depending on whether or not infection is primary or recurrent (secondary) and whether or not the host is immunocompetent or has a compromised immune system. Unique manifestations develop in the fetus.

CMV infection in children and adults. Among individuals with a normal immune response, the typical course of CMV is either no symptoms or a mononucleosis-like illness. In symptomatic patients, the most common symptoms include malaise, fever, and night sweats, and the most common associated laboratory abnormalities are elevation in liver function tests and a decreased white blood cell count, with a predominance of lymphocytes.⁸

Immunocompromised individuals are at risk for significant morbidity and mortality resulting from CMV. Illness may be the result of reactivation of latent infection due to decreased immune function or may be acquired as a result of treatment such as transplantation of CMV-positive organs or tissues, including bone marrow. Virtually any organ system can be affected, with potential for permanent organ damage and death. Severe systemic infection also can occur.

CMV infection in the fetus and neonate. As noted previously, fetal infection develops as a result of transplacental passage coincident with maternal infection. The risk of CMV transmission to the fetus and the severity of fetal injury vary based on gestational age at fetal infection and whether or not maternal infection is primary or secondary.

In most studies, primary maternal infections are associated with higher rates of fetal infection and more severe fetal and neonatal disease manifestations.^2,7,9,10 Primary infections carry an overall 30% to 40% risk of transmission to the fetus.^7,11 The risk of fetal transmission is much lower with a recurrent infection and is usually less than 2%.¹¹ Due to their greater overall incidence, secondary infections account for the majority of cases of fetal and neonatal CMV disease.⁷ Importantly, although secondary infections generally have been regarded as having a lower risk and lower severity of fetal and neonatal disease, several recent studies have demonstrated rates of complications similar to, and even exceeding, those of primary infections.^12-15 The TABLE provides a summary of the risks of fetal transmission and symptomatic fetal infection based on trimester of pregnancy.^2,11,16-18

In the fetus, CMV may affect multiple organ systems. Among sonographic and magnetic resonance imaging (MRI) findings, central nervous system (CNS) anomalies are the most common.^19,20 These can include microcephaly, ventriculomegaly, and periventricular calcifications. The gastrointestinal system also is frequently affected, and findings include echogenic bowel, hepatosplenomegaly, and liver calcifications. Lastly, isolated effusions, placentomegaly, fetal growth restriction, and even frank hydrops can develop. More favorable neurologic outcomes have been demonstrated in infants with no prenatal brain imaging abnormalities.^20,21 However, the role of MRI in prenatal prognosis currently is not well defined.

FIGURE 1 illustrates selected sonographic findings associated with fetal CMV infection.

Continue to: Diagnosing CMV infection...

Diagnosing CMV infection

Maternal infection

If maternal CMV infection is suspected based on a symptomatic illness or an abnormal fetal ultrasound exam, the first diagnostic test should be an assessment of IgM and IgG serology. If the former test results are positive and the latter negative, the diagnosis of acute CMV infection is confirmed. A positive serum CMV DNA polymerase chain reaction (PCR) test adds additional assurance that the diagnosis is correct. Primary infection, as noted above, poses the greatest risk of serious injury to the fetus.¹

A frequent diagnostic dilemma arises when both the IgM and IgG antibody are positive. Remember that CMV IgM antibody can remain positive for 9 to 12 months after a primary infection and can reappear in the maternal serum in the face of a recurrent or reactivated infection. When confronted by both a positive IgM and positive IgG result, the clinician should then order IgG avidity testing. If the avidity is low to moderate, which reflects poor binding of antibody to the virus, the patient likely has an acute infection. If the avidity is high, which reflects enhanced binding of antibody to virus, the patient probably has a recurrent or reactivated infection; this scenario poses less danger to the developing fetus. The presence of CMV DNA in serum is also more consistent with acute infection, although viremia still can occur with recurrent infection. FIGURE 2 presents a suggested algorithm for the diagnosis of CMV in the pregnant patient.¹

If a diagnosis of maternal CMV infection is confirmed, liver function tests should be obtained to determine if CMV hepatitis is present. If the liver function tests are abnormal, a coagulation profile also should be performed to identify the mother who might be at risk for peripartum hemorrhage.

Fetal infection

The single best test for confirmation of congenital CMV infection is detection of viral DNA and quantitation of viral load in the amniotic fluid by PCR. If the amniocentesis is performed prior to 20 weeks’ gestation and is negative, the test should be repeated in approximately 4 weeks.^1,19,24

Detection of viral DNA indicates congenital infection. The ultimate task, however, is to determine if the infection has injured the fetus. Detailed ultrasound examination is the key to identifying fetal injury. As noted previously, the principal ultrasonographic findings that suggest congenital CMV infection include^{2,19,20,21,25}:

• hydropic placenta
• fetal growth restriction
• microcephaly (head circumference more than 3 standard deviations below the mean)
• periventricular calcifications
• enlarged liver
• echogenic bowel
• ascites
• fetal hydrops.

Management: Evidence on CMV hyperimmune globulin, valacyclovir

If the immunocompetent mother has clinical manifestations of infection, she should receive symptomatic treatment. She should be encouraged to rest as much as possible, stay well hydrated, and use acetaminophen (1,000 mg every 6 to 8 hours) as needed for malaise and fever.

However, if the mother is immunocompromised and has signs of serious complications, such as chorioretinitis, hepatitis, or pneumonia, more aggressive therapy is indicated. Drugs used in this setting include foscarnet and ganciclovir and are best prescribed in consultation with a medical infectious disease specialist.

At this time, no consistently effective therapy for congenital infection is available. Therefore, if a patient has primary CMV infection in the first half of pregnancy, particularly in the first trimester, she should be counseled that the risk of fetal infection is approximately 40% and that approximately 5% to 15% of infants will be severely affected at birth. Given this information, some patients may opt for pregnancy termination.

In 2005, a report from Nigro and colleagues stimulated great hope that CMV-specific hyperimmune globulin (CytoGam) might be of value for both treatment and prophylaxis for congenital infection.²⁶ These authors studied 157 women with confirmed primary CMV infection. One-hundred forty-eight women were asymptomatic and were identified by routine serologic screening, 8 had symptomatic infection, and 1 was identified because of abnormal fetal ultrasound findings. Forty-five women had CMV detected in amniotic fluid by PCR or culture more than 6 weeks before study enrollment. Thirty-one of these women were treated with intravenous hyperimmune globulin (200 U or 200 mg/kg maternal body weight); 14 declined treatment. Seven of the latter women had infants who were acutely symptomatic at the time of delivery; only 1 of the 31 treated women had an affected neonate (adjusted odds ratio [OR], 0.02; P<.001). In this same study, 84 women did not have a diagnostic amniocentesis because their infection occurred within 6 weeks of enrollment, their gestational age was less than 20 weeks, or they declined the procedure. Thirty-seven of these women received hyperimmune globulin (100 U or 100 mg/kg) every month until delivery, and 47 declined treatment. Six of the treated women delivered infected infants compared with 19 of the untreated women (adjusted OR, 0.32; P<.04).

Although these results were quite encouraging, several problems existed with the study’s design, as noted in an editorial that accompanied the study’s publication.²⁷ First, the study was not randomized or placebo controlled. Second, patients were not stratified based on the severity of fetal ultrasound abnormalities. Third, the dosing of hyperimmune globulin varied; 9 of the 31 patients in the treatment group received additional infusions of drug into either the amniotic fluid or fetal umbilical vein. Moreover, patients in the prophylaxis group actually received a higher cumulative dose of hyperimmune globulin than patients in the treatment group.

Two subsequent investigations that were better designed were unable to verify the effectiveness of hyperimmune globulin. In 2014, Revello and colleagues reported the results of a prospective, randomized, placebo-controlled, double-blinded study of 124 women at 5 to 26 weeks’ gestation with confirmed primary CMV infection.²⁸ The rate of congenital infection was 30% in the group treated with hyperimmune globulin and 44% in the placebo group (P=.13). There also was no significant difference in the concentration of serum CMV DNA in treated versus untreated mothers. Moreover, the number of adverse obstetric events (preterm delivery, fetal growth restriction, intrahepatic cholestasis of pregnancy, and postpartum preeclampsia) in the treatment group was higher than in the placebo group, 13% versus 2%.

In 2021, Hughes and colleagues published the results of a multicenter, double-blind trial in 399 women who had a diagnosis of primary CMV infection before 23 weeks’ gestation.²⁹ The primary outcome was defined as a composite of congenital CMV infection or fetal/neonatal death. An adverse primary outcome occurred in 22.7% of the patients who received hyperimmune globulin and 19.4% of those who received placebo (relative risk, 1.17; 95% confidence interval [CI], 0.80–1.72; P=.42).
 

Continue to: Jacquemard and colleagues...

Jacquemard and colleagues then proposed a different approach.³⁰ In a small pilot study of 20 patients, these authors used high doses of oral valacylovir (2 g 4 times daily) and documented therapeutic drug concentrations and a decline in CMV viral load in fetal serum. Patients were not stratified by severity of fetal injury at onset of treatment, so the authors were unable to define which fetuses were most likely to benefit from treatment.

In a follow-up investigation, Leruez-Ville and colleagues reported another small series in which high-dose oral valacyclovir (8 g daily) was used for treatment.³¹ They excluded fetuses with severe brain anomalies and fetuses with no sonographic evidence of injury. The median gestational age at diagnosis was 26 weeks. Thirty-four of 43 treated fetuses were free of injury at birth. In addition, the viral load in the neonate’s serum decreased significantly after treatment, and the platelet count increased. The authors then compared these outcomes to a historical cohort and confirmed that treatment increased the proportion of asymptomatic neonates from 43% without treatment to 82% with treatment (P<.05 with no overlapping confidence intervals).

We conclude from these investigations that hyperimmune globulin is unlikely to be of value in treating congenital CMV infection, especially if the fetus already has sonographic findings of severe injury. High-dose oral valacyclovir also is unlikely to be of value in severely affected fetuses, particularly those with evidence of CNS injury. However, antiviral therapy may be of modest value in situations when the fetus is less severely injured.

Preventive measures

Since no definitive treatment is available for congenital CMV infection, our efforts as clinicians should focus on measures that may prevent transmission of infection to the pregnant patient. These measures include:

• Encouraging patients to use careful handwashing techniques when handling infant diapers and toys.
• Encouraging patients to adopt safe sexual practices if not already engaged in a mutually faithful, monogamous relationship.
• Using CMV-negative blood when transfusing a pregnant woman or a fetus.

At the present time, unfortunately, a readily available and highly effective therapy for prevention of CMV infection is not available.

CASE Congenital infection diagnosed

The ultrasound findings are most consistent with congenital CMV infection, especially given the patient’s work as an elementary schoolteacher. The diagnosis of maternal infection is best established by conventional serology (positive IgM, negative IgM) and detection of viral DNA in maternal blood by PCR testing. The diagnosis of congenital infection is best confirmed by documentation of viral DNA in the amniotic fluid by PCR testing. Given that this fetus already has evidence of moderate to severe injury, no treatment is likely to be effective in reversing the abnormal ultrasound findings. Pregnancy termination may be an option, depending upon the patient’s desires and the legal restrictions prevalent in the patient’s geographic area. ●